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B-Cell Activation and Proliferation - I
B-cells are comprehensively discussed in this Sqadia Video. Depending on the nature of the antigen, B-cell activation proceeds by two different routes, one dependent upon TH cells, the other not. The B-cell response to thymus-dependent (TD) antigens requires direct contact with TH cells, not simply exposure to TH-derived cytokines. Antigens that can activate B cells in the absence of this kind of direct participation by TH cells are known as thymus-independent (TI) antigens. TI antigens are divided into types 1 and 2 and they activate B cells by different mechanisms. Some bacterial cell-wall components, including lipopolysaccharide (LPS) function as type 1 thymus-independent (TI-1) antigens. Type 2 thymus-independent (TI-2) antigens are highly repetitious molecules such as polymeric proteins (e.g., bacterial flagellin) or bacterial cell-wall polysaccharides with repeating polysaccharide units. The response to TI antigens is generally weaker, no memory cells are formed, and IgM is the predominant antibody secreted, reflecting a low level of class switching.
B-Cell Activation and Proliferation – II
All isotypes of mIg have very short cytoplasmic tails. Both mIgM and mIgD on B cells extend into the cytoplasm by only three amino acids; the mIgA tail consists of 14 amino acids; and the mIgG and mIgE tails contains 28 amino acids. The initial stages of signal transduction by an activated B-cell receptor. Phosphorylation of tyrosines within the ITAMs of the BCR by receptor associated PTKs is among the earliest events in B-cell activation and plays a key role in bringing other critical PTKs to the BCR and in their activation. The antigen-mediated crosslinking of BCRs initiates a number of signalling cascades that ultimately result in the cell’s responses to the crosslinking of its surface immunoglobulin by antigen.
B-Cell Activation and Proliferation – III
- Compartmentalization of function within receptor subunits: Both the B-cell and T-cell pathways begin with antigen receptors that are composed of an antigen binding and a signalling unit.
- Activation by membrane-associated Src protein tyrosine kinases: The receptor-associated PTKs (Lck in T cells and Lyn, Blk, and Fyn in B cells) catalyze phosphorylation during the early stages of signal transduction that are essential to the formation of a functional receptor signaling complex.
- Assembly of a large signaling complex with protein tyrosine-kinase activity: The phosphorylated tyrosines in the ITAMs of the BCR and TCR provide docking sites for the molecules that endow these receptors with PTK activity; ZAP-70 in T cells and Syk in B cells.
- Recruitment of other signal-transduction pathways: Signals from the BCR and TCR result in the production of the second messengers IP3 and DAG. IP3 causes the release of Ca2+ from intracellular stores, and DAG activates PKC.
- Changes in gene expression: One of the important outcomes of signal-transduction processes set in motion with engagement of the BCR or the TCR is the generation or translocation to the nucleus of active transcription factors that stimulate or inhibit the transcription of specific genes.
B-Cell Activation and Proliferation – IV
Stimulation through antigen receptors can be modified significantly by signals through coreceptors. Recall that costimulation through CD28 is an essential feature of effective positive stimulation of T lymphocytes, while signaling through CTLA-4 inhibits the response of the T cell. Phosphorylation of CD19 permits it to bind a number of signaling molecules, including the protein tyrosine kinase Lyn. The delivery of these signaling molecules to the BCR complex contributes to the activation process, and the coreceptor. On the other hand, treatment of B cells from mice in which CD19 has been knocked out with anti-BCR antibody fails to induce these pathways. Furthermore, CD19 knockout mice make greatly diminished antibody response to most antigens.
B-Cell Activation and Proliferation – V
Cytokine-mediated progression is required for B-cell proliferation. The probable sequence of events in B-cell activation by a thymus-dependent (TD) antigen. This process is considerably more complex than activation induced by thymus independent (TI) antigens. Micrographs of T-B conjugates reveal that the TH cells in antigen-specific conjugates have reorganized the Golgi apparatus and the microtubular-organizing center toward the junction with the B cell. This structural adjustment facilitates the release of cytokines toward the antigen-specific B cell. The signals from CD40 are transduced by a number of intracellular signaling pathways, ultimately resulting in changes in gene expression. B cell begins to express receptors for various cytokines. Binding of cytokines released from TH cell in a directed fashion sends signals that support the progression of the B cell to DNA synthesis and to differentiation.