ADVANCED MOLECULAR IMMUNOLOGY
INTRODUCTION 4-9-2023
Recognition mechanisms of innate immunity Recognition mechanisms of adaptive immunity
Fast (hours) Slow (days to weeks)
Fixed Variable
Limited number of specificities Numerous highly selective specificities
Constant during response Improve during response
Innate cells can distinguish ‘’self’’ and ‘’non-self’’
Macrophage receptors recognize the cell surface carbohydrates of bacterial cells but not those of human cells
Natural killer cell receptors recognize changes at the surface of human cells that are caused by viral infection
Innate response to pathogens: various receptors involved in phagocytosis and signalling
Phagocytosis
- macrophage receptors that recognize components of microbial surfaces
- micro-organisms are bound by phagocytic receptors on the macrophage surface
Signalling
- structure of Toll-like receptor: contains an intracellular TIR domain
(C-terminus) and extracellular pathogen-recognition domain (N
terminus)
Innate response to degradation and innate cell activation:
- binding of bacteria of phagocytic receptors on macrophages induces
their engulfment and degradation
- binding of bacterial components to signalling receptors on
macrophages induces the synthesis of inflammatory cytokines
Adaptive immunity starts in secondary lymphoid organs → immune cells travel from lymph nodes through
veins and efferent lymphatic system to the heart, they travel back from the heart to the lymph nodes through
arteries and afferent lymphatic system
,Macrophages and DCs take up the pathogen, pathogen-carrying cells travel through the afferent lymphatic
system to the lymph nodes where they present the antigen to the adaptive immune system
Dendritic cells in peripheral tissue are immature, they are good at phagocytosis → increase expression of
lysosomal protein. After uptake of antigen, the DCs are activated, start migrating through the lymphatic
circulation while maturing. During maturation, the ability to present antigen increases and ability to
phagocytose decreases. In the lymphoid tissues the mature DCs present antigens to the adaptive immune cells
Complement: opsonisation of bacteria with specific antibodies → attracts immune cells
resulting in phagocytosis and destruction → phagocytosis occurs readily when bacteria
are covered in antibodies
Antibodies contain a constant and variable region, the variable region contains the
antigen-binding sites
Opsonization: coverage with antibodies to increase attraction
→ complement further stimulates phagocytosis
Activation of complement system without opsonization; activation of complement can
also be when you have extracellular particles, which are recognized by IgM, that then
changes its confirmation and forms a binding site → does not bind to bacteria but to
cells directly to activate the complement system → no opsonization
Complement factors:
- factors present in serum, lymph, and extracellular fluids
- synthesized by the liver
- bind pathogens, causing them to undergo phagocytosis
- without these factors, many bacteria would not be phagocytosed
,After antigen recognition, T and B cells become effector cells that either secrete soluble factors or produce
antibodies
B lymphocytes are generated in the bone marrow, T lymphocytes are generated in the thymus
Specificity of the antigen receptor is different for each lymphocyte, but the receptors on individual
lymphocytes are identical
Required for rearrangement of immunoglobulin genes: RAG enzyme expression (recombination-activating
genes), only lymphocytes express RAG enzymes
B cell receptor diversity
- gene rearrangement gives diversity
- more diversity during immune response by somatic hypermutation:
high-affinity antibodies are selected
during maturation in germinal centres (affinity maturation)
B lymphocytes/B cells differentiate either towards antibody-secreting plasma cells or memory B cells. Upon
reinfection, memory B cells are triggered, after which they start acting as plasma cells
T cell receptor diversity
- by gene rearrangement in the thymus
T cells recognize antigenic peptides and HLA (MHC)
pathogen protein in cell → antigen processing by breakdown of protein → presentation
of peptide by MHC molecule → recognition of antigen MHC complex by T cell receptor
(TCR)
Major Histocompatibility Complex (MHC) – (Human Leukocyte Antigens HLA)
Two classes:
- MHCI (HLA class I)
- MHCII (HLA class II)
Antigenic peptides are situated in antigen binding sites non-covalently
Peptides in antigen binding site: 9 amino acids on average
MHCI and MHCII molecules present peptides from different cellular compartments:
- MHCI from cytosol (green)
- MHCII from phagosomes → lysosomes → class II compartment (red)
, Dendritic cells take up bacterial antigens in the skin and then move to enter a draining lymphatic vessel
→ DCs bearing antigen enter the draining lymph node, where they settle in the T cell areas → naïve T
cells monitor antigens presented by DCs, naïve T cells recirculate through secondary lymphoid organs
Three signal paradigm:
1. Antigen recognition through MHC
2. Co-stimulation
3. Cytokines
Two signals are needed to active naïve T cells:
1. Recognition peptide in MHC
2. Co-stimulation → T cells that recognize self-antigens in absence of co-stimulation become anergic
Signal 3: cytokines → Th subset specification
CD8+ T cells become cytotoxic effector cells, CD4+ T cells can differentiate into different subsets of effector
cells under influence of these cytokines
Effector CD4 T cells: Th1, Th17, Th2, Tfh and T regulatory cells (Treg)
Co-stimulation is only required during activation of naïve T cells
INTRODUCTION 4-9-2023
Recognition mechanisms of innate immunity Recognition mechanisms of adaptive immunity
Fast (hours) Slow (days to weeks)
Fixed Variable
Limited number of specificities Numerous highly selective specificities
Constant during response Improve during response
Innate cells can distinguish ‘’self’’ and ‘’non-self’’
Macrophage receptors recognize the cell surface carbohydrates of bacterial cells but not those of human cells
Natural killer cell receptors recognize changes at the surface of human cells that are caused by viral infection
Innate response to pathogens: various receptors involved in phagocytosis and signalling
Phagocytosis
- macrophage receptors that recognize components of microbial surfaces
- micro-organisms are bound by phagocytic receptors on the macrophage surface
Signalling
- structure of Toll-like receptor: contains an intracellular TIR domain
(C-terminus) and extracellular pathogen-recognition domain (N
terminus)
Innate response to degradation and innate cell activation:
- binding of bacteria of phagocytic receptors on macrophages induces
their engulfment and degradation
- binding of bacterial components to signalling receptors on
macrophages induces the synthesis of inflammatory cytokines
Adaptive immunity starts in secondary lymphoid organs → immune cells travel from lymph nodes through
veins and efferent lymphatic system to the heart, they travel back from the heart to the lymph nodes through
arteries and afferent lymphatic system
,Macrophages and DCs take up the pathogen, pathogen-carrying cells travel through the afferent lymphatic
system to the lymph nodes where they present the antigen to the adaptive immune system
Dendritic cells in peripheral tissue are immature, they are good at phagocytosis → increase expression of
lysosomal protein. After uptake of antigen, the DCs are activated, start migrating through the lymphatic
circulation while maturing. During maturation, the ability to present antigen increases and ability to
phagocytose decreases. In the lymphoid tissues the mature DCs present antigens to the adaptive immune cells
Complement: opsonisation of bacteria with specific antibodies → attracts immune cells
resulting in phagocytosis and destruction → phagocytosis occurs readily when bacteria
are covered in antibodies
Antibodies contain a constant and variable region, the variable region contains the
antigen-binding sites
Opsonization: coverage with antibodies to increase attraction
→ complement further stimulates phagocytosis
Activation of complement system without opsonization; activation of complement can
also be when you have extracellular particles, which are recognized by IgM, that then
changes its confirmation and forms a binding site → does not bind to bacteria but to
cells directly to activate the complement system → no opsonization
Complement factors:
- factors present in serum, lymph, and extracellular fluids
- synthesized by the liver
- bind pathogens, causing them to undergo phagocytosis
- without these factors, many bacteria would not be phagocytosed
,After antigen recognition, T and B cells become effector cells that either secrete soluble factors or produce
antibodies
B lymphocytes are generated in the bone marrow, T lymphocytes are generated in the thymus
Specificity of the antigen receptor is different for each lymphocyte, but the receptors on individual
lymphocytes are identical
Required for rearrangement of immunoglobulin genes: RAG enzyme expression (recombination-activating
genes), only lymphocytes express RAG enzymes
B cell receptor diversity
- gene rearrangement gives diversity
- more diversity during immune response by somatic hypermutation:
high-affinity antibodies are selected
during maturation in germinal centres (affinity maturation)
B lymphocytes/B cells differentiate either towards antibody-secreting plasma cells or memory B cells. Upon
reinfection, memory B cells are triggered, after which they start acting as plasma cells
T cell receptor diversity
- by gene rearrangement in the thymus
T cells recognize antigenic peptides and HLA (MHC)
pathogen protein in cell → antigen processing by breakdown of protein → presentation
of peptide by MHC molecule → recognition of antigen MHC complex by T cell receptor
(TCR)
Major Histocompatibility Complex (MHC) – (Human Leukocyte Antigens HLA)
Two classes:
- MHCI (HLA class I)
- MHCII (HLA class II)
Antigenic peptides are situated in antigen binding sites non-covalently
Peptides in antigen binding site: 9 amino acids on average
MHCI and MHCII molecules present peptides from different cellular compartments:
- MHCI from cytosol (green)
- MHCII from phagosomes → lysosomes → class II compartment (red)
, Dendritic cells take up bacterial antigens in the skin and then move to enter a draining lymphatic vessel
→ DCs bearing antigen enter the draining lymph node, where they settle in the T cell areas → naïve T
cells monitor antigens presented by DCs, naïve T cells recirculate through secondary lymphoid organs
Three signal paradigm:
1. Antigen recognition through MHC
2. Co-stimulation
3. Cytokines
Two signals are needed to active naïve T cells:
1. Recognition peptide in MHC
2. Co-stimulation → T cells that recognize self-antigens in absence of co-stimulation become anergic
Signal 3: cytokines → Th subset specification
CD8+ T cells become cytotoxic effector cells, CD4+ T cells can differentiate into different subsets of effector
cells under influence of these cytokines
Effector CD4 T cells: Th1, Th17, Th2, Tfh and T regulatory cells (Treg)
Co-stimulation is only required during activation of naïve T cells
