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The functional consequence of this modulation of b

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The functional consequence of this modulation ofB-cell signaling can be observed in multiple settings. Bcells first express the CD21-CD19-CD81 coreceptor asthey migrate from the bone marrow into the periphery,generally referred to as the transitional stage that hasimportant implications in the elimination of self-reactiveB cells and in the positive selection of B1 cells [95]. B1cells, which are the chief sources of natural antibody withrepertoires that are highly biased toward conserved anti-gens (e.g., nuclear antigens), are a long-lived and physi-ologically distinct population of B cells [2]. Complementseems to function in the selection and maintenance of B1cells, as CR2-deficient mice have an altered repertoire ofnatural antibody, which can be observed by a marked re-duction in injury following ischemia/reperfusion despitenormal levels of IgM [96, 97]. These mice also have re-
Complement in host immunity42npgCell Research | Vol 20 No 1 | January 2010duced numbers of B1a cells and show impaired general-ized antibody production [98].In addition to modulating B1 activity and the produc-tion of natural antibodies, cross-linking of the CD21-CD19-CD81 coreceptor complex with BCR enhancesB-cell immunity in later stages of B-cell differentiationas well. Coupling C3d to low-affinity antigen, which (ifuncoupled) would cause B-cell death, results in not onlysurvival but also B-cell activation and production of an-tibody, suggesting a role of complement in the ‘instruc-tion’ of naive B cells in the periphery [99]. Similarly,activation of mature peripheral and follicular B cells bycomplement-opsonized antigen leads to their migrationto the lymphoid T-cell:B-cell boundary, where helper Tcells provide costimulation via CD40, leading to B-cellactivation and expansion. Subsequently, activated B cellsinitiate the formation of germinal centers (GCs), whereCRs on B cells enhance BCR signaling, leading to effec-tive differentiation into plasma and memory B cells [89,90]. This is supported by the observation that antigen-specific B cells lacking CR1/CR2 fail to survive within aGC when put in competition with WT B cells, insinuat-ing that coreceptor signaling is vital to clonal selectionof B cells and in the absence of this complement-assistedcosignaling, B cells fail to compete and undergo celldeath [100]. FDCs are central to this process as they arespecialized stromal cells that secrete the B-lymphocytechemoattractant, help to organize GCs, and provide ef-fective means of trapping and retaining antigen withinB-cell follicles and displaying them to both naive andGC B cells [101]. FDCs express relatively high levels ofCR1 and CR2 and effectively retain C3-coated immunecomplexes within the lymphoid follicles, promoting theantigen selection of high-affinity GC B cells [92]. Fur-thermore, post-GC B cells require complement on FDCsfor an efficient maintenance of long-term memory Bcells, affinity maturation, and effective recall responses [102].

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