Lecture 1 – Innate and Adaptive Immunity
CD: Cluster of Differentiation
Techniques to diagnose and monitor disease
● Immunohistochemistry (IHC), Enzyme linked immunosorbent assay (ELISA), Flow cytometry
● Immunotherapy: Modulation of immunological effector functions to treat disease. Biologicals,
‘engineered’ antibodies
a. Flow cytometer: cell in solution, cell sucked up in small flow of liquid → measuring of cells that
are in fluid stream → cell passes a laser beam, and by the way that the light is spread you will
get size of the cell
b. FACS: fluorescence activated cell sorting —> we can sort cells based on the fluorescent colour
they are carrying. Eg. mark t cell green b cell red —> give these cells a charge and those
deflection. plates separate the cells —> separate tubes with different types of cells (sorting
bacteria etc)
Immunity
innate: rapid. TLR 4: recognizes LPS (lipopolysaccharide) on gram -
bacteria
Adaptive: APC presents small peptides in context of MHC to T cells or b
cells —> differentiation and proliferation
● generating new b and t cells specificities all the time (repertoire)
—> anticipatory system (wasteful), many of them are killed
(central tolerance prevent autoimmunity) —> evolutionarily
speaking it pays off
HLA (human leukocyte antigen): human specific MHC I & II —> sits
on the surface of human white blood cells
Antigen: structure that can induce antibody dependent response
Spleen: filters RBC due to signal from CD molecules (eat me)
Lymphocytes: B cell & T cell originates in bone marrow, but T cell matures in Thymus
Characteristics of foreign matter:
● Life form of infection: extracellular, intracellular
● Location of infection: gut, skin, blood
Challenges of immunity
A universe of microorganisms: Different structures, life-forms and size
Threat:
● Bacteria and viruses grow exponentially the body must respond in
time once an infection occurs
● Rapid evolution of microorganisms adaptable system necessary
● The immune system must accomplish this without destroying the
body itself (discrimination self/non-self)
Ineffective immunity: SCID (genetic disorder, absence of functional T
cells, prone to infections) and AIDS (caused by HIV targets immune cells (CD4+ T cells and DC) and
undermines immune function, susceptible to a variety of bacterial, fungal and viral infections)
,Hyperactive/incorrect immunity: asthma/allergies (uncontrolled allergic reactions to innocent
substances/allergens e.g., house dust mites), autoimmunity (immune reaction to self tissues due to
unbalanced immune regulation e.g., T1 diabetes, RA, etc)
Organisation of the immune system
● Prevention (barriers)
● Fast response (innate immunity)
● Extracellular (humoral immunity) and
intracellular (cellular immunity) microbes
● Adaption (adaptive immunity)
● Specificity (innate and adaptive)
Physical & chemical barriers → prevent infection
Physical barriers: Skin, respiratory tract, GI tract
● → Continuous epithelia protect against entry
of microbes
Chemical barriers: antibacterial enzymes in saliva, tears, mucus, plus stomach acid, gut bacteria
Innate immunity: first line of defense
● Initial & rapid response (hours)
● Limited specificity (PAMP → PRRs) – germline encoded
● Components: humoral (complement system, cytokines) & cellular (phagocytes–MP&NP– & NK
cells)
● Diversity: limited (fixed variety of PRRs)
● No memory → always responds in the same way
2 main functions of innate immunity
1. Elimination of insults: phagocytosis, lysis
2. Observation of insults: inflammation, activation of
adaptive immunity
Cells of innate immunity:
Functions: phagocytosis, APC, antigen transport, cytotoxicity, cytokine
mediated functions, etc
Components of innate immunity:
1. Complement system
● Humoral part of innate immunity
● Defense against extracellular pathogens
● Collection of circulating and membrane-associated proteins
● Many of these are proteolytic enzymes → enzymatic cascade
3 pathways: alternative, classical (IgM), lectin (MBL) → MAC
3 functions: inflammation, lysis of microbes, opsonization
2. NK cells
● are lymphocytes, but has no receptor (no TCR&BCR)
● respond to intracellular microbes
, ● Kill these cells directly
● Respond to IL-12 from macrophages
● Produce IFN-γ → IFN-γ activates
macrophages to kill phagocytosed
microbes
Mechanism (activation & inhibition)
● do not attack normal cells because of
inhibitory receptors
● Inhibitory receptors recognize MHC-I
which is present on all nucleated cell
● In infected cells MHC-I expression is
reduced inhibitory receptors are not
engaged cell is killed
3. Granulocytes–monocytes
● PMN: polymorphonuclear → nucleus can take up diff shapes
● Granulocytes: very fragile when taken out of the cell, but they lyse
quite rarely and mess up your whole system
● PBMC: peripheral blood mononuclear cells → granulocytes are
absent, present: monocytes, MP, T cells
4. The neutrophil
● Main cell of innate immunity & acute inflammation
● Rapidly recruited to site of infection
● In response to phagocytic stimulus undergo an oxidative
burst and degranulation
● The most abundant leukocytes in the blood (6k/microliter)
Functions
● Find: rolling, adhesion, transmigration (chemotaxis)
● Eat: phagocytosis
● Kill: ROS, Lysosomal enzymes
, Chemotaxis of neutrophils
Neutrophils follow chemical gradients to SOI
● soluble bacterial product (fMLP)
● Complement factors (C5a)
● Cytokines (IL-8)
● Leukotriene B4
Chemotactic factors bind to cell surface receptors
● Induce calcium mobilization
● Assembly of cytoskeletal contractile elements
EBV: epstein barr virus related to certain cancers. infectious
mononucleosis —> risk of MS (multiple sclerosis) doubles: 1 in 1000
Recognition of microbes
Pathogen associated molecular Patterns (PAMPs) → conserved molecular motifs shared
by classes of microbes e.g
● sugar residues (mannose)
● lipoproteins (lipopolysaccharide: LPS)
● Nucleotides (ssRNA dsDNA unmethylated nucleotides (CpG))
Pattern recognition receptors (PRR) → Diverse receptors to recognize PAMP
● e.g. Mannose receptors, toll-like receptors (LPS, CpG, viral DNA, viral RNA)
● Each individual has of fixed variety of PRRs (few genes, germline encoded)
● Non-clonal: all cells of a lineage express the same receptors
TLR: 3 locations
1. TLR on the cell surface membrane → recognises extracellular PAMP
2. TLR on the endosomal membrane → deals with viral DNA/RNA (intracellular
viral replication)
3. Cytosolic TLR:
● (NLR) NOD like receptors: not membrane bound, float in cytoplasm →
another monitoring system for what is going on inside
● (RLR) RIG like receptors → recognises viral RNA
only if it has 3 phosphate on it (more specific)
Effects of PRR activation
PAMP recognised by PRR induces kinase interactions which
will lead to transcription factors activation and thereby:
1. Enhanced phagocytosis → pathogen elimination
2. Cytokines and chemokines → communication
3. Co-stimulatory molecules → activation of adaptive immunity
4. Antigen presentation molecules → activation of adaptive immunity
5. Adhesion molecules → cell-cell interaction
Cytokines
● Large group of small molecules (±5-20 kD) important for cell communication and
signaling and cell movement
CD: Cluster of Differentiation
Techniques to diagnose and monitor disease
● Immunohistochemistry (IHC), Enzyme linked immunosorbent assay (ELISA), Flow cytometry
● Immunotherapy: Modulation of immunological effector functions to treat disease. Biologicals,
‘engineered’ antibodies
a. Flow cytometer: cell in solution, cell sucked up in small flow of liquid → measuring of cells that
are in fluid stream → cell passes a laser beam, and by the way that the light is spread you will
get size of the cell
b. FACS: fluorescence activated cell sorting —> we can sort cells based on the fluorescent colour
they are carrying. Eg. mark t cell green b cell red —> give these cells a charge and those
deflection. plates separate the cells —> separate tubes with different types of cells (sorting
bacteria etc)
Immunity
innate: rapid. TLR 4: recognizes LPS (lipopolysaccharide) on gram -
bacteria
Adaptive: APC presents small peptides in context of MHC to T cells or b
cells —> differentiation and proliferation
● generating new b and t cells specificities all the time (repertoire)
—> anticipatory system (wasteful), many of them are killed
(central tolerance prevent autoimmunity) —> evolutionarily
speaking it pays off
HLA (human leukocyte antigen): human specific MHC I & II —> sits
on the surface of human white blood cells
Antigen: structure that can induce antibody dependent response
Spleen: filters RBC due to signal from CD molecules (eat me)
Lymphocytes: B cell & T cell originates in bone marrow, but T cell matures in Thymus
Characteristics of foreign matter:
● Life form of infection: extracellular, intracellular
● Location of infection: gut, skin, blood
Challenges of immunity
A universe of microorganisms: Different structures, life-forms and size
Threat:
● Bacteria and viruses grow exponentially the body must respond in
time once an infection occurs
● Rapid evolution of microorganisms adaptable system necessary
● The immune system must accomplish this without destroying the
body itself (discrimination self/non-self)
Ineffective immunity: SCID (genetic disorder, absence of functional T
cells, prone to infections) and AIDS (caused by HIV targets immune cells (CD4+ T cells and DC) and
undermines immune function, susceptible to a variety of bacterial, fungal and viral infections)
,Hyperactive/incorrect immunity: asthma/allergies (uncontrolled allergic reactions to innocent
substances/allergens e.g., house dust mites), autoimmunity (immune reaction to self tissues due to
unbalanced immune regulation e.g., T1 diabetes, RA, etc)
Organisation of the immune system
● Prevention (barriers)
● Fast response (innate immunity)
● Extracellular (humoral immunity) and
intracellular (cellular immunity) microbes
● Adaption (adaptive immunity)
● Specificity (innate and adaptive)
Physical & chemical barriers → prevent infection
Physical barriers: Skin, respiratory tract, GI tract
● → Continuous epithelia protect against entry
of microbes
Chemical barriers: antibacterial enzymes in saliva, tears, mucus, plus stomach acid, gut bacteria
Innate immunity: first line of defense
● Initial & rapid response (hours)
● Limited specificity (PAMP → PRRs) – germline encoded
● Components: humoral (complement system, cytokines) & cellular (phagocytes–MP&NP– & NK
cells)
● Diversity: limited (fixed variety of PRRs)
● No memory → always responds in the same way
2 main functions of innate immunity
1. Elimination of insults: phagocytosis, lysis
2. Observation of insults: inflammation, activation of
adaptive immunity
Cells of innate immunity:
Functions: phagocytosis, APC, antigen transport, cytotoxicity, cytokine
mediated functions, etc
Components of innate immunity:
1. Complement system
● Humoral part of innate immunity
● Defense against extracellular pathogens
● Collection of circulating and membrane-associated proteins
● Many of these are proteolytic enzymes → enzymatic cascade
3 pathways: alternative, classical (IgM), lectin (MBL) → MAC
3 functions: inflammation, lysis of microbes, opsonization
2. NK cells
● are lymphocytes, but has no receptor (no TCR&BCR)
● respond to intracellular microbes
, ● Kill these cells directly
● Respond to IL-12 from macrophages
● Produce IFN-γ → IFN-γ activates
macrophages to kill phagocytosed
microbes
Mechanism (activation & inhibition)
● do not attack normal cells because of
inhibitory receptors
● Inhibitory receptors recognize MHC-I
which is present on all nucleated cell
● In infected cells MHC-I expression is
reduced inhibitory receptors are not
engaged cell is killed
3. Granulocytes–monocytes
● PMN: polymorphonuclear → nucleus can take up diff shapes
● Granulocytes: very fragile when taken out of the cell, but they lyse
quite rarely and mess up your whole system
● PBMC: peripheral blood mononuclear cells → granulocytes are
absent, present: monocytes, MP, T cells
4. The neutrophil
● Main cell of innate immunity & acute inflammation
● Rapidly recruited to site of infection
● In response to phagocytic stimulus undergo an oxidative
burst and degranulation
● The most abundant leukocytes in the blood (6k/microliter)
Functions
● Find: rolling, adhesion, transmigration (chemotaxis)
● Eat: phagocytosis
● Kill: ROS, Lysosomal enzymes
, Chemotaxis of neutrophils
Neutrophils follow chemical gradients to SOI
● soluble bacterial product (fMLP)
● Complement factors (C5a)
● Cytokines (IL-8)
● Leukotriene B4
Chemotactic factors bind to cell surface receptors
● Induce calcium mobilization
● Assembly of cytoskeletal contractile elements
EBV: epstein barr virus related to certain cancers. infectious
mononucleosis —> risk of MS (multiple sclerosis) doubles: 1 in 1000
Recognition of microbes
Pathogen associated molecular Patterns (PAMPs) → conserved molecular motifs shared
by classes of microbes e.g
● sugar residues (mannose)
● lipoproteins (lipopolysaccharide: LPS)
● Nucleotides (ssRNA dsDNA unmethylated nucleotides (CpG))
Pattern recognition receptors (PRR) → Diverse receptors to recognize PAMP
● e.g. Mannose receptors, toll-like receptors (LPS, CpG, viral DNA, viral RNA)
● Each individual has of fixed variety of PRRs (few genes, germline encoded)
● Non-clonal: all cells of a lineage express the same receptors
TLR: 3 locations
1. TLR on the cell surface membrane → recognises extracellular PAMP
2. TLR on the endosomal membrane → deals with viral DNA/RNA (intracellular
viral replication)
3. Cytosolic TLR:
● (NLR) NOD like receptors: not membrane bound, float in cytoplasm →
another monitoring system for what is going on inside
● (RLR) RIG like receptors → recognises viral RNA
only if it has 3 phosphate on it (more specific)
Effects of PRR activation
PAMP recognised by PRR induces kinase interactions which
will lead to transcription factors activation and thereby:
1. Enhanced phagocytosis → pathogen elimination
2. Cytokines and chemokines → communication
3. Co-stimulatory molecules → activation of adaptive immunity
4. Antigen presentation molecules → activation of adaptive immunity
5. Adhesion molecules → cell-cell interaction
Cytokines
● Large group of small molecules (±5-20 kD) important for cell communication and
signaling and cell movement
