B-Cell Generation, Activation and Differentiation - I

by Arfeen, Zain

Immunology

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05:25
B-Cell Generation, Activation and Differentiation - I
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10:20
B-Cell Maturation - I
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09:20
B-Cell Maturation – II
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13:43
B-Cell Maturation – III
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11:56
B-Cell Maturation – IV
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15:12
B-Cell Maturation - V

Lecture´s Description

B-Cell Maturation - I
This Sqadia lecture elucidate about B-cells which play important role in our immune system. The production of plasma cells and memory B cells can be divided into three broad stages: generation of mature, immunocompetent B cells (maturation), activation of mature B cells when they interact with antigen, and differentiation of activated B cells into plasma cells and memory B cells. A mature B cell leaves the bone marrow expressing membrane-bound immunoglobulin (mIgM and mIgD) with a single antigenic specificity. These naive B cells, which have not encountered antigen, circulate in the blood and lymph and are carried to the secondary lymphoid organs, most notably the spleen and lymph nodes. If a B cell is activated by the antigen specific to its membrane-bound antibody, the cell proliferates (clonal expansion) and differentiates to generate a population of antibody-secreting plasma cells and memory B cells. Affinity maturation is the progressive increase in the average affinity of the antibodies produced.


B-Cell Maturation – II
B-cell development begins as lymphoid stem cells differentiate into the earliest distinctive B-lineage cell—the progenitor B cell (pro-B cell)—which expresses a transmembrane tyrosine phosphatase called CD45R. Proliferation and differentiation of pro-B cells into precursor B cells (pre-B cells) requires the microenvironment provided by the bone-marrow stromal cells. The stromal cells play two important roles: they interact directly with pro-B and pre-B cells, and they secrete various cytokines, notably IL-7, that support the developmental process. At the earliest developmental stage, pro-B cells require direct contact with stromal cells in the bone marrow. This interaction is mediated by several cell-adhesion molecules, including VLA-4 on the pro-B cell and its ligand, VCAM-1, on the stromal cell.


B-Cell Maturation – III
B-cell maturation depends on rearrangement of the immunoglobulin DNA in the lymphoid stem cells. The recombinase enzymes RAG-1 and RAG-2, which are required for both heavy-chain and light-chain gene rearrangements, are expressed during the pro-B and pre-B cell stages. The bone-marrow phase of B-cell development culminates in the production of an IgM-bearing immature B cell. At this stage of development, the B cell is not fully functional, and antigen induces death or unresponsiveness (anergy) rather than division and differentiation. Although IgD is a characteristic cell-surface marker of mature naive B cells, its function is not clear. However, since immunoglobulin knockout mice have essentially normal numbers of fully functional B cells, IgD is not essential to either B-cell development or antigen responsiveness.


B-Cell Maturation – IV
In the pre-B cell, the membrane chain is associated with the surrogate light chain, a complex consisting of two proteins: a V-like sequence called Vpre-B and a C-like sequence called ʎ5, which associate noncovalently to form a light-chain–like structure. Experiments in which particular transcription factors are knocked out by gene disruption have shown that four such factors, E2A, early B-cell factor (EBF), B-cell– specific activator protein (BSAP) and Sox-4 are particularly important for B-cell development. These findings point to important roles for both of these transcription factors early in B-cell development, and they may play essential roles in the early stages of commitment to the B-cell lineage.


B-Cell Maturation - V
Monoclonal antibodies are available that can recognize all of these antigenic markers, making it possible to recognize and isolate the various stages of B-cell development by the techniques of immunohistology and flow cytometry. There is a subset of B cells, called B-1 B cells, that arise before B-2 B cells, the major group of B cells in humans and mice. In humans and mice, B-1 B cells compose about 5% of the total B-cell population. They appear during fetal life, express surface IgM but little or no IgD, and are marked by the display of CD5. 90% of the B cells produced each day die without ever leaving the bone marrow. Some of this loss is attributable to negative selection and subsequent elimination (clonal deletion) of immature B cells that express auto-antibodies against self-antigens in the bone marrow. Nemazee and Burki showed that negative selection of immature B cells does not always result in their immediate deletion. Instead, maturation of the self-reactive cell is arrested while the B cell “edits” the light-chain gene of its receptor.

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