INHOUD
Hoofdstuk 1: het immuunsysteem.................................................................................................................................1
Inleiding .......................................................................................................................................................................1
Belangrijke concepten van het humane immuunsysteem.......................................................................................1
Innate immuunsysteem ..........................................................................................................................................1
Adaptief immuunsysteem ......................................................................................................................................2
Primaire immuunrespons ...................................................................................................................................2
Secundaire immuunrespons ..............................................................................................................................2
Klonale selectie .......................................................................................................................................................2
The good, the bad and the ugly van het immuunsysteem.......................................................................................3
Dysfuncties ..............................................................................................................................................................3
Transplantatie .........................................................................................................................................................3
Kanker ......................................................................................................................................................................3
Tolerantie.................................................................................................................................................................3
Hoofdstuk 2: cellen, organen en omgeving van het immuunsysteem ........................................................................4
Cellen van het immuunsysteem.................................................................................................................................4
Common myeloïde progenitor...............................................................................................................................4
Erythrocyten (RBC)..............................................................................................................................................4
Monocyten ..........................................................................................................................................................4
Granulocyten.......................................................................................................................................................5
Megakaryocyten (BP) .........................................................................................................................................7
Common lymphoid progenitor...............................................................................................................................7
B-lymfocyten .......................................................................................................................................................7
T-lymfocyten .......................................................................................................................................................8
Natural killer cellen (NK-cellen) .........................................................................................................................8
Diagnostische technieken...........................................................................................................................................8
Perifeer bloeduitstrijkje..........................................................................................................................................8
Hematoxyline-eosine (H&E)...............................................................................................................................8
May-Grünwald Giemsa (MGG)...........................................................................................................................8
Flowcytometrie .......................................................................................................................................................9
Primaire lymfoïde organen.........................................................................................................................................9
Beenmerg ................................................................................................................................................................9
Thymus.................................................................................................................................................................. 11
Secundaire lymfoïde organen ................................................................................................................................. 13
Lymfeknopen........................................................................................................................................................ 13
Milt ........................................................................................................................................................................ 15
, Mucosa-associated lymphoid tissue (MALT)...................................................................................................... 15
Barrière organen ...................................................................................................................................................... 16
Hoofdstuk 3: herkenning en respons .......................................................................................................................... 17
Signaaltransductie.................................................................................................................................................... 17
Definities............................................................................................................................................................... 17
Ligand-receptor binding ...................................................................................................................................... 17
Antigen-receptor binding ................................................................................................................................ 18
Combinatie receptoreiwitten.......................................................................................................................... 18
Proces.................................................................................................................................................................... 18
Lipid rafts en R-multimerisatie........................................................................................................................ 18
Fosforylatie tyrosine-residu’s.......................................................................................................................... 19
Intracellulaire adapter-eiwitten...................................................................................................................... 19
Gemeenschappelijk downstream pathways .................................................................................................. 20
Receptoren in immuunsysteem .............................................................................................................................. 20
Immunoglobuline superfamilie (adaptive)......................................................................................................... 20
B-cel receptor (BCR) (antistoffen – immunoglobulines) ............................................................................... 21
Structuur ...................................................................................................................................................... 21
Antigen-herkenning..................................................................................................................................... 22
Isotypes ........................................................................................................................................................ 22
BCR-complex ................................................................................................................................................ 23
T-cel receptor (TCR) (adaptive)....................................................................................................................... 23
Structuur ...................................................................................................................................................... 23
TCR-complex ................................................................................................................................................ 24
Pattern recognition receptoren (PRR) (innate) .................................................................................................. 24
Complement receptoren (innate) en Fc-receptoren......................................................................................... 24
Cytokine receptoren (innate) .............................................................................................................................. 25
Werking ............................................................................................................................................................ 25
6 superfamilies ................................................................................................................................................. 26
Interleukine-1 (IL-1) familie ........................................................................................................................ 26
Hematopoïetine famillie (klasse 1)............................................................................................................. 27
Interferon familie (klasse 2)........................................................................................................................ 28
Tumor necrosis factor (TNF) familie........................................................................................................... 28
Interleukine-17 (IL-17) familie .................................................................................................................... 29
Chemokine familie....................................................................................................................................... 30
Hoofdstuk 4: innate immuunsysteem......................................................................................................................... 31
Anatomische barrière tegen infectie ...................................................................................................................... 31
Epitheliale fysieke barrière.................................................................................................................................. 31
, Epitheliale chemische barrière............................................................................................................................ 31
Cellulaire innate immuunrespons ........................................................................................................................... 31
Toll-like receptor (TLR)......................................................................................................................................... 32
C-type lectin receptor (CLR) ................................................................................................................................ 33
NOD-like receptor (NLR) ...................................................................................................................................... 33
RIG-I-like receptor (RLR) ...................................................................................................................................... 33
AIM2-like receptor (ALR) ..................................................................................................................................... 33
cGAS en STING...................................................................................................................................................... 34
Effector innate immuunrespons ............................................................................................................................. 34
Expressie van innate immuunsysteem eiwitten ................................................................................................ 34
Fagocytose............................................................................................................................................................ 35
Opsonisatie....................................................................................................................................................... 36
Gecontroleerde celdood...................................................................................................................................... 37
Inflammatoire respons ........................................................................................................................................ 37
Innate lymfoïde cellen (ILC)............................................................................................................................. 38
Natural killer cellen (NK) ............................................................................................................................. 39
Lymphoid tissue inducer cells (LTi)............................................................................................................. 39
Regulatie innate en inflammatoire respons ........................................................................................................... 39
Interactie tussen innate en adaptief immuunsysteem ......................................................................................... 40
Hoofdstuk 5: complement systeem ............................................................................................................................ 41
Klassieke pathway .................................................................................................................................................... 42
Lectine of mannose-binding lectine (MBL) pathway ............................................................................................. 42
Alternatieve pathway .............................................................................................................................................. 43
Thick-over pathway.............................................................................................................................................. 43
Properdine-geactiveerde pathway ..................................................................................................................... 43
Protease-geactiveerde pathway ......................................................................................................................... 44
Functies complementsysteem ................................................................................................................................ 44
Connectie complement-tagged pathogenen en effectorcellen........................................................................ 45
Versterking gastheer-verdediging tegen infecties............................................................................................. 45
Situeren op interface innate en adaptief immuunsysteem .............................................................................. 45
Actief in contractiefase van immuunrespons .................................................................................................... 46
Regulatie complementsysteem............................................................................................................................... 46
Complement-deficiënties .................................................................................................................................... 47
Microbiële strategieën om complementsysteem te omzeilen ......................................................................... 47
Hoofdstuk 6: organisatie en expressie van lymfocyte receptor genen .................................................................... 48
Immunoglobulines (Ig) genen ................................................................................................................................. 48
Inleiding ................................................................................................................................................................ 48
, Multigene organisatie.......................................................................................................................................... 48
κ-lichte keten.................................................................................................................................................... 48
λ-lichte keten.................................................................................................................................................... 48
Zware keten...................................................................................................................................................... 48
Mechanisme van V(D)J-recombinatie................................................................................................................. 49
Betrokken eiwitten .......................................................................................................................................... 49
Recombination-signaal sequenties (RSSs) ................................................................................................. 50
Recombination activating gene (RAG) 1/2 ................................................................................................ 51
Proces ............................................................................................................................................................... 51
Regulatie........................................................................................................................................................... 52
Intranucleaire localisatie van antigen receptor chromatine............................................................................. 52
Allelic exclusion .................................................................................................................................................... 52
B-cel receptor (BCR)................................................................................................................................................. 53
Autoreactieve BCR ............................................................................................................................................... 53
Expressie B-cel receptor (BCR) ............................................................................................................................ 53
T-cel receptor (TCR) ................................................................................................................................................. 53
Genen en expressie.............................................................................................................................................. 53
Vergelijking mechanismen voor vorming en expressie BCR of TCR ..................................................................... 54
Hoofdstuk 7: major histocompatibility complex (MHC) en antigenpresentatie...................................................... 55
Structuur en functie van MHC-moleculen.............................................................................................................. 55
MHC klasse I molecule......................................................................................................................................... 55
MHC-klasse II molecule........................................................................................................................................ 55
Peptide-binding aan MHC klasse I en II moleculen............................................................................................ 56
Organisatie en overerving van MHC....................................................................................................................... 56
Rol en expressie van MHC ....................................................................................................................................... 56
MHC I-moleculen presenteren intracellulaire antigen peptiden...................................................................... 57
MHC II-moleculen presenteren zowel intracellulaire als extracellulaire antigen peptiden ........................... 57
Types antigen-presenterende cellen (APC)........................................................................................................ 57
Antigen-processing pathway ............................................................................................................................... 57
Endogene pathway van antigen processing en presentatie......................................................................... 57
Exogene pathway van antigen processing en presentatie ........................................................................... 58
Cross-presentatie van exogene antigenen ................................................................................................ 59
Presentatie van niet-peptide antigenen .................................................................................................... 59
Hoofdstuk 8: T-cel ontwikkeling.................................................................................................................................. 60
Ontwikkeling T-cellen in thymus ............................................................................................................................. 60
Vroege thymocyte ontwikkeling ......................................................................................................................... 60
Positieve en negatieve selectie....................................................................................................................... 61
, Lineage commitment....................................................................................................................................... 62
Verlaten thymus en finale maturatie.................................................................................................................. 63
Mechanismen om zelf-tolerantie te behouden ..................................................................................................... 63
Hoofdstuk 9: B-cel ontwikkeling.................................................................................................................................. 64
Plaats hematopoïese................................................................................................................................................ 64
Ontwikkeling B-cellen in beenmerg........................................................................................................................ 64
Stadia hematopoïese ........................................................................................................................................... 64
Ontwikkeling B-1 B-cellen en marginale zone B-cellen ..................................................................................... 66
Vergelijking B-cel en T-cel ontwikkeling................................................................................................................. 66
Hoofdstuk 10: T-cel activatie, helper subset differentiatie en geheugen ................................................................ 68
T-cel activatie: 2-signaal-hypothese ....................................................................................................................... 68
Co-stimulatoire signalen..................................................................................................................................... 69
Immunologische synaps .................................................................................................................................. 69
Positieve co-stimulatoire signalen.................................................................................................................. 70
Proces.................................................................................................................................................................... 71
T-cel activatie: APC................................................................................................................................................... 71
T-cel activatie: superantigenen............................................................................................................................... 72
T-cel differentiatie.................................................................................................................................................... 72
Co-stimulatoire signalen...................................................................................................................................... 72
Cytokines .......................................................................................................................................................... 72
Helper T-cellen subsets........................................................................................................................................ 73
TH1/TH2 cross regulatie.................................................................................................................................... 74
TH17/TREG cross regulatie ................................................................................................................................. 75
TFH-cellen .......................................................................................................................................................... 76
TH9-cellen.......................................................................................................................................................... 76
TH22-cellen ....................................................................................................................................................... 76
T-cel differentiatie: TH cel plasticiteit ..................................................................................................................... 76
TH-cellen in gezondheid en ziekte ........................................................................................................................... 77
T-cel geheugen ......................................................................................................................................................... 77
Hoofdstuk 11: B-cel activatie, differentiatie en geheugen........................................................................................ 78
B-cel activatie: clonale selectie hypothese ............................................................................................................ 78
B-cel activatie: T depente B-cel reactie .................................................................................................................. 78
Immunologische synaps ...................................................................................................................................... 79
Ag-endocytose...................................................................................................................................................... 79
Chemokine geleide B-cel migratie ...................................................................................................................... 79
Vroege fase....................................................................................................................................................... 79
Verdere proliferatie en differentiatie B-cellen .............................................................................................. 79
, Plasmacellen ................................................................................................................................................ 80
Vorming germinale centra .......................................................................................................................... 80
Vroege geheugen B-cellen (IgM) ................................................................................................................ 81
Einde respons ................................................................................................................................................... 82
B-cel activatie: T indepente B-cel reactie (dia 109) ............................................................................................... 82
Respons................................................................................................................................................................. 82
B-1 B-cellen ...................................................................................................................................................... 82
Marginale zone B-cellen (B-2 B-cellen) .......................................................................................................... 83
Negatieve regulatie B-cellen ............................................................................................................................... 83
Hoofdstuk 12: effector respons................................................................................................................................... 84
Antistof-gemedieerde immuniteit .......................................................................................................................... 84
FCR ......................................................................................................................................................................... 84
FCγR.................................................................................................................................................................... 85
FcεR .................................................................................................................................................................... 85
FCαR ................................................................................................................................................................... 85
FCμR en FCα/μR .................................................................................................................................................. 86
Poly-IgR............................................................................................................................................................. 86
FCRn.................................................................................................................................................................... 86
IgM-Ab .................................................................................................................................................................. 86
IgG-Ab ................................................................................................................................................................... 86
IgA-Ab.................................................................................................................................................................... 87
IgE-Ab .................................................................................................................................................................... 87
IgD-Ab ................................................................................................................................................................... 87
Cel-gemedieerde immuniteit .................................................................................................................................. 87
Cytotoxische T-lymfocyten (CTL) cellen.............................................................................................................. 87
TCR-activatie .................................................................................................................................................... 88
Killing-mechanisme CTL-cellen ....................................................................................................................... 88
NKT-cellen............................................................................................................................................................. 89
NK-cellen............................................................................................................................................................... 89
Receptoren ....................................................................................................................................................... 89
Missing self-model........................................................................................................................................... 90
Licensing en regulering ........................................................................................................................................ 90
Hoofdstuk 13: barrière-immuniteit............................................................................................................................. 91
Barrière-immuniteit ................................................................................................................................................. 91
Intestinale immuniteit ............................................................................................................................................. 92
Cellen .................................................................................................................................................................... 92
Barrièrefunctie ..................................................................................................................................................... 92
, Ag-APC interactie ................................................................................................................................................. 93
Immuunhomeostase............................................................................................................................................ 93
Cytokines .......................................................................................................................................................... 94
Mechanisme..................................................................................................................................................... 94
Commensale flora ................................................................................................................................................ 95
Respons op ziekteverwekkers ............................................................................................................................. 95
Respiratoir immuunsysteem ................................................................................................................................... 97
Huid........................................................................................................................................................................... 98
Hoofdstuk 14: adaptieve immuunrespons in tijd en ruimte ..................................................................................... 99
Homeostase: gedrag van immuuncellen voor ze in contact komen met Ag ....................................................... 99
Immuunrespons bij contact met Ag ..................................................................................................................... 100
Aangeboren (innate) immuunrespons ............................................................................................................. 100
Adaptive immuunrespons ................................................................................................................................. 101
Effector en geheugen immuunrespons ............................................................................................................ 102
Voorbeelden........................................................................................................................................................... 102
Hoofdstuk 15: allergie, hypersensitiviteit en chronische inflammatie ................................................................... 103
Hypersensitiviteitsreactie...................................................................................................................................... 103
Type-I hypersensitiviteitsreactie (allergie – IgE) .............................................................................................. 103
Mediatoren..................................................................................................................................................... 104
Histamine ................................................................................................................................................... 104
Leukotriënen en prostaglandines ............................................................................................................. 104
Cytokines en chemokines.......................................................................................................................... 105
Fasen............................................................................................................................................................... 105
Categorieën .................................................................................................................................................... 105
Systemische anafylaxie ............................................................................................................................. 105
Gelokaliseerde overgevoeligheidsreactie................................................................................................ 105
Voedselallergieën ...................................................................................................................................... 106
Omgevingsfactoren........................................................................................................................................ 106
Diagnostische test.......................................................................................................................................... 107
Behandelingen ............................................................................................................................................... 107
Type-II hypersensitiviteitsreactie (antistof-gemedieerd – IgM, IgG).............................................................. 107
Transfusiereacties (ABO-incompatibiliteit).................................................................................................. 107
Type-III hypersensitiviteitsreactie (immuuncomplexen)................................................................................. 108
Type-IV hypersensitiviteitsreactie (cel) ............................................................................................................ 109
Sensibilisatie fase........................................................................................................................................... 109
Effector fase ................................................................................................................................................... 109
Diagnostische test.......................................................................................................................................... 109
, Contactdermatitis .......................................................................................................................................... 110
Chronische inflammatie......................................................................................................................................... 110
Infectieuze oorzaken.......................................................................................................................................... 110
Niet-infectieuze oorzaken ................................................................................................................................. 110
Hoofdstuk 16: tolerantie, auto-immuniteit, transplantatie .................................................................................... 112
Tolerantie................................................................................................................................................................ 112
Antigeen-sequestratie ....................................................................................................................................... 112
Centrale tolerantie............................................................................................................................................. 112
Perifere tolerantie.............................................................................................................................................. 112
Regulatoire CD4 T-cellen (CD4 TREG) ............................................................................................................. 113
Regulatoire CD8 T-cellen (CD8 TREG) ............................................................................................................. 113
Regulatoire B-cellen (BREG) ............................................................................................................................ 113
Myeloïd-derived suppressor cells (MDSC) ................................................................................................... 113
Auto-immuniteit..................................................................................................................................................... 114
Orgaanspecifieke auto-immuniteit................................................................................................................... 115
Systemische auto-immuniteit ........................................................................................................................... 115
Gevoeligheid voor auto-immuunziekten.......................................................................................................... 116
Behandeling........................................................................................................................................................ 117
Breedspectrum therapie ............................................................................................................................... 117
Therapie gericht op specifieke celtypen of pathways................................................................................. 117
Therapie gericht op blokkeren ontstekingsproces ...................................................................................... 117
Therapie gericht op interferentie met co-stimulatie .................................................................................. 118
Antigeen-specifieke immunotherapie.......................................................................................................... 118
Transplantatie ........................................................................................................................................................ 118
Afstoting (rejectie) ............................................................................................................................................. 118
Mate en type van immuunrespons .............................................................................................................. 118
Specificiteit en geheugen bij afstoten allograft ........................................................................................... 118
Sommige organen meer geschikt dan andere voor klinische transplantatie ............................................ 118
Klinisch verloop.............................................................................................................................................. 119
Immunosuppressieve therapie ..................................................................................................................... 119
Hoofdstuk 17: infectieuze ziekten en vaccinatie...................................................................................................... 121
Belang van barrière-immuniteit en innate immuunsysteem.............................................................................. 121
Slijmvlies- of barrière-infecties worden onder controle gehouden door T H2-type immuunreacties .......... 121
Extracellulaire pathogenen moeten herkend worden en aangevallen mbv extracellulaire hulpmiddelen 121
Mechanisme die geïnfecteerde gastheercellen herkennen, zijn nodig om intracellulaire infecties te
bestrijden............................................................................................................................................................ 121
Virale infecties........................................................................................................................................................ 122
, Aangeboren immuunrespons............................................................................................................................ 122
Adaptieve immuunrespons ............................................................................................................................... 122
Geheugenrespons .............................................................................................................................................. 123
Influenza ......................................................................................................................................................... 123
Bacteriële infecties................................................................................................................................................. 124
Tuberculose ........................................................................................................................................................ 124
Difterie ................................................................................................................................................................ 125
Parasitaire infecties................................................................................................................................................ 125
Malaria................................................................................................................................................................ 125
Afrikaanse slaapziekte ....................................................................................................................................... 125
Leishmaniasis...................................................................................................................................................... 125
Ziekten door parasitaire wormen ..................................................................................................................... 125
Schimmelinfecties .................................................................................................................................................. 126
Aangeboren immuniteit .................................................................................................................................... 126
Adaptieve immuniteit ........................................................................................................................................ 127
Emerging en re-emerging infecties....................................................................................................................... 127
Vaccinatie ............................................................................................................................................................... 127
Immunisatie........................................................................................................................................................ 127
Passieve immunisatie .................................................................................................................................... 127
Actieve immunisatie ...................................................................................................................................... 128
Vaccinatiestrategieën ........................................................................................................................................ 128
Levende, verzwakte vaccins .......................................................................................................................... 128
Geïnactiveerde of gedoode vaccins.............................................................................................................. 128
Subeenheid vaccins ....................................................................................................................................... 129
Recombinante vectorvaccins ........................................................................................................................ 129
DNA-vaccins.................................................................................................................................................... 129
RNA-vaccins.................................................................................................................................................... 130
Geconjugeerde of multivalente vaccins ........................................................................................................... 130
Adjuvantia........................................................................................................................................................... 130
Hoofdstuk 18: immuundeficiënties........................................................................................................................... 131
Primaire immuundeficiënties (PID)....................................................................................................................... 131
Onderliggende genetische afwijkingen ............................................................................................................ 131
Combined immunodeficiënties (CID) ........................................................................................................... 132
B-cel immuundeficiënties.............................................................................................................................. 134
Innate-immuundeficiënties (IS) .................................................................................................................... 135
Complement-deficiënties (immuun-regulatie) ............................................................................................ 135
NK-cellen-deficiënties.................................................................................................................................... 136
, Auto-immuun deficiënties............................................................................................................................. 136
Behandeling........................................................................................................................................................ 136
Secundaire immuundeficiënties ........................................................................................................................... 137
HIV....................................................................................................................................................................... 137
Rol van co-receptoren ................................................................................................................................... 139
Ziektestadia .................................................................................................................................................... 139
Behandeling.................................................................................................................................................... 140
Vaccinatie ....................................................................................................................................................... 140
Hoofdstuk 19: kanker en immuunsysteem............................................................................................................... 141
Inleiding .................................................................................................................................................................. 141
Kanker-geassocieerde genen ................................................................................................................................ 141
Maligne transformatie van cellen ......................................................................................................................... 142
Oncogenen ......................................................................................................................................................... 142
Tumorsuppressorgenen..................................................................................................................................... 143
Apoptotische genen........................................................................................................................................... 143
Tumor-antigenen ................................................................................................................................................... 144
Tumor-specifieke antigenen (TSA).................................................................................................................... 144
Tumor-geassocieerde antigenen (TAA) ............................................................................................................ 144
Immuunrespons tov kanker .................................................................................................................................. 144
Aangeboren inhibitoren .................................................................................................................................... 145
Adaptief immuunsysteem ................................................................................................................................. 145
Rol van cytokines................................................................................................................................................ 145
Factoren die immuunrespons beïnvloeden ..................................................................................................... 145
Chronische ontsteking................................................................................................................................... 145
Anti-tumor-versterkende antilichamen ....................................................................................................... 146
Actieve immunosuppressie ........................................................................................................................... 146
Factoren die immuunrespons ontwijken ......................................................................................................... 146
Verminderde MHC-expressie........................................................................................................................ 146
Resistentie tumorcellen tov apoptose-signalen .......................................................................................... 146
Slechte co-stimulatie door tumorcellen....................................................................................................... 146
Immuuntherapie .................................................................................................................................................... 146
Monoklonale antilichamen................................................................................................................................ 146
Celtherapie ......................................................................................................................................................... 147
Tumor-specifieke T-cellen ............................................................................................................................. 147
CAR-T-cellen ................................................................................................................................................... 147
Vaccins ................................................................................................................................................................ 147
Co-stimulatie ...................................................................................................................................................... 147
Hoofdstuk 1: het immuunsysteem.................................................................................................................................1
Inleiding .......................................................................................................................................................................1
Belangrijke concepten van het humane immuunsysteem.......................................................................................1
Innate immuunsysteem ..........................................................................................................................................1
Adaptief immuunsysteem ......................................................................................................................................2
Primaire immuunrespons ...................................................................................................................................2
Secundaire immuunrespons ..............................................................................................................................2
Klonale selectie .......................................................................................................................................................2
The good, the bad and the ugly van het immuunsysteem.......................................................................................3
Dysfuncties ..............................................................................................................................................................3
Transplantatie .........................................................................................................................................................3
Kanker ......................................................................................................................................................................3
Tolerantie.................................................................................................................................................................3
Hoofdstuk 2: cellen, organen en omgeving van het immuunsysteem ........................................................................4
Cellen van het immuunsysteem.................................................................................................................................4
Common myeloïde progenitor...............................................................................................................................4
Erythrocyten (RBC)..............................................................................................................................................4
Monocyten ..........................................................................................................................................................4
Granulocyten.......................................................................................................................................................5
Megakaryocyten (BP) .........................................................................................................................................7
Common lymphoid progenitor...............................................................................................................................7
B-lymfocyten .......................................................................................................................................................7
T-lymfocyten .......................................................................................................................................................8
Natural killer cellen (NK-cellen) .........................................................................................................................8
Diagnostische technieken...........................................................................................................................................8
Perifeer bloeduitstrijkje..........................................................................................................................................8
Hematoxyline-eosine (H&E)...............................................................................................................................8
May-Grünwald Giemsa (MGG)...........................................................................................................................8
Flowcytometrie .......................................................................................................................................................9
Primaire lymfoïde organen.........................................................................................................................................9
Beenmerg ................................................................................................................................................................9
Thymus.................................................................................................................................................................. 11
Secundaire lymfoïde organen ................................................................................................................................. 13
Lymfeknopen........................................................................................................................................................ 13
Milt ........................................................................................................................................................................ 15
, Mucosa-associated lymphoid tissue (MALT)...................................................................................................... 15
Barrière organen ...................................................................................................................................................... 16
Hoofdstuk 3: herkenning en respons .......................................................................................................................... 17
Signaaltransductie.................................................................................................................................................... 17
Definities............................................................................................................................................................... 17
Ligand-receptor binding ...................................................................................................................................... 17
Antigen-receptor binding ................................................................................................................................ 18
Combinatie receptoreiwitten.......................................................................................................................... 18
Proces.................................................................................................................................................................... 18
Lipid rafts en R-multimerisatie........................................................................................................................ 18
Fosforylatie tyrosine-residu’s.......................................................................................................................... 19
Intracellulaire adapter-eiwitten...................................................................................................................... 19
Gemeenschappelijk downstream pathways .................................................................................................. 20
Receptoren in immuunsysteem .............................................................................................................................. 20
Immunoglobuline superfamilie (adaptive)......................................................................................................... 20
B-cel receptor (BCR) (antistoffen – immunoglobulines) ............................................................................... 21
Structuur ...................................................................................................................................................... 21
Antigen-herkenning..................................................................................................................................... 22
Isotypes ........................................................................................................................................................ 22
BCR-complex ................................................................................................................................................ 23
T-cel receptor (TCR) (adaptive)....................................................................................................................... 23
Structuur ...................................................................................................................................................... 23
TCR-complex ................................................................................................................................................ 24
Pattern recognition receptoren (PRR) (innate) .................................................................................................. 24
Complement receptoren (innate) en Fc-receptoren......................................................................................... 24
Cytokine receptoren (innate) .............................................................................................................................. 25
Werking ............................................................................................................................................................ 25
6 superfamilies ................................................................................................................................................. 26
Interleukine-1 (IL-1) familie ........................................................................................................................ 26
Hematopoïetine famillie (klasse 1)............................................................................................................. 27
Interferon familie (klasse 2)........................................................................................................................ 28
Tumor necrosis factor (TNF) familie........................................................................................................... 28
Interleukine-17 (IL-17) familie .................................................................................................................... 29
Chemokine familie....................................................................................................................................... 30
Hoofdstuk 4: innate immuunsysteem......................................................................................................................... 31
Anatomische barrière tegen infectie ...................................................................................................................... 31
Epitheliale fysieke barrière.................................................................................................................................. 31
, Epitheliale chemische barrière............................................................................................................................ 31
Cellulaire innate immuunrespons ........................................................................................................................... 31
Toll-like receptor (TLR)......................................................................................................................................... 32
C-type lectin receptor (CLR) ................................................................................................................................ 33
NOD-like receptor (NLR) ...................................................................................................................................... 33
RIG-I-like receptor (RLR) ...................................................................................................................................... 33
AIM2-like receptor (ALR) ..................................................................................................................................... 33
cGAS en STING...................................................................................................................................................... 34
Effector innate immuunrespons ............................................................................................................................. 34
Expressie van innate immuunsysteem eiwitten ................................................................................................ 34
Fagocytose............................................................................................................................................................ 35
Opsonisatie....................................................................................................................................................... 36
Gecontroleerde celdood...................................................................................................................................... 37
Inflammatoire respons ........................................................................................................................................ 37
Innate lymfoïde cellen (ILC)............................................................................................................................. 38
Natural killer cellen (NK) ............................................................................................................................. 39
Lymphoid tissue inducer cells (LTi)............................................................................................................. 39
Regulatie innate en inflammatoire respons ........................................................................................................... 39
Interactie tussen innate en adaptief immuunsysteem ......................................................................................... 40
Hoofdstuk 5: complement systeem ............................................................................................................................ 41
Klassieke pathway .................................................................................................................................................... 42
Lectine of mannose-binding lectine (MBL) pathway ............................................................................................. 42
Alternatieve pathway .............................................................................................................................................. 43
Thick-over pathway.............................................................................................................................................. 43
Properdine-geactiveerde pathway ..................................................................................................................... 43
Protease-geactiveerde pathway ......................................................................................................................... 44
Functies complementsysteem ................................................................................................................................ 44
Connectie complement-tagged pathogenen en effectorcellen........................................................................ 45
Versterking gastheer-verdediging tegen infecties............................................................................................. 45
Situeren op interface innate en adaptief immuunsysteem .............................................................................. 45
Actief in contractiefase van immuunrespons .................................................................................................... 46
Regulatie complementsysteem............................................................................................................................... 46
Complement-deficiënties .................................................................................................................................... 47
Microbiële strategieën om complementsysteem te omzeilen ......................................................................... 47
Hoofdstuk 6: organisatie en expressie van lymfocyte receptor genen .................................................................... 48
Immunoglobulines (Ig) genen ................................................................................................................................. 48
Inleiding ................................................................................................................................................................ 48
, Multigene organisatie.......................................................................................................................................... 48
κ-lichte keten.................................................................................................................................................... 48
λ-lichte keten.................................................................................................................................................... 48
Zware keten...................................................................................................................................................... 48
Mechanisme van V(D)J-recombinatie................................................................................................................. 49
Betrokken eiwitten .......................................................................................................................................... 49
Recombination-signaal sequenties (RSSs) ................................................................................................. 50
Recombination activating gene (RAG) 1/2 ................................................................................................ 51
Proces ............................................................................................................................................................... 51
Regulatie........................................................................................................................................................... 52
Intranucleaire localisatie van antigen receptor chromatine............................................................................. 52
Allelic exclusion .................................................................................................................................................... 52
B-cel receptor (BCR)................................................................................................................................................. 53
Autoreactieve BCR ............................................................................................................................................... 53
Expressie B-cel receptor (BCR) ............................................................................................................................ 53
T-cel receptor (TCR) ................................................................................................................................................. 53
Genen en expressie.............................................................................................................................................. 53
Vergelijking mechanismen voor vorming en expressie BCR of TCR ..................................................................... 54
Hoofdstuk 7: major histocompatibility complex (MHC) en antigenpresentatie...................................................... 55
Structuur en functie van MHC-moleculen.............................................................................................................. 55
MHC klasse I molecule......................................................................................................................................... 55
MHC-klasse II molecule........................................................................................................................................ 55
Peptide-binding aan MHC klasse I en II moleculen............................................................................................ 56
Organisatie en overerving van MHC....................................................................................................................... 56
Rol en expressie van MHC ....................................................................................................................................... 56
MHC I-moleculen presenteren intracellulaire antigen peptiden...................................................................... 57
MHC II-moleculen presenteren zowel intracellulaire als extracellulaire antigen peptiden ........................... 57
Types antigen-presenterende cellen (APC)........................................................................................................ 57
Antigen-processing pathway ............................................................................................................................... 57
Endogene pathway van antigen processing en presentatie......................................................................... 57
Exogene pathway van antigen processing en presentatie ........................................................................... 58
Cross-presentatie van exogene antigenen ................................................................................................ 59
Presentatie van niet-peptide antigenen .................................................................................................... 59
Hoofdstuk 8: T-cel ontwikkeling.................................................................................................................................. 60
Ontwikkeling T-cellen in thymus ............................................................................................................................. 60
Vroege thymocyte ontwikkeling ......................................................................................................................... 60
Positieve en negatieve selectie....................................................................................................................... 61
, Lineage commitment....................................................................................................................................... 62
Verlaten thymus en finale maturatie.................................................................................................................. 63
Mechanismen om zelf-tolerantie te behouden ..................................................................................................... 63
Hoofdstuk 9: B-cel ontwikkeling.................................................................................................................................. 64
Plaats hematopoïese................................................................................................................................................ 64
Ontwikkeling B-cellen in beenmerg........................................................................................................................ 64
Stadia hematopoïese ........................................................................................................................................... 64
Ontwikkeling B-1 B-cellen en marginale zone B-cellen ..................................................................................... 66
Vergelijking B-cel en T-cel ontwikkeling................................................................................................................. 66
Hoofdstuk 10: T-cel activatie, helper subset differentiatie en geheugen ................................................................ 68
T-cel activatie: 2-signaal-hypothese ....................................................................................................................... 68
Co-stimulatoire signalen..................................................................................................................................... 69
Immunologische synaps .................................................................................................................................. 69
Positieve co-stimulatoire signalen.................................................................................................................. 70
Proces.................................................................................................................................................................... 71
T-cel activatie: APC................................................................................................................................................... 71
T-cel activatie: superantigenen............................................................................................................................... 72
T-cel differentiatie.................................................................................................................................................... 72
Co-stimulatoire signalen...................................................................................................................................... 72
Cytokines .......................................................................................................................................................... 72
Helper T-cellen subsets........................................................................................................................................ 73
TH1/TH2 cross regulatie.................................................................................................................................... 74
TH17/TREG cross regulatie ................................................................................................................................. 75
TFH-cellen .......................................................................................................................................................... 76
TH9-cellen.......................................................................................................................................................... 76
TH22-cellen ....................................................................................................................................................... 76
T-cel differentiatie: TH cel plasticiteit ..................................................................................................................... 76
TH-cellen in gezondheid en ziekte ........................................................................................................................... 77
T-cel geheugen ......................................................................................................................................................... 77
Hoofdstuk 11: B-cel activatie, differentiatie en geheugen........................................................................................ 78
B-cel activatie: clonale selectie hypothese ............................................................................................................ 78
B-cel activatie: T depente B-cel reactie .................................................................................................................. 78
Immunologische synaps ...................................................................................................................................... 79
Ag-endocytose...................................................................................................................................................... 79
Chemokine geleide B-cel migratie ...................................................................................................................... 79
Vroege fase....................................................................................................................................................... 79
Verdere proliferatie en differentiatie B-cellen .............................................................................................. 79
, Plasmacellen ................................................................................................................................................ 80
Vorming germinale centra .......................................................................................................................... 80
Vroege geheugen B-cellen (IgM) ................................................................................................................ 81
Einde respons ................................................................................................................................................... 82
B-cel activatie: T indepente B-cel reactie (dia 109) ............................................................................................... 82
Respons................................................................................................................................................................. 82
B-1 B-cellen ...................................................................................................................................................... 82
Marginale zone B-cellen (B-2 B-cellen) .......................................................................................................... 83
Negatieve regulatie B-cellen ............................................................................................................................... 83
Hoofdstuk 12: effector respons................................................................................................................................... 84
Antistof-gemedieerde immuniteit .......................................................................................................................... 84
FCR ......................................................................................................................................................................... 84
FCγR.................................................................................................................................................................... 85
FcεR .................................................................................................................................................................... 85
FCαR ................................................................................................................................................................... 85
FCμR en FCα/μR .................................................................................................................................................. 86
Poly-IgR............................................................................................................................................................. 86
FCRn.................................................................................................................................................................... 86
IgM-Ab .................................................................................................................................................................. 86
IgG-Ab ................................................................................................................................................................... 86
IgA-Ab.................................................................................................................................................................... 87
IgE-Ab .................................................................................................................................................................... 87
IgD-Ab ................................................................................................................................................................... 87
Cel-gemedieerde immuniteit .................................................................................................................................. 87
Cytotoxische T-lymfocyten (CTL) cellen.............................................................................................................. 87
TCR-activatie .................................................................................................................................................... 88
Killing-mechanisme CTL-cellen ....................................................................................................................... 88
NKT-cellen............................................................................................................................................................. 89
NK-cellen............................................................................................................................................................... 89
Receptoren ....................................................................................................................................................... 89
Missing self-model........................................................................................................................................... 90
Licensing en regulering ........................................................................................................................................ 90
Hoofdstuk 13: barrière-immuniteit............................................................................................................................. 91
Barrière-immuniteit ................................................................................................................................................. 91
Intestinale immuniteit ............................................................................................................................................. 92
Cellen .................................................................................................................................................................... 92
Barrièrefunctie ..................................................................................................................................................... 92
, Ag-APC interactie ................................................................................................................................................. 93
Immuunhomeostase............................................................................................................................................ 93
Cytokines .......................................................................................................................................................... 94
Mechanisme..................................................................................................................................................... 94
Commensale flora ................................................................................................................................................ 95
Respons op ziekteverwekkers ............................................................................................................................. 95
Respiratoir immuunsysteem ................................................................................................................................... 97
Huid........................................................................................................................................................................... 98
Hoofdstuk 14: adaptieve immuunrespons in tijd en ruimte ..................................................................................... 99
Homeostase: gedrag van immuuncellen voor ze in contact komen met Ag ....................................................... 99
Immuunrespons bij contact met Ag ..................................................................................................................... 100
Aangeboren (innate) immuunrespons ............................................................................................................. 100
Adaptive immuunrespons ................................................................................................................................. 101
Effector en geheugen immuunrespons ............................................................................................................ 102
Voorbeelden........................................................................................................................................................... 102
Hoofdstuk 15: allergie, hypersensitiviteit en chronische inflammatie ................................................................... 103
Hypersensitiviteitsreactie...................................................................................................................................... 103
Type-I hypersensitiviteitsreactie (allergie – IgE) .............................................................................................. 103
Mediatoren..................................................................................................................................................... 104
Histamine ................................................................................................................................................... 104
Leukotriënen en prostaglandines ............................................................................................................. 104
Cytokines en chemokines.......................................................................................................................... 105
Fasen............................................................................................................................................................... 105
Categorieën .................................................................................................................................................... 105
Systemische anafylaxie ............................................................................................................................. 105
Gelokaliseerde overgevoeligheidsreactie................................................................................................ 105
Voedselallergieën ...................................................................................................................................... 106
Omgevingsfactoren........................................................................................................................................ 106
Diagnostische test.......................................................................................................................................... 107
Behandelingen ............................................................................................................................................... 107
Type-II hypersensitiviteitsreactie (antistof-gemedieerd – IgM, IgG).............................................................. 107
Transfusiereacties (ABO-incompatibiliteit).................................................................................................. 107
Type-III hypersensitiviteitsreactie (immuuncomplexen)................................................................................. 108
Type-IV hypersensitiviteitsreactie (cel) ............................................................................................................ 109
Sensibilisatie fase........................................................................................................................................... 109
Effector fase ................................................................................................................................................... 109
Diagnostische test.......................................................................................................................................... 109
, Contactdermatitis .......................................................................................................................................... 110
Chronische inflammatie......................................................................................................................................... 110
Infectieuze oorzaken.......................................................................................................................................... 110
Niet-infectieuze oorzaken ................................................................................................................................. 110
Hoofdstuk 16: tolerantie, auto-immuniteit, transplantatie .................................................................................... 112
Tolerantie................................................................................................................................................................ 112
Antigeen-sequestratie ....................................................................................................................................... 112
Centrale tolerantie............................................................................................................................................. 112
Perifere tolerantie.............................................................................................................................................. 112
Regulatoire CD4 T-cellen (CD4 TREG) ............................................................................................................. 113
Regulatoire CD8 T-cellen (CD8 TREG) ............................................................................................................. 113
Regulatoire B-cellen (BREG) ............................................................................................................................ 113
Myeloïd-derived suppressor cells (MDSC) ................................................................................................... 113
Auto-immuniteit..................................................................................................................................................... 114
Orgaanspecifieke auto-immuniteit................................................................................................................... 115
Systemische auto-immuniteit ........................................................................................................................... 115
Gevoeligheid voor auto-immuunziekten.......................................................................................................... 116
Behandeling........................................................................................................................................................ 117
Breedspectrum therapie ............................................................................................................................... 117
Therapie gericht op specifieke celtypen of pathways................................................................................. 117
Therapie gericht op blokkeren ontstekingsproces ...................................................................................... 117
Therapie gericht op interferentie met co-stimulatie .................................................................................. 118
Antigeen-specifieke immunotherapie.......................................................................................................... 118
Transplantatie ........................................................................................................................................................ 118
Afstoting (rejectie) ............................................................................................................................................. 118
Mate en type van immuunrespons .............................................................................................................. 118
Specificiteit en geheugen bij afstoten allograft ........................................................................................... 118
Sommige organen meer geschikt dan andere voor klinische transplantatie ............................................ 118
Klinisch verloop.............................................................................................................................................. 119
Immunosuppressieve therapie ..................................................................................................................... 119
Hoofdstuk 17: infectieuze ziekten en vaccinatie...................................................................................................... 121
Belang van barrière-immuniteit en innate immuunsysteem.............................................................................. 121
Slijmvlies- of barrière-infecties worden onder controle gehouden door T H2-type immuunreacties .......... 121
Extracellulaire pathogenen moeten herkend worden en aangevallen mbv extracellulaire hulpmiddelen 121
Mechanisme die geïnfecteerde gastheercellen herkennen, zijn nodig om intracellulaire infecties te
bestrijden............................................................................................................................................................ 121
Virale infecties........................................................................................................................................................ 122
, Aangeboren immuunrespons............................................................................................................................ 122
Adaptieve immuunrespons ............................................................................................................................... 122
Geheugenrespons .............................................................................................................................................. 123
Influenza ......................................................................................................................................................... 123
Bacteriële infecties................................................................................................................................................. 124
Tuberculose ........................................................................................................................................................ 124
Difterie ................................................................................................................................................................ 125
Parasitaire infecties................................................................................................................................................ 125
Malaria................................................................................................................................................................ 125
Afrikaanse slaapziekte ....................................................................................................................................... 125
Leishmaniasis...................................................................................................................................................... 125
Ziekten door parasitaire wormen ..................................................................................................................... 125
Schimmelinfecties .................................................................................................................................................. 126
Aangeboren immuniteit .................................................................................................................................... 126
Adaptieve immuniteit ........................................................................................................................................ 127
Emerging en re-emerging infecties....................................................................................................................... 127
Vaccinatie ............................................................................................................................................................... 127
Immunisatie........................................................................................................................................................ 127
Passieve immunisatie .................................................................................................................................... 127
Actieve immunisatie ...................................................................................................................................... 128
Vaccinatiestrategieën ........................................................................................................................................ 128
Levende, verzwakte vaccins .......................................................................................................................... 128
Geïnactiveerde of gedoode vaccins.............................................................................................................. 128
Subeenheid vaccins ....................................................................................................................................... 129
Recombinante vectorvaccins ........................................................................................................................ 129
DNA-vaccins.................................................................................................................................................... 129
RNA-vaccins.................................................................................................................................................... 130
Geconjugeerde of multivalente vaccins ........................................................................................................... 130
Adjuvantia........................................................................................................................................................... 130
Hoofdstuk 18: immuundeficiënties........................................................................................................................... 131
Primaire immuundeficiënties (PID)....................................................................................................................... 131
Onderliggende genetische afwijkingen ............................................................................................................ 131
Combined immunodeficiënties (CID) ........................................................................................................... 132
B-cel immuundeficiënties.............................................................................................................................. 134
Innate-immuundeficiënties (IS) .................................................................................................................... 135
Complement-deficiënties (immuun-regulatie) ............................................................................................ 135
NK-cellen-deficiënties.................................................................................................................................... 136
, Auto-immuun deficiënties............................................................................................................................. 136
Behandeling........................................................................................................................................................ 136
Secundaire immuundeficiënties ........................................................................................................................... 137
HIV....................................................................................................................................................................... 137
Rol van co-receptoren ................................................................................................................................... 139
Ziektestadia .................................................................................................................................................... 139
Behandeling.................................................................................................................................................... 140
Vaccinatie ....................................................................................................................................................... 140
Hoofdstuk 19: kanker en immuunsysteem............................................................................................................... 141
Inleiding .................................................................................................................................................................. 141
Kanker-geassocieerde genen ................................................................................................................................ 141
Maligne transformatie van cellen ......................................................................................................................... 142
Oncogenen ......................................................................................................................................................... 142
Tumorsuppressorgenen..................................................................................................................................... 143
Apoptotische genen........................................................................................................................................... 143
Tumor-antigenen ................................................................................................................................................... 144
Tumor-specifieke antigenen (TSA).................................................................................................................... 144
Tumor-geassocieerde antigenen (TAA) ............................................................................................................ 144
Immuunrespons tov kanker .................................................................................................................................. 144
Aangeboren inhibitoren .................................................................................................................................... 145
Adaptief immuunsysteem ................................................................................................................................. 145
Rol van cytokines................................................................................................................................................ 145
Factoren die immuunrespons beïnvloeden ..................................................................................................... 145
Chronische ontsteking................................................................................................................................... 145
Anti-tumor-versterkende antilichamen ....................................................................................................... 146
Actieve immunosuppressie ........................................................................................................................... 146
Factoren die immuunrespons ontwijken ......................................................................................................... 146
Verminderde MHC-expressie........................................................................................................................ 146
Resistentie tumorcellen tov apoptose-signalen .......................................................................................... 146
Slechte co-stimulatie door tumorcellen....................................................................................................... 146
Immuuntherapie .................................................................................................................................................... 146
Monoklonale antilichamen................................................................................................................................ 146
Celtherapie ......................................................................................................................................................... 147
Tumor-specifieke T-cellen ............................................................................................................................. 147
CAR-T-cellen ................................................................................................................................................... 147
Vaccins ................................................................................................................................................................ 147
Co-stimulatie ...................................................................................................................................................... 147
