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Summary Immunology and Immunology & Disease
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Summary Immunology and Immunology & Disease
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Cellular and Molecular Immunology
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Summary immunology (NWI-BB019B)
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Summary Immunology - Biology year 2
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Immune system: protects your body from infectious agents and cancerKoch’s postulate
1. The germ is found in diseased but not healthy organisms
2. The germ can be isolated from the diseased organism
3. The germ causes disease when transferred
4. The germ can be isolated again
LYMPHOID TISSUES
Primary lymphoid tissue: bone marrow, thymus
Secondary lymphoid structures: spleen, lymph nodes: the lymph is filtered and inspected for
presence of pathogens
- initiation of adaptive immune responses takes place in the lymph nodes, lymph and lymphocytes
are then transported back via the thoracic duct into the bloodstream at the vena cava
- supply of antigen in epithelium (MALT (mucosa, M-cells)), lymph (lymph nodes) and blood (spleen)
Lymph node
- parafollicular cortex = paracortex = T cell zone
- B cell zone (secondary follicle) exist of germinal center and
mantle zone: memory B cell generation (IgM -> IgG) and
selection in germinal center
- medulla contains sinuses that collect the lymph again, ends in
the efferent lymphatic vessel
- high endothelial venule (HEV): naive lymphocytes enter the
lymph node from the bloodstream (physiological migration)
Spleen
- white pulp: contains lymphocytes
- red pulp (venous sinusoids + red pulp cords): where blood vessels open, here is blood present
- red pulp cords: contains macrophages, plasmacells, lymphocytes -> filter blood)
- periarteriolar lymphocyte sheath (PALS): contains T lymphocytes
- marginal zone: contains (memory) B lymphocytes, function not known
- primary follicle: contains B lymphocytes (secondary follicle: germinal center + mantle zone)
MIGRATION OF LYMPHOCYTES
Homing to lymph nodes:
1. Primary adhesion: L-selectin -> addressin (PNAd): reduces speed
- chemokines give high affinity of binding
2. Activation: chemokines activate integrins (LFA-1) on lymphocytes
,- bent integrin: low affinity
- extended integrin: high affinity
3. Stable interaction: LFA-1 -> ICAM-1 (on endothelial cell)
4. Diapedesis: cells migrate through intact walls of capillaries to HEV
5. Inside lymph node: CXCL13 interacts with CXCR5 on B cell (follicle),
CCL19/21 interacts with CCR7 on T-cell (paracortical area)
Recirculation of lymphocytes through lymph node
- free antigens go via afferent lymphatic vessel to B zone (follicle) in lymph node
- activated (mature) dendritic cell goes to T zone (paracortical area) in lymph node
- antigen present: activated T-cells (by DC) will express CXCR5 and activated B-cells (by free antigen)
will express CCR7 -> B and T cell meet in interface of B cell follicle by chemokines (CXCL13,
CCL19/21) attracting each other
Egress of lymphocytes from the lymph nodes: sphingosine-1-phosphate
- low S1PR1 expression in activated T cell due to CD69
- S1PR1 re-expression in effector T cell days after activation and in naïve T cell minutes to hours later
due to low S1P -> S1P induces leaving of activated T cell and non-activated naïve T cell
Migration of T-lymphocytes to tissue
- E- or P-selectin ligand on T-cell, CXCL10 (others) present, E- or P-selectin on endothelium
- integrin (LFA-1 or VLA-4) and CXCR3 (others) on T-cell, ICAM-1 or VCAM-1 on endothelium
- E- and P-selectin will be induced on the endothelium during the inflammatory response, by
cytokines produced by macrophages
- naïve T cells lack the capacity to interact with E-selectin or P-selectin, and can therefore not exit the
bloodstream
- after effector function, most T cells will enter apoptosis
CELLS OF THE INNATE IMMUNE SYSTEM
- epithelia: barrier function and production anti-microbial substances
- white blood cells (leucocytes): most important cells in the immune system, originate from the
hematopoietic stem cell, mature leucocytes often circulate the body using blood and lymph systems,
tissue also harbour a large number
of specialized tissue-resident
leucocytes
1. Macrophage (monocyte in
blood): phagocytosis of microbes
and dead cells and activation of
bactericidal mechanisms, antigen
presentation, are critical for tissue
repair processes
- M1 (classical): phagocytosis
- M2 (non-classical): repair, fibrosis
- TLR, cytokine receptor,
complement receptor
(phagocytosis of microbe into
phagosome)
- cytokine production to induce inflammation (TNF, IL-1, chemokines -> leukocyte recruitment;
IL-12 -> TH1 differentiation, IFN-γ production)
- phagocyte oxidase -> reactive (radical) oxygen species (ROS) -> killing of microbes (lysosomal-
,mediated destruction, proteolysis)
- iNOS -> nitric oxide (NO) (induced by TNF-β) -> killing of microbes
- tissue-resident cells (self-renewal), can differentiate to microglia (CNS), Kupffer cells (liver),
Alveolar macrophages (lung) and osteoclasts (bone)
2. Eosinophilic granulocyte: killing of antibody-coated parasites, present in mucosa of lung,
urogenital tract and gastrointestinal tract
3. Natural killer (NK) cell: releases lytic granules that kill some transformed (tumour/stressed cells)
or virus-infected cells, subtype of ILC1 (response against intracellular microbes), produce cytokines:
interferon IFN-γ (after receival of IL-12 from macrophage) for macrophage activation -> killing of
phagocytosed microbes
- IFN-γ promotes MHC-II presentation
- T lymphocyte-like cells, without T cell receptor
4. Dendritic cell: process extracellular antigens through pinocytosis for presentation to T cells, detect
tissue damage and presence of pathogens such as viruses, bacteria or fungi
- classical/conventional: primary function is the activation of naïve T cells
- plasmacytoid: anti-viral response via IFN type I production
5. Basophilic granulocyte: promotion of allergic responses, through IgE bound on its cell surface it
contributes to immunity against parasites, relatively rare
6. Neutrophilic granulocyte: phagocytosis and activation of bactericidal (killing) mechanisms, most
common leucocyte (polymorphonuclear neutrophilic granulocytes (PMN))
7. Mast cell: release of granules containing histamine and active agents, tissue resident cell of barrier
tissues (skin, lung mucosa, urogenital and GI tract), recognize parasites through IgE bound on its cell
surface (PMN)
(8). Innate lymphoid cells (ILCs): resemble T cells but do not have an antigen-specific receptor
- activated by cytokines and contribute to resistance to viruses and parasites
- different types of ILCs with different effector functions
Cytokines and chemokines: secreted, small signalling proteins (intercellular communicators)
- pleiotropic: different effects on different cells
- redundant: shared functions
- types: interleukins, interferons, chemokines
- mechanism: binding (dimer/trimer) to cell surface receptor -> signalling transduction cascade ->
transcriptional changes
- cytokines regulate their own receptor expression, high affinity of binding -> low concentrations are
effective
- tight regulation of cellular cytokine responses: feedback loops, decoy receptors, inhibitors
- receptors often oligomerization upon cytokine binding -> induces signalling
- individual receptor subunits shared by different cytokines
1. Local inflammation: by TNFα and IL-1 -> activation of endothelial cells and leukocytes
2. Systemic inflammatory effects: of TNFα, IL-1 and IL-6 on different organs (brain: fever, liver: acute
phase proteins (activate complement opsonization), bone marrow: leukocyte production)
Tumor Necrosis Factor (TNF) (interleukin): mediator of acute inflammation (bacteria, tissue damage)
- βα (prime member), TNF-β (lymphotoxin)
- main producer: activated macrophages
- trimer, 17 kDa monomer
- signal via TNF-receptor-associated-factors (TRAF) -> transcription factor activation, NF-κβ, AP-1
, -> upregulate inflammatory gene expression, apoptosis, endothelial activation
- excess amounts of TNF can induce shock, thrombosis and cachexia: septic shock (drop in bloodflow)
Interleukin-1 (IL-1): similar function to TNF-α (activation of DC?)
- cooperation between IL-1 and TNF-α
- also produced (next to activated macrophages) by many other activated cell types (unlike TNF):
polymorphonuclear neutrophilic granulocytes (PMN), endothelial and epithelial cells
- IL-1β activated by proteolysis (caspase 1, inflammasome)
- IL-1α also active without proteolysis
- IL-1 receptor -> MyD88 -> TRAF6 -> NF-κβ and AP-1 activation -> inflammatory gene expression,
endothelial activation (signals the same as many PRRs)
- complex regulation by: soluble IL-1 receptor antagonist (sIL-1RA), soluble IL-1 receptor, decoy
receptors -> critical cytokine: activity is tightly controlled at several levels
Humoral immune system
- complement system (I)
- anti-microbial peptides (I)
- antibodies (A) directed to extracellular pathogens (bacteria, parasites, fungi, parasitic worms
(helminths)
- vaccination: passive immunization: can be transferred directly by antibody transfer, does not
induce memory
Cellular immune system
- phagocytes: granulocytes, macrophages (I)
- antigen presentation: dendritic cells, macrophages (A)
- cytotoxicity: lymphocytes (A) directed to intracellular pathogens (viruses, bacteria, protozoa,
parasites)
- vaccination: requires active immunization: using dead or inactivated microbes (A), induces memory
INNATE IMMUNE SYSTEM
- specificity: groups of micro-organisms
- fast response, first defence
- always active and present
- encoded in the germline DNA
- memory response by epigenetic programming only (DNA modification -> changes in gene
expression -> increased strength ‘trained immunity’)
PRRs (pattern recognition receptors): recognize PAMPs and DAMPs
- PAMPs: pathogen-associated molecular pattern: molecular structures produced by groups/classes
of microbes (sugar residues (mannose), lipoproteins (LPS), nucleotides (ssRNA, dsDNA, unmethylated
nucleotides (CpG))) -> triggers inflammation upon infection
- DAMPs: damage-associated molecular patterns: molecules secreted by damaged, dead cells,
normally not exposed to immune cells as they are on the inside of healthy cells (DNA, RNA,
chromatin, ATP, mitochondrial components) -> triggers sterile inflammation
- some PPRs (CRP, MBL) are secreted and present in serum
- activation/binding leads to phagocytosis, antiviral state (if production of IFN type I genes (IFNα/β)),
acute inflammation or activation of acquired immune system (by production of pro-inflammatory
cytokines and chemokines (IL-1, TNFα, IL-6))
- PRRs are non-clonal: all cells of a lineage express the same receptors
- each individual has a fixed variety of PRRs (few genes, germline encoded)
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