1 Developing immune system
Infectious organisms
- Mircobiology: Virus, bacterica, fungi
- Parasitology: Protozoa, Metazoa
Immune system protection
An infection (with immune response) gives rise to an inflammatory response, but not every
inflammatory response is due to an infection.
First line of defence is the physical barrier (plus innate immune system), separating the extern from
the intern environment; epithelial and mucosa. The epithelia produced antimicrobial peptides (AMP)
which kills bacteria, fungi, and capsulated viruses by disrupting their membranes due to lysosomes.
The low pH present in sweat- and sebaceous glands has an antimicrobial function. The Langerhans
cells present in the epidermis are a source of dendritic skin cells.
1.1 Components of the immune system
Cellular immunity: T cell mediated response, active at location of antigen-presenting tissue (APC),
primarily driven by mature T cells , macrophages, and the release of cytokines in response to an
antigen; slow response, cell lysis and programmed death to intracellular pathogens and cancer cells,
MHC class I proteins involved.
Humoral immunity: antibody-mediated response, active in extracellular fluids, primarily driven by B
cell lymphocytes, fast response upon detection, antibody-mediated destruction or neutralization of
extracellular pathogens, MHC class II proteins involved.
Innate immune system: first line of defence, non-specific, immediately prevent spread pathogens (0-
96 hours), antigen independent:
Macrophage
- Cellular immunity, long living cells, APC
- Differentiated from monocytes (leukocytes), mostly present in the lungs (pulmonary
macrophage)
- Detecting, engulfing and destroying pathogens/apoptotic cells: phagocytosis
o Sentinel cell: sense and monitor the present of foreign material
- Main source of cytokines to activate and recruit other cells during inflammation (IL)
Cytokines
- Humeral immunity
- Mediate cell communication (autocrine, paracrine, endocrine)
o Inflammatory response: pro-/anti-inflammatory
o Signal transduction
- E.g IL-6 as a measure of inflammation
- Chemokines
o Chemoattractant cytokines, activated by chemical gradient (chemotaxis)
Chemokine directed cell migration to site of infection dependent of the
gradient of chemokines (they move to the highest concentration).
o Regulate lymphoid organ development and T-cell differentiation, mediate tumour
cell metastasis
1
, - Interferons (IFN)
o Specific antiviral cytokine, anti-intracellular
o Interfere viral replication
C reactive protein (CRP)
- Humeral immunity
- Regulator inflammatory processes (and important marker, mainly bacterial infections)
- Activates complement pathway, binds to Fc receptors and acts as an opsonin (opsonisation)
Complement pathway
- Activated by CRP
- Composed of peptides derived from the liver
- Induces inflammation (recruits phagocytes); C3a/C5a (chemotaxis) / Opsonisation; C3b
(labelling pathogens, ‘opsonizing flag’) / Lysis via the membrane attack complex (MAC)
- Complement routes
o Classic (adaptive): Antigen-antibody complexes with the antibody isotypes IgG and
IgM
o Alternative (innate): activated by C3 hydrolysis, foreign material, pathogens, or
damaged cells
o Lectine-mamose: Activated by carbohydrate binding (acute phase response)
All routes active C3-convertase which converts C3 into C3a and C3b
Mast cells
- Cellular immunity
- Responds to cytokines and complements C3a/C5a
- Granulated tissue cells that degranulate in response to tissue injury and initiate inflammatory
reactions trough vasoactive properties of histamine
- Produces histamine > vasodilation
- Already contains antibodies > fast reaction e.g. venom
Neutrophils
- Cellular immunity, granulocyte (lytic enzymes in granules)
- Respond to chemotaxis > phagocytosis bacteria to disrupt exponential growth (quick but shot
lived)
Eosinophils
- Cellular immunity, granulocyte
- Triggering of inflammatory responses in allergic disorders, defence against parasites
Basophils
- Cellular immunity, (largest) granulocyte with longest lifespan
- Play a role in viral infection
Natural killer cells (NK)
- Cellular immunity, response to chemotaxis (leukocyte)
- Activated by missing self: attacks cells that fail to express sufficient levels of MHC class I
molecules of the host > effector lymphocytes or apoptosis of antigens
2
, - Mainly viral infections or tumour cells (intracellular)
Dendritic cells
- Cellular immunity, APC cells
- Link innate and adaptive immunity
- Capture, process, and present antigens to adaptive immune cells and mediate their
polarization in effector cells
o Present processed antigen material on the cell surface and present to T cells
MHC1 (major histocompatibility complex) > CD8 T cell
MHC2 > CD4 T cell
- Activate T-cells; antigen presenting, co-stimulatory molecules, cytokine production
Adaptive immune system: acquired/specific immunity, long term response (>96 hours), antigen
dependent:
T cells / T lymphocytes:
- Cd4 T cells
o Cellular immunity
o T helper cells
o Th2 cell
Help B lymphocytes and produce antibodies
IL-5 / IL-13 / IL-4
Parasitic infections
Activating eosinophils
Increase peristalsis
o Th17 cell
Mucosal / skin
Extracellular
Activating phagocytosis (IL-17)
o Th1 cell
Mediate inflammatory reactions and immunity to intracellular microees
Producing cytokines for macrophages activation
INF-gamma
- CD8 T cells
o Cellular immunity
o Cytotoxic T cells
o Kills infected cells
o Difference between NK cells, CD8 will become memory cells
- Regulatory T cells
B cells / B lymphocytes
- Humeral immunity, APC
- Activated by Th2 cells and antigens (free floating)
- Produce antibody molecules
- Participate in T-cell activation via APC, stimulation and cytokine production
- Can turn into 2 types
o Plasma cell: Mostly bone marrow
o Memory B/T cell: Mostly bone marrow, or circular
3
, Antibodies
- Humeral immunity
- Opsonisation
- Complement activation
- Neutralisation
- APC
- IgM: 1st ones present, measurement recent infection or not, complement activation
- IgA: isotype switching (only with T cell help), for mucosal defence, neutralisation
- IgE: activates mast cells, parasitic infections/allergies
- IgG: [ ] systemic, placental absorption, has all functions
2 Journal club developing immune system
Mendelian inheritance patterns: Autosomal dominant inheritance, autosomal recessive inheritance,
X-linked inheritance and complex inheritance.
Segregation analysis = Transforming genetic models to data of the phenotype of biological family
members. This to hypothesize the way of inheritance regarding the trait or disease studied. Checking
whether the variant segregates into other family members.
Patter recognition receptors (PRR): A receptor class which can directly recognize ligands of
pathogen, apoptotic host cells, and damaged senescent cells. They are the bridge between
nonspecific and specific immunity. In the innate immune system, the PPRs can be separated in 5
classes based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization
domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type
lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs).
Pathogen-associated molecular patterns (PAMP): highly conserved molecular structures of
pathogenic microorganisms (lipids, proteins, nucleic acids (e.g. lipopolysaccharides (LPS), lipoteichoic
acid (LTA), and bacterial DNA). They are essential for pathogen survival. Due to their distinct unique
molecular or subcellular characteristics, they are separatable from host cells. Via the PRRs, the
immune cells identify and respond to these PAMPs.
Toll-like receptors: membrane-bound signal receptors, with two general functions; to bind
specifically to the ligand, and to transmit signals. The initiated signal transduction will amplify the
effect of anti-pathogen infection, so that the inflammatory response immune cells can be activated,
and produce and secrete a variety of pro-inflammatory and antiviral factors. They are both of cell
surface and inside the cells (intercellular bacteria). (mostly innate immune system)
3 The neonatal immune system
Under 1 y/o and under 5 y/o, are specific ages for some diseases. Why specific infections in children?
Immune system less developed, easier exposed, more contact (e.g. nappies, unclean surfaces), …
This doesn’t mean that the immune system is immunocompromised in children or deficient, the
system is just not matured yet, it is correct for that phase of life.
The neonatal immune system is formed by multiple factors: innate immune system, maternal
antibodies (+/- 3 months), vaccinations, breastfeeding, c-section or natural birth related to the
microbiome, intrauterine infections.
4
Infectious organisms
- Mircobiology: Virus, bacterica, fungi
- Parasitology: Protozoa, Metazoa
Immune system protection
An infection (with immune response) gives rise to an inflammatory response, but not every
inflammatory response is due to an infection.
First line of defence is the physical barrier (plus innate immune system), separating the extern from
the intern environment; epithelial and mucosa. The epithelia produced antimicrobial peptides (AMP)
which kills bacteria, fungi, and capsulated viruses by disrupting their membranes due to lysosomes.
The low pH present in sweat- and sebaceous glands has an antimicrobial function. The Langerhans
cells present in the epidermis are a source of dendritic skin cells.
1.1 Components of the immune system
Cellular immunity: T cell mediated response, active at location of antigen-presenting tissue (APC),
primarily driven by mature T cells , macrophages, and the release of cytokines in response to an
antigen; slow response, cell lysis and programmed death to intracellular pathogens and cancer cells,
MHC class I proteins involved.
Humoral immunity: antibody-mediated response, active in extracellular fluids, primarily driven by B
cell lymphocytes, fast response upon detection, antibody-mediated destruction or neutralization of
extracellular pathogens, MHC class II proteins involved.
Innate immune system: first line of defence, non-specific, immediately prevent spread pathogens (0-
96 hours), antigen independent:
Macrophage
- Cellular immunity, long living cells, APC
- Differentiated from monocytes (leukocytes), mostly present in the lungs (pulmonary
macrophage)
- Detecting, engulfing and destroying pathogens/apoptotic cells: phagocytosis
o Sentinel cell: sense and monitor the present of foreign material
- Main source of cytokines to activate and recruit other cells during inflammation (IL)
Cytokines
- Humeral immunity
- Mediate cell communication (autocrine, paracrine, endocrine)
o Inflammatory response: pro-/anti-inflammatory
o Signal transduction
- E.g IL-6 as a measure of inflammation
- Chemokines
o Chemoattractant cytokines, activated by chemical gradient (chemotaxis)
Chemokine directed cell migration to site of infection dependent of the
gradient of chemokines (they move to the highest concentration).
o Regulate lymphoid organ development and T-cell differentiation, mediate tumour
cell metastasis
1
, - Interferons (IFN)
o Specific antiviral cytokine, anti-intracellular
o Interfere viral replication
C reactive protein (CRP)
- Humeral immunity
- Regulator inflammatory processes (and important marker, mainly bacterial infections)
- Activates complement pathway, binds to Fc receptors and acts as an opsonin (opsonisation)
Complement pathway
- Activated by CRP
- Composed of peptides derived from the liver
- Induces inflammation (recruits phagocytes); C3a/C5a (chemotaxis) / Opsonisation; C3b
(labelling pathogens, ‘opsonizing flag’) / Lysis via the membrane attack complex (MAC)
- Complement routes
o Classic (adaptive): Antigen-antibody complexes with the antibody isotypes IgG and
IgM
o Alternative (innate): activated by C3 hydrolysis, foreign material, pathogens, or
damaged cells
o Lectine-mamose: Activated by carbohydrate binding (acute phase response)
All routes active C3-convertase which converts C3 into C3a and C3b
Mast cells
- Cellular immunity
- Responds to cytokines and complements C3a/C5a
- Granulated tissue cells that degranulate in response to tissue injury and initiate inflammatory
reactions trough vasoactive properties of histamine
- Produces histamine > vasodilation
- Already contains antibodies > fast reaction e.g. venom
Neutrophils
- Cellular immunity, granulocyte (lytic enzymes in granules)
- Respond to chemotaxis > phagocytosis bacteria to disrupt exponential growth (quick but shot
lived)
Eosinophils
- Cellular immunity, granulocyte
- Triggering of inflammatory responses in allergic disorders, defence against parasites
Basophils
- Cellular immunity, (largest) granulocyte with longest lifespan
- Play a role in viral infection
Natural killer cells (NK)
- Cellular immunity, response to chemotaxis (leukocyte)
- Activated by missing self: attacks cells that fail to express sufficient levels of MHC class I
molecules of the host > effector lymphocytes or apoptosis of antigens
2
, - Mainly viral infections or tumour cells (intracellular)
Dendritic cells
- Cellular immunity, APC cells
- Link innate and adaptive immunity
- Capture, process, and present antigens to adaptive immune cells and mediate their
polarization in effector cells
o Present processed antigen material on the cell surface and present to T cells
MHC1 (major histocompatibility complex) > CD8 T cell
MHC2 > CD4 T cell
- Activate T-cells; antigen presenting, co-stimulatory molecules, cytokine production
Adaptive immune system: acquired/specific immunity, long term response (>96 hours), antigen
dependent:
T cells / T lymphocytes:
- Cd4 T cells
o Cellular immunity
o T helper cells
o Th2 cell
Help B lymphocytes and produce antibodies
IL-5 / IL-13 / IL-4
Parasitic infections
Activating eosinophils
Increase peristalsis
o Th17 cell
Mucosal / skin
Extracellular
Activating phagocytosis (IL-17)
o Th1 cell
Mediate inflammatory reactions and immunity to intracellular microees
Producing cytokines for macrophages activation
INF-gamma
- CD8 T cells
o Cellular immunity
o Cytotoxic T cells
o Kills infected cells
o Difference between NK cells, CD8 will become memory cells
- Regulatory T cells
B cells / B lymphocytes
- Humeral immunity, APC
- Activated by Th2 cells and antigens (free floating)
- Produce antibody molecules
- Participate in T-cell activation via APC, stimulation and cytokine production
- Can turn into 2 types
o Plasma cell: Mostly bone marrow
o Memory B/T cell: Mostly bone marrow, or circular
3
, Antibodies
- Humeral immunity
- Opsonisation
- Complement activation
- Neutralisation
- APC
- IgM: 1st ones present, measurement recent infection or not, complement activation
- IgA: isotype switching (only with T cell help), for mucosal defence, neutralisation
- IgE: activates mast cells, parasitic infections/allergies
- IgG: [ ] systemic, placental absorption, has all functions
2 Journal club developing immune system
Mendelian inheritance patterns: Autosomal dominant inheritance, autosomal recessive inheritance,
X-linked inheritance and complex inheritance.
Segregation analysis = Transforming genetic models to data of the phenotype of biological family
members. This to hypothesize the way of inheritance regarding the trait or disease studied. Checking
whether the variant segregates into other family members.
Patter recognition receptors (PRR): A receptor class which can directly recognize ligands of
pathogen, apoptotic host cells, and damaged senescent cells. They are the bridge between
nonspecific and specific immunity. In the innate immune system, the PPRs can be separated in 5
classes based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization
domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type
lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs).
Pathogen-associated molecular patterns (PAMP): highly conserved molecular structures of
pathogenic microorganisms (lipids, proteins, nucleic acids (e.g. lipopolysaccharides (LPS), lipoteichoic
acid (LTA), and bacterial DNA). They are essential for pathogen survival. Due to their distinct unique
molecular or subcellular characteristics, they are separatable from host cells. Via the PRRs, the
immune cells identify and respond to these PAMPs.
Toll-like receptors: membrane-bound signal receptors, with two general functions; to bind
specifically to the ligand, and to transmit signals. The initiated signal transduction will amplify the
effect of anti-pathogen infection, so that the inflammatory response immune cells can be activated,
and produce and secrete a variety of pro-inflammatory and antiviral factors. They are both of cell
surface and inside the cells (intercellular bacteria). (mostly innate immune system)
3 The neonatal immune system
Under 1 y/o and under 5 y/o, are specific ages for some diseases. Why specific infections in children?
Immune system less developed, easier exposed, more contact (e.g. nappies, unclean surfaces), …
This doesn’t mean that the immune system is immunocompromised in children or deficient, the
system is just not matured yet, it is correct for that phase of life.
The neonatal immune system is formed by multiple factors: innate immune system, maternal
antibodies (+/- 3 months), vaccinations, breastfeeding, c-section or natural birth related to the
microbiome, intrauterine infections.
4
