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Where and how do all these things take place?
B – CELL ACTIVATION Where and how do all these things take place?
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B-cell recycling in the absence of antigen
(lymph node) B cells in blood T cell area B cell area Efferens lymph
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Recirculating B cells are trapped by foreign antigens in lymphoid organs
B cells leave blood & enter lymph node via high endothelial venules B cells proliferate rapidly Antigen enters node in afferent lymphatic Y Germinal centre releases B cells that differentiate into plasma cells GERMINAL CENTRE Transient structure of Intense proliferation
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FDC depends on the presence of
Antigen is bound on the surface of follicular dendritic cells (FDC) FDC FDC bind immune complexes (Ag-Ab ) Ag detectable for 12 months following immunization A single cell binds various antigens FDC depends on the presence of TNF-α, LTα, LTβ B cells recognize Ag on the surface of FDC This concept is being challenged now, and there has been some backtracking in the current text. It is possible that the FDCs provide persistent Ag to long-lived plasma cells. On the surface of FDC immune complexes form the so-called iccosomes that can be released and taken up later by the surrounding germinal center B cells
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„Dating” in the peripheral lymphoid organs
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The structure of the germinal centre
Somatic hypermutation LZ FDC DZ Somatic hypermutation LZ: light zone DZ: dark zone FDC: follicular dendritic cell
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IMMUNOLOGICAL MEMORY – B CELLS
Germinal Centre reaction proliferation somatic hypermutation affinity maturation Memory B cells previously activated passed affinity maturation present in the circulation rapidly proliferate and differentiate to plasma cell upon re-activation, or enter the GC reaction again Plasma cells provides serological memory: pre-existing neutralizing Abs to pathogens or toxins B B FDC B FDC B T B B B B B B plasma cell B B B B B T B
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Somatic hypermutation
Selection Repeated cycle Somatic hypermutation 9
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T CELL DEPENDENT B CELL ACTIVATION IN LYMPHOID ORGANS
BLIMP expresszió B-lymphocyte induced maturation protein IgM IgG IgA IgE
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Regulation of memory vs plasma cell differentiation
B cell T cell - activated Bcl-6 szuppresszor BLIMP gátló CD40 signaling 11
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DEVELOPMENT OF B CELL MEMORY IN THE FOLLICLE
Memory B cell apoptosis T CD40 CD40L Follicular dendritic cell (FDC) FcR CD21 Ag NO Ag
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CELL INTERACTIONS IN PERIPHERAL LYMPHOID TISSUES
Marginal zone Arteriole Germinal center T cell area – PALS paracortex DC – T cell contact DC Proliferating B cells centroblasts T B B – T cell contact Somatic hypermutation Additional gene rearrangement Isotype switch Plasma cell differentiation Antibody production Memory B cells
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SELECTION OF HIGH AFFINITY B CELLS UPON INTERACTION WITH FOLLICULAR DENDRITIC CELLS
Inhibition of apoptosis Tight junction B cell VLA-4 LFA-1 VCAM-1 ICAM-1 BCR CD21 C3d
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INTERACTION OF ANTIGEN-SPECIFIC T AND B CELLS
FDC CD40 Fas B cell differentiation apoptosis CD40L FasL GC T cell B and T cells recognize the same antigen
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How antigen-specific Ab production is maintained?
MODEL 2. MODEL 1. memory B cell plasma cell Bystander help: Cross-reactive antigens TLR ligands Cytokines... Memory B cells continuously differentiate into plasma cells Long-lived plasma cells in the bone marrow MODEL 3. Repeated activation with the antigen drives B cell activation and plasma cell differentiation role of follicular dendritic cells in antigen storage (months-years?) Polio: reinfections with Sabin vaccine strain subclinical infections (Diphteria in 10% of the population) hidden antigens (Measles genes persist in neurons – can induce Subacute Sclerosing Panencephalitis)
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CELL INTERACTIONS IN THE PARACORTEX
DC CD40 CD40L Antigen recognition by B and T lymphocytes T cell MHC TCR B7 CD28 B cell
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RECEPTOR MEDIATED CELL ACTIVATION Conformational change
Ligand Ligand Cross - linking Conformational change SIGNAL SIGNAL
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CROSS – LINKING OF THE RECEPTOR INITIATES A SIGNALING CASCADE
ligand kinase activation phosphorylation recruitment of adaptors SIGNAL Gene transcription Activation of transcription factors
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THE IgM B-CELL RECEPTOR
a a THE IgM B-CELL RECEPTOR antigen binding mIg molecule H L V b a Ig-a/Ig-b heterodimer Signal transduction Lyn Kinases Syk Btk SHP-1 Phosphatases SLP-65/BLNK PLC HS1 Vav Adaptors + substrates
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SIGNALING UNITS OF THE B-CELL RECEPTOR
Ig-a/CD79a a b Y Ig-b/CD79b Ig domain + CHO ITAM ITAM: YxxL x7 YxxI ITAM: Immunoreceptor Tyrosine-based Activation Motif
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RECENT MODEL OF B-CELL RECEPTOR MEDIATED SIGNALING Subsequent activation of 2 kinases
1. Cross-linking Ag Lyn 2. Src-family kinase activation P and ITAM phosphorylation 3. Syk recruitment and activation Syk 4. SLP phosphorylation + Ca release SLP P Calcium release P = ITAM
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Main steps of B-cell signal transduction
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Activation of B-cells by receptor crosslinking
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Antigenic determinant C3d THE CO-STIMULATORY ROLE OF CR2 (CD21) COMPLEMENT RECEPTOR IN B – LYMPHOCYTES ANTIGEN CD21/CR2 CD19 Y TAPA=CD81 B-CELL Enhanced B-cell activation
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THE NEURAMIC ACID RECEPTOR CD22 INHIBITS ACTIVATION THROUGH THE A B-CELL RECEPTOR
Tissue cells Bacterium Mannose Neuraminic acid B Cell Antigen CD22 Inhibited B cell activation
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KINETICS OF LYMPHOCYTE ACTIVATION
ANTIGEN SIGNAL1. Nyugvó limfocita G0 sejtosztódás DNA synthesis Effector cell Memory cell Transport Membrane change RNA and protein synthesis Resting lymphocyte G0 Ko-receptor Adhesion molecule Cytokines SIGNAL2. Resting lymphocyte G0 PTK activation RNA synthesis Free Ca Protein synthesis Protein phosphorylation DNA synthesis Lymphoblast 0 10sec 1min 5min hr hrs hrs hrs
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ANTIBODY – METIDATED EFFECTOR FUNCTIONS
Neutralization – binding of the antibody inhibits the adhesion of the pathogen, its entry or multipolication Opsonization – binding of antibodies induces complement activation and promotes binding to immun cells through complement (CR1) and immunoglobulin binding (FcR) receptors Antibody isotypes differ in their complement activating and FcR binding capabilities
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EFFECTOR FUNCTIONS OF ANTIBODIES
INHIBITION Binding of bacteria to epithelial cells Binding of viruses to receptor Binding of bacterial toxins to target cells NEUTRALIZATION Small proportion of antibodies PLASMA CELL OPSONIZATION Binding of antibody increases phagocytosis FcR FcR CR1 Complement C3b COMPLEMENT ACTIVATION Opsonization by C3b PHAGOCYTES ENGULFMENT, DEGRADATION
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Models of Human Rhinovirus 14 neutralised by monoclonal antibodies
30 strongly neutralising McAb 60 strongly neutralising McAb Fab regions Human Rhinovirus 14 - a common cold virus 30nm Models of Human Rhinovirus 14 neutralised by monoclonal antibodies 60 weakly neutralising McAb Fab regions
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Electron micrographs of Antibodies and complement opsonising Epstein Barr Virus (EBV)
Negatively stained EBV EBV coated with antibodies and activated complement components EBV coated with a corona of anti-EBV antibodies
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T – CELLS PROMOTE B – CELL DIFFERENTIATION
ANTIGEN CYTOKINES PLASMA CELL ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY HOW T – CELLS RECOGNIZE ANTIGENS?
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