Signals from a Self-Antigen Induce Positive Selection in Early B Cell Ontogeny but Are Tolerogenic in Adults (original) (raw)
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Immunity, 2000
are generated and maintained through continuous IgM signaling, and, as a result, the B1 repertoire is enriched with some antibody specificities (Bhat et al., 1992; Ar-Summary nold et al., 1994; Hardy et al., 1994). Inactivation of molecules associated with signaling through surface IgM-Using immunoglobulin heavy chain transgenic mice, we show that B cell clones reaching the long-lived pool ligand interactions (btk, Ig␣ tail, CD19, vav, PKC, PI3 kinase-p85␣, etc.) decreases the B1 significantly more are heterogeneous: some are enriched in the CD21 high compartment (mostly marginal zone [MZ]), others re-than the B2 compartment. The mature B2 population appears less enriched for side primarily in the follicles (FO). Altering the composition of the B cell receptor through N region additions certain specificities compared to B1; however, a low level of IgM receptor engagement is required for their decreases the rate of clonal production and the MZ enrichment. This process can be recapitulated by puri-development and maintenance (Cyster et al., 1996; Lam et al., 1997). Phenotypic and topographical heterogeneity fied CD21 low B cells and is due to a preferential clonal survival that requires a functional btk tyrosine kinase. exists within the mature B2 cell population with IgM lo IgD hi CD21 int CD23 hi recirculating cells located in B lymphoid We also show that generation of the MZ population is dependent on CD19. These findings suggest that the follicles (FO) in spleen and lymph nodes and IgM hi IgD lo CD21 hi CD23 lo nonrecirculating cells enriched primarily MZ B cell repertoire is positively selected and have functional implications for antigenic responses ef-in the marginal zone (MZ) of the spleen (Gray et al., 1982; Oliver et al., 1997). However, because the complex fected by B cells from this microenvironment. intrasplenic trafficking pathways are not fully understood, there is not a perfect correlation between the Introduction phenotype and topography of splenic B cell subsets. Studies in rats have shown that thoracic duct recirculat-The generation and selection of B lymphocytes to create ing cells contain MZ B cell precursors and also that a diverse and flexible repertoire that will thwart pathomemory cells colonize the marginal zone from where gens is the result of a series of developmental programs they are mobilized by a new antigen encounter (Kumaraand checkpoints (Rolink and Melchers, 1996; Goodnow, ratne and MacLennan, 1982; Liu et al., 1991).
Scandinavian Journal of Immunology, 1990
Cord blood and fetal liver B cells were immortalized using Epsleln Barr virus, and IgM antibodies from theresullinglinesandclones were examined for their binding to a variety of autoantigens and microorganisms by ELISA and fluorescence assays. Auto-antigens lested included Fc of IgG, ssDNA and dsDNA, cardiolipin. histories I 4, collagens type I and II. thyroglobulin. cytoskeletal components, and a tissue section screen. Of 71 cell lines tested, all but 19 showed some autoreactivity. All 32 fetal liver lines reacted to some seif-antigens. In cord blood clones, 16 out of 26 bound to auto-antigens. Many of the clones reacted with more than one auto-antigen and were 'polyrcactive'. Some of the cord blood clones bound to extracts of microorganisms , showing specificity for both endogenous and exogenous antigens. The high frequency of CD5 ' B cells in the cord blood (> SQ"A.) and felal liver (> 70"'!i) argues for many of these ciones being derived from this subset. Therefore, our data support the concept that many 'early' B cells produce polyreactive IgM which can bind to a variety of different auto-antigens and microorganisms. These IgM antibodies are similar to those described by others as 'natural antibodies',