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COMPONENTS OF THE BCR. Ig molecules do not have ITAMS. Ig a and Ig b have ITAMS. Ig molecules recognize antigen. Ig a and Ig b transduce signals. BCR CROSSLINKING INITIATES SIGNAL TRANSDUCTION. All isotypes of Ig initiate the same signal transduction cascade.
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COMPONENTS OF THE BCR Ig molecules do not have ITAMS Iga and Igb have ITAMS Ig molecules recognize antigen Iga and Igb transduce signals
BCR CROSSLINKING INITIATES SIGNAL TRANSDUCTION All isotypes of Ig initiate the same signal transduction cascade
BCR CLUSTERING LEADS TO ITAM PHOSPHORYLATION The first step: activation of tyrosine kinases blk, lyn, fyn The second step: blk, fyn or lyn phophorylate ITAM on Igb The third step: Syk docks on Igb and sets off the cascade
THE BCR SIGNALING CASCADE Clustering allows CD45 to activate blk, lyn, fyn Activated tyr kinases phosphorylate ITAMS Syc docks Signal cascade leads to gene transcription
THE BCR CO-RECEPTOR Signaling is enhanced by other proteins that associate with BCR Three components to the Co-receptor: CD19, CD21 (CR2), CD81 CD19 is the signaling component BCR associated lyn phosphorylates CD19
B CELL ACTIVATION REQUIRES TWO SIGNALS • Interaction with antigen initiates the antibody response • The second signal can be provided by an “armed” helper T cell • Some microbial antigens can provide both signal and are • T cell independent or TI antigens
TO PROVIDE HELP THE T CELL AND B CELL MUST RECOGNIZE THE SAME ANTIGEN The T cell and B cell recognize different parts of the same antigen T cells only recognize peptide (protein antigen)
T AND B CELL RECOGNITION OF BACTERIA The association of protein with bacterial polysaccharide allows a TD response
T-B Contact: • T cells “face” B cell • Contact prevents IL-4 from • assisting irrelevant B cells
T-B INTERACTION LEADS TO A PRIMARY FOCUS • B Cells can mature to plasma cells or • B cells can enter follicles and form a germinal center
T CELL PRODUCTS STIMULATE B CELL PROLIFERATION AND DIFFERENTIATION • CD40L (T) with CD40 (B) • IL-4 causes B cell proliferation and isotype switching • IL-5 and IL-6 are involved in maturation and Ig secretion • CD30 (B) with CD30L (T) • BLyS and its receptor TACI on B Cells TNF/TNF receptor family
B CELL MATURATION IS ASSOCIATED WITH CHANGES IN THE FORM OF EXPRESSED IMMUNOGLOBULIN M + ++++ +/- S - ++++ +++++++
M1 1 2 3 s ALL CH GENES ARE ORGANIZED SIMILARLY M1 M2 1 2 3 4 s Cm 1 2 3 4 M2 M1 s Ce 1 2 3 M1 M2 s Cg2b Ca
A. M1 1 2 3 s Ca sec AAAAAn mem AAAAAn B. M2 M1 1 2 3 4 s Cm sec AAAAAn mem AAAAAn MEMBRANE AND SECRETED FORMS OF Ig ARE GENERATED BY DIFFERENTIAL mRNA PROCESSING
Some of the B cells from the primary focus initiate a germinal center
CENTROBLASTS WITH HIGH AFFINITY BCR ARE RESCUED Survival signals can come from T cells or FDCs Most B cells die Surviving B cells can become plasma cells or memory cells
VDJ Cm Cd Cg3 Cg1 Cg2b Cg2a Ce Ca Sm Sg3 Sg1 Sg2b Sg2a Se Sa Ig3 Ig1 Ig2b Ig2a Ie Ia TGF-b+ LPS VDJ Cm Cd Cg3 Cg1 Cg2b Cg2a Ce Ca Sm Sg3 Sg1 Sg2b Sg2a Se Sa Ig3 Ig1 Ig2b Ig2a Ie Ia Sm/Sa Ia Cm Cd Ce VDJ Ca + Sm/Sa Cg3 Cg2a Cg1 Cg2b STEPS IN ISOTYPE SWITCHING