B Cell Differentiation, Activation, and Memory Generation

Are B cells that are exported from the bone marrow functionally mature or immature?

IMMATURE

What are the two subsets of immature B cells

Trasitional 1 and Transitional 2; differ in gene expression as they progress through the spleen for further maturation

What happens when T2 B cell completes maturation and is tested for autoreactivity?

will become B2 B cells (follicular B cells); tend to express antigen receptors that participate in immune response; will give rise to germinal center response

What is the germinal center response?

class switching and somatic hypermutation

What are B1 and marginal zone B cells used for?

used for recognizing carbohydrates; involved in T independent responses (B2 needs T cell help)

What are B2 B cells?

follicular B cells; most B cells will become this; T cell dependent

What do B1 B cells do?

found in gut and lungs; self-renewing; produced from fetal liver precurosors; express only IgM; focus on carbohydrates and fungi

What are marginal zone B cells?

goes through maturation in spleen; long lived and self renewing; produce mainly IgM; respond to carbohydrates and proteins

What is the clonal selection hypothesis?

each B cell bears a single type of Ig receptor; on stimulation, each cell will create a clone of cells bearing the same Ag receptor as the original

What is a germinal center?

structures that are generated in secondary lymphoid organs that promotes class switch high affinity humoral response

What is a T-dependent antigen?

peptides; follicular B cells typically respond to this type of antigen; have normal 3 signals

What is a T-independent antigen?

TI-1 and TI-2; have signals that replaces the need of a T cell for B cell activation

What is the difference between TI-1 and TI-2?

TI-1 Ag bind to B cells through PRRs and mlgs; TI-2 cross-link large numbers of BCRs

Describe a T dependent B cell response

B cell binds Ag via BCR; induces activation and proliferation (formation of germinal centers); some Ag is internalized and processed (presented on cell surface in MHC Class II molecules); interaction with helper T cells provides conditions for differentiation and memory cell production

What are the three outcomes of B cells that undergo a T dependent response?

plasma cell (IL-6), class-switched memory B cell, and IgM+, IgD- memory B cell

What does IL-21 do?

improves binding of T cell to B cell in T cell dependent responses

What are the three outcomes of somatic hypermutations in T cell dependent response?

low affinity binding so goes through apoptosis, improved affinity for binding (gives three outcomes listed earlier), or autoreactive B cell is made so it goes through apoptosis

How do B cells interact with Ag in the lymph nodes/spleen?

small soluble Ag from lymphatic circulation by follicular B cells; large Ag captured by subcapsular sinus macrophages and handed off to B cells in the follicles; follicular dendritic cells (FDCs) serve as Ag concentration site for future selection and differentiation

What happens when B cell recognizes cell-bound Ag?

results in membrane spreading; initial interactions induce a clustering of BCRs and their cognate antigens; next, the B cell rapidly spreads over teh target membrane before contracting back

What causes clustering of B cell receptors upon Ag binding?

Ag binding induces conformational change in Cu4 domain; this causes oligomerization of Ag-bound IgM molecules in the plane of the membrane; the molecules move into lipid rafts of the membrane (allows association of BCR signaling molecules, triggering B cell signaling cascades)

What does Ag receptor clustering induce?

internalization and Ag presentation by B cell; once signaling begins, BCR-Ag complexes are internalized; internalize Ag are processed in exogenous pathway; Ag peptide fragments are presented in MHC Class II molecules on the B cell surface to solicit T cell help

Where do B cells migrate to once they are activated?

spleen (interfollicular zone) to find antigen specific T cells; where co-stimulation will take place and creation of germinal centers, class switch, and somatic hypermutation

Describe the initiation of the germinal center reaction and formation of mature GC

once B cell and T cell interact, they will migrate into interfollicular zone to activate B cell and to provide co-stimulation; germinal center will form and expand through the days; there is a light zone (T follicular helper cells and FDCs, class switching and T cell B cell interaction (CD40/CD40L interaction)) and dark zone (B cells only, somatic hypermutation); B cells will express genes that give the signal that they have gone from naive B cell to germinal center B cell

What genes are important for transitioning from a naive B cell to a germinal B cell?

BCL-6 (enforces germinal center phenotype), PAX-5, BLIMP-1 (drives differentiation into plasma cell), XPB-1

What exactly does somatic hypermutation do in the germinal center?

SHM produces individual point mutation in heavy and light chain rearrangements; mutations increases over time and with repeated exposures; AID is in charge of this

What exactly does somatic class switch recombination do in the germinal center?

recombination occurs between donor and acceptor switch regions; tandem repeats of short, G-rich sequences; contain targeting sites for AID; occurs within the GC after antigen contact

What determines the fate of Ag-activated B cells?

transcription factors; Pax5 and BCL-6 promote germinal center B cells; BLIMP-1 and IRF-4 promote plasma cell outcome

What is APRIL AND BCMA?

binds to receptors on soluble cells (plasma cells) to promote their survival

What is a plasmablast?

immature plasma cell that are short lived and produced quickly during immune response

Why is IgG in high quantity and have high affinity during the secondary response?

because memory cells can make a very quick and effective immune response