Membrane cholesterol can only be lowered by 50% to still maintain good B cell viability; however, it could reasonably be argued the cholesterol-dependent rafts needed to initiate signaling are either hard to draw out or tolerate a moderate reduction in cholesterol and GM1 content material. stimulated. In contrast, when plasma membrane cholesterol is definitely lowered and GM1 sphingolipid markers of membrane rafts are depleted in naive B cells, this does not diminish BCR signaling to calcium or RelA. These results provide a possible explanation for the signaling changes in clonal anergy and indicate that a ML224 main function of membrane cholesterol in B cells is not to initiate BCR signaling, but instead to terminate a subset of signals by quick receptor internalization. A central paradox in the cell biology of the immune system revolves around understanding how the same receptor for antigen can either transmission immunogenically to stimulate proliferation and differentiation in response to foreign antigens, or transmission tolerogenically to inactivate or get rid of cells that bind to self-antigens. A clear example of this paradox is the trend of clonal anergy in B lymphocytes. Anergy is an Rabbit Polyclonal to CDH11 active process of immunological self-tolerance brought about by exposure to self-antigens by which self-reactive lymphocytes adopt a state where they may be refractory to making an immune response to antigen. Instead, anergic B cells make tolerance-promoting reactions to antigen, such as exclusion from lymphoid follicles, apoptosis, or active inhibition of plasma cell differentiation. Related biochemical changes in B cell receptor (BCR) signaling in anergic cells have been identified by analyzing hen egg lysozyme (HEL)-specific B cells that have become anergic to HEL by maturing in animals expressing HEL systemically and comparing them with developmentally matched B cells bearing the same receptor that are naive. In anergic cells, BCR signaling in response to antigen is definitely uncoupled from NF-B and c-Jun N-terminal kinase (JNK) but continues to activate extracellular signalCregulated kinase (ERK) and calcium oscillations that travel NFAT nuclear shuttling (1, 2). These changes in signaling ML224 have major transcriptional and practical consequences (3). The lack of NF-B activation prevents induction of NF-B target genes, such as c-myc, IRF4, bcl-XL, and A1 that are normally required for B cell proliferative reactions to antigen. The continuing activation of NFAT is likely to induce CD5 and CD72, which have inhibitory tasks, and the chronic activation of ERK inhibits plasma cell differentiation (4). Related changes in BCR signaling have been recorded in anergic B cells ML224 from several transgenic models (5, 6). A key query is definitely how BCR signaling is definitely qualitatively modified in anergic B cells. In ML224 naive but not anergic cells, antigen causes IgM and IgD BCRs to partition into a biochemical cell portion that is relatively resistant to detergent extraction and associated with the cytoskeleton. This happens before BCR phosphorylation and is unaffected by inhibition of BCR phosphorylation and src kinase activity (7). These results lead to the hypothesis that anergy stems from changes in the subcellular partitioning or trafficking of BCRs. An alternative hypothesis is favored by work in cell lines showing that Ig and Ig dissociate from membrane IgM and IgD after antigen activation and BCR desensitization (8). Moreover, when chimeric BCRs that do not associate with Ig and Ig are coexpressed with normal BCRs, a minority of these unsheathed BCRs interfere with signaling to antigen in a way that resembles anergy (9). Resolving how BCR signaling is definitely modified in anergic B cells is made more difficult because of fundamental questions about the basic mechanism of BCR transmission.
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