B Cell Activation and Germinal Centers

B cells develop in stages: stem cell → pro B → pre B → immature B → mature B.
Mature B cells migrate through secondary lymphoid organs, surveying for antigens via BCR.
T-dependent antigens (protein antigens): Require two signals: BCR engagement (signal 1) and co-stimulation (signal 2) via CD40-CD40L and cytokines.
T-independent antigens (LPS or carbohydrates): Lead to B cell activation through direct BCR crosslinking; mostly IgM, modest affinity, no memory.
B cell activation involves Ig- $alpha$ and Ig- $beta$ chains with ITAMs that become phosphorylated initiating a signaling cascade. BCR co-receptor (CD121, CD19, CD181) is also involved.
Sequence of events for T-dependent B cell response: Antigen binds to BCR (signal 1), antigen is internalized and presented on MHC II to T helper cell. T cell activation leads to CD40L upregulation (signal 2) on B cell and cytokine production.

Germinal centers are sites in secondary lymphoid organs where B cells proliferate, differentiate, increase antibody affinity, and switch antibody classes.
They form after B cell activation by T-dependent antigens.
B cells enter lymph nodes via high endothelial venules (HEV) and proliferate rapidly.

Affinity maturation is the increase in average antibody affinity for its antigen.
It occurs in germinal centers through somatic hypermutation of Ig genes and selection of B cells with higher affinity for the antigen, presented by follicular dendritic cells.
High-affinity B cells become long-lived plasma cells and memory B cells.
Mutations target antigen-binding regions (CDRs) of the antibody, improving the fit for the antigen.

Somatic hypermutation occurs in germinal centers, generating point mutations in variable regions, especially CDRs.
AID (activation-induced cytidine deaminase) deaminates cytosine into uracil, leading to error-prone repair and mutations.
B cells with the best affinity survive and differentiate, while others undergo apoptosis.

Isotype switching is the mechanism by which antibodies with the same specificity are generated with different isotypes (e.g., IgM, IgG, IgA, IgE).
Enables antibodies to perform different functions.
Involves rearrangement of DNA using SWITCH regions, regulated by T cell cytokines.
Other Ig isotypes (IgG, IgA, IgE) are generated by Class-Switch Recombination (CSR) at Switch sites.

Plasma cells develop in secondary lymphoid organs and secrete antibodies.
Memory B cells are generated in germinal centers, isotype-switched, have higher affinity for the antigen, and are longer-lived.