Immunology: Test 2 - B Cell Development

1. Repertoire assembly - generation of diverse and clonally expressed B-cell receptors in the bone marrow
2. Negative selection - alteration, elimination or inactivation of B-cell receptors that bind to components of the human body
3. Postive selection - promotion of a fraction of immature B cells to become mature B cells in the secondary lymphoid tissues
4. Searching for infection - recirculation of mature B cells between lymph, blood, and secondary lymphoid tissues
5. finding infection - activation and clonal expansion of B cells by pathogen-derived antigens in secondary lymphoid tissues
6. attacking infection - differentiation to antibody-secreting plasma cells and memory B cells in secondary lymphoid tissue

1. physical adhesion and signals through integrins: VLA-4:VCAM-1
2. provide cytokines (and other growth factors) and chemokines for recruitment and retention such as IL-7, SCF, SDF-1 (CXCL12)

1. stem cell
2. early pro-B cell
3. late pro-B cell
4. large pre-B cell
5. small pre-B cell
6. immature B cell
7. mature B cell

-programmed in the cell
- a balance between pro-apoptotic factors and anti-apoptotic factors
-apoptosis can be induced or inhibited
-mitochondran disfunction leads to caspase function which leads to cell death

-productively rearranged heavy chain associates with the surrogate light chain (before the If light chain gene is rearranged)
-pre-BCR signalling induces cell survival and allelic exclusion at the other heavy chain locus (RAG-1/2 gene expression is inhibited, closes the chomatin in heavy chain locus, reducing access to RAG-1/2)
-required for pre-B cellst o develop
-later recplaced by BCR -membrane-bound IgM associated with another membrane-boun dprotein heterodimer Ig-alpha/Ig-beta
-the ligand for the pre-BCR is itself - autonomous crosslinking

-cyoplasmic tails get closer, they move together in membrane to bind to common antigen

-allelic exclusion give homogenous B-cell recptors with high-avidity binding
-no allelic exclusion gives heterogeneous B-cell receptors with low-avidity binding

-large pre-B cells go through 5-6 rrounds of cell division before becoming the small pre-B cell (multpile clones iwth same heavy chain)
-unlike with tthe hevy chain, several attempts can be made to rearrange a single light chain locus
-so about 85% of the pre-B cell population will make it to the next stage (as opposed to about 50% at previous checkpoint

1. Pu.1 and Ikaros are required to express E2A in subset of stem cells, E2A then induces EBF
2. E2A and EBF induce expression genes, including RAG-1/2, allowing for V(D)J recombiantion to occur
3. E2A and eBF also induce expression of PAx-5
4. Pax-5 then leads to expression of other b cell genes like Cd14 and Ig-alpha, VpreB, Btk, and BLNK

-before each rearrangment, each gene segment undegoes a small amount of transcription
-this appears necessary to open up the locus (unwind chromatin) to make it accessible to the V(D)J Recombinase
-this is directed by B cell-specific transcription factors (like PAx-5) and thus serves in part as the mechanism for why the Ig loci are rearranged but not the TCR loci

-signal transduction via the functional havy chain product along with the surrogate light cahin induces the pre-B cell to survive, stop hevy chain gene rearrangement, and procee to light-chain rearrangemtn

- initial steps triggered by receptor associated tyrosine kinases of the Src family
-triggeres multiple signaling pathways in parallel - small G proteins, second-messengers such as IP3 and DAG, and mutipple trasncription factors

Side

-only about 10% of B cells maturing per day in the bone marrow actually migrate out into peripohery
-b cells that produce an Ig that cna bind to self-antigen (auto-antibodies) are removed through a process of negative selection (thru clonal deletion) = self tolerance
-slef-reactice B cells are retained in the bone marrow and their development is arrested

-receptor editing - process where successive Ig light chain rearrangments are tested for self-reactivity
-immature B cells makes a new light chain and thus an IgM with a different specificity
-if the new receptor is self-reactive, light-chain genes continue rearraging (successive new receptors are self-reactive. no further rearrangments are possible and the immature B cell undergoes apoptosis)
-if the new receptor is not self-reactive the B cell leaves the bone marrow