B cell activations

B Cell Activation

Yoavanit Srivaro M.D.

Outlines

• Overview of humoral immune responses

• Antigen recognition and antigen induced B cell activation

• Helper T Cell-dependent antibody responses to protein antigens

• Antibody responses to T-independent antigens

Outlines





FIGURE 12-1 Phases of the humoral immune response.

Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.













FIGURE 12-2 .Primary and secondary humoral immune responses.


























FIGURE 12-3 Distinct B cell subsets mediate different types of antibody responses.






Outlines





Antigen recognition and antigen induced B cell activation

• Antigen Capture and Delivery to B Cells

• Activation of B Cells by Antigens and Other Signals

• Functional Responses of B Cells to Antigens

FIGURE 12-4 Pathways of antigen delivery to follicular B cells.
















FIGURE 7-18 B cell antigen receptor complex..






FIGURE 7-19 Signal transduction by the BCR complex.












FIGURE 12-5 Role of CR2 and Toll-like receptors in B cell activation.






















FIGURE 12-6 Functional responses induced by antigen-mediated cross-linking of the BCR complex.







Outlines





Helper T Cell-dependent antibody responses to protein antigens

• The Sequence of Events During T Cell–Dependent Antibody Responses

• Initial Activation and Migration of Helper B Cells and T Cells

• Antigen Presentation by B Cells and the Hapten-Carrier Effect

• Role of CD40L:CD40 Interaction in T-Dependent B Cell

Activation

• Extrafollicular B Cell Activation

• The Germinal Center Reaction






Activation



FIGURE 12-7 Sequence of events in humoral immune responses to T cell–dependent protein antigens.












Activation



FIGURE 12-8 Migration of B cells and helper T cells and T-B interaction.











Activation



FIGURE 12-9 Antigen presentation on B cells to helper Tcells.










Hapten-carrier effect

• First

: Hapten-specific B cells

: Protein (carrier)–specific helper T cells

• Second

: Hapten & carrier portions :physically linked

• Third

: Interaction is class II MHC restricted







Activation



FIGURE 12-10 Mechanisms of helper T cell–mediatedB cell activation.

FIGURE 12-10 Mechanisms of helper T cell–mediatedB cell activation.

FIGURE 7-24 Signaling through the TNF receptor can result in NF-κBand MAP kinase activation or in the induction of apoptotic death.




Latent membrane protein 1

of EBV



of EBV

Trigger B cell prolifertion



of EBV

Trigger B cell prolifertion

Lymphoma







Activation



Extrafollicular B Cell Activation

• Provides an early antibody response to protein antigens

• Produce low-affinity antibodies that can circulate and limit the spread of an infection

• Sets up the formation of the more slowly developing but more effective germinal center response


Extrafollicular B Cell Activation

• Helps generate follicular helper T cells (TFH cells) that migrate into the follicle

• The antibody-secreting cells that are generated in extrafollicular foci, including

1.Circulating plasmablasts

2.Tissue plasma cells







Activation



FIGURE 12-11 Germinal centers in secondary lymphoid organs.


FIGURE 12-12 The germinal center reaction in a lymph node.











• The Induction of Follicular Helper T Cells

• Heavy Chain Isotype (Class) Switching

• Affinity Maturation: Somatic Mutation of IgGenes and Selection of High-Affinity B Cells

• B Cell Differentiation into Antibody-Secreting Plasma Cells

• Generation of Memory B Cells

• Role of Transcriptional Regulators in Determining the Fate of Activated B Cells

FIGURE 12-13 Molecular events in follicular helper T cell generation.








Follicular helper T cell

• Secrete cytokines

1. IL-21

2. IFN-γ

3. IL-4

4. Low levels of IL-17

all of these cytokines participate in isotype switching

Interleukine-21

• Required for germinal center development

• Contributes to the generation of plasma cells in the germinal center reaction

• Facilitates germinal center B cell selection events and the differentiation of activated B cells into plasmablasts









FIGURE 12-14 Ig heavy chain isotype switching.






Selective deficiency of IgA production

• Inherit mutant versions of the TACI gene, which encodes a receptor for cytokines of the TNF family, BAFF and APRIL.


Figure 3-9 Diagram of human immunoglobulin (Ig) class switch recombination from IgM or IgD expression to IgE.

Jelinek DF.,Li JT. Middleton's Allergy ; 8th edition. 2014. p. 30-44

































Affinity Maturation: Somatic Mutation of IgGenes and Selection of High-Affinity B Cells

• First

: Clustered in the V regions

: Mostly in -binding CDR

• Second

: More mutations in IgG than in IgM

• Third

: Correlates with increasing affinities of the AB for the Ag that induced the response.


FIGURE 12-17 An overview of affinity maturation.


FIGURE 12-19 B cell selection in germinal centers.

Selection of High-Affinity B Cells

• First

:Antigen recognition by itself induces expression of anti-apoptotic proteins of the Bcl-2 family.

• Second

:High-affinity B cells will preferentially endocytose -->

--> Present antigen --> Interact with the limiting numbers of TFH --> Signal via CD40L --> Promote the survival of the B cells

• Third

:Some TFH cells express Fas ligand









B Cell Differentiation into Antibody-Secreting Plasma Cells

Short-lived plasma cells

• Generated during T-independent responses and early during T cell dependent responses in extrafollicular B cell foci

• Found in secondary lymphoid organs and in peripheral non-lymphoid tissues.

Long-lived plasma cells

• Generated in T-dependent

germinal center responses to protein antigens

• Signals from the B cell antigen receptor and IL-21 cooperate in the generation of plasma cells and their precursors, called plasmablasts.


FIGURE 2-8 Morphology of plasma cells.









Generation of Memory B Cells

• Generated during the germinal center

reaction and are capable of making rapid

responses to subsequent introduction of

antigen.









Role of Transcriptional Regulators in Determining the Fate of Activated B Cells

• Bcl-6

• Blimp-1

• IRF4


Outlines





Antibody responses to T-independent antigens

• Subsets of B Cells That Respond to T Independent Antigens

• Mechanisms of T-Independent Antibody Responses

• Protection Mediated by T-Independent Antibodies









Mechanisms of T-Independent Antibody Responses

• T-independent antigens are capable of stimulating B cell proliferation and differentiation in the absence of T cell help

• Most important TI antigens are :Polysaccharides

:Glycolipids

:Nucleic acids






Protection Mediated by T Independent Antibodies

• Bacterial cell wall polysaccharides

• Natural antibodies


Natural antibodies

• Low-affinity anti-carbohydrate antibodies

• Postulated to be produced by

1.Peritoneal B-1 cells

2.Marginal zone B cells in the spleen

• Protection against bacterial infections &Facilitate phagocytosis of apoptotic cells.

• Anti-ABO blood group antibodies



Thank You

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B cell activations