Censoring of autoreactive B cell development by the pre-B cell receptor.
ABSTRACT Antibody diversity occurs randomly as B cells recombine their immunoglobulin (Ig) heavy- and light-chain genes during development. This process inevitably generates reactivity against self structures, and several mechanisms prevent the development of autoreactive B cells. We report here a role for the pre-B cell receptor, composed of Ig heavy and surrogate light chains, in the negative selection of cells expressing Ig heavy chains with the potential to generate autoantibodies. Surrogate light-chain-deficient (SLC-/-) mice harbored elevated levels of antinuclear antibodies (ANAs) in their serum and showed evidence of escape of pre-B cells expressing prototypic autoantibody heavy chains from negative selection, leading to mature autoantibody secreting CD21-CD23- B cells in the periphery. Thus, the pre-B cell receptor appears to censor the development of certain autoantibody-secreting cells and may represent an important factor in multifactorial autoimmune diseases.
- SourceAvailable from: Bonnie B Blomberg
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- "This suggests that reduced SLC levels are sufficient to bias B-cell repertoires toward PC reactivity. Keenan et al. (2008) have shown heightened autoreactivity, for example, to DNA and nuclear antigens, in B cells that develop in SLC-deficient mice. Our data are consistent with this view and now suggest that B cells reactive to PC, an apoptotic self-antigen, continue to be selected for B-cell maturation when SLC is reduced. "
ABSTRACT: In aged mice, new B-cell development is diminished and the antibody repertoire becomes more autoreactive. Our studies suggest that (i) apoptosis contributes to reduced B lymphopoiesis in old age and preferentially eliminates those B-cell precursors with higher levels of the surrogate light chain (SLC) proteins (λ5/VpreB) and (ii) λ5(low) B-cell precursors generate new B cells which show increased reactivity to the self-antigen/bacterial antigen phosphorylcholine (PC). Pro-B cells in old bone marrow as well as pro-B cells from young adult λ5-deficient mice are resistant to cytokine-induced apoptosis (TNFα; TGFβ), indicating that low λ5 expression in pro-B cells is sufficient to cause increased survival. Transfer of TNFα-producing 'age-associated B cells' (ABC; CD21/35(-) CD23(-) ) or follicular (FO) B cells from aged mice into RAG-2 KO recipients led to preferential loss of λ5(high) pro-B cells, but retention of λ5(low) , apoptosis-resistant pro-B cells. In old mice, there is increased reactivity to PC in both immature bone marrow B cells and mature splenic FO B cells. In young mice, absence of λ5 expression led to a similar increase in PC reactivity among bone marrow and splenic B cells. We propose that in old age, increased apoptosis, mediated in part by TNFα-producing B cells, results in preferential loss of SLC(high) pro-B cells within the bone marrow. Further B-cell development then occurs via an 'SLC(low) ' pathway that not only impairs B-cell generation, but promotes autoreactivity within the naïve antibody repertoires in the bone marrow and periphery. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Aging cell 02/2015; 14(3). DOI:10.1111/acel.12302 · 5.94 Impact Factor
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- "An interesting finding in our model was that Syk ki B cells were preferentially selected and more readily survived within the pool of splenic MZ B cells . Earlier publications reported that after substantial reduction of auto - reactive potential during positive ( Keenan et al , 2008 ) and essentially negative ( Wardemann et al , 2003 ) central selection , the IgM þ IgD þ T2 stage checkpoint of peripheral B cell development is decisive for FO versus MZ fate decision ( Pillai and Cariappa , 2009 ) . An alternative reason for the preferential selection / survival of MZ B cells in our model could be a preferential MZ fill up caused by lymphopenia , a phenomenon described for several BCR transgenic lines . "
ABSTRACT: The spleen tyrosine kinase family members Syk and Zap-70 are pivotal signal transducers downstream of antigen receptors and exhibit overlapping expression patterns at early lymphocytic developmental stages. To assess their differential kinase fitness in vivo, we generated mice, which carry a Zap-70 cDNA knock-in controlled by intrinsic Syk promoter elements that disrupts wild-type Syk expression. Kinase replacement severely compromised Erk1/2-mediated survival and proper selection of developing B cells at central and peripheral checkpoints, demonstrating critical dependence on BCR signalling quality. Furthermore, ITAM- and hemITAM-mediated activation of platelets and neutrophils was completely blunted, while surprisingly FcγR-mediated phagocytosis in macrophages was retained. The alteration in BCR signalling quality resulted in preferential development and survival of marginal zone B cells and prominent autoreactivity, causing the generation of anti-insulin antibodies and age-related glomerulonephritis. Development of concomitant fasting glucose intolerance in knock-in mice highlights aberrant B cell selection as a potential risk factor for type 1 diabetes, and suggests altered BCR signalling as a mechanism to cause biased cellular and Ig repertoire selection, ultimately contributing to B cell-mediated autoimmune predisposition.The EMBO Journal 06/2012; 31(15):3363-74. DOI:10.1038/emboj.2012.169 · 10.75 Impact Factor
Conference Paper: A new storage scheme for conflict-free vector access[Show abstract] [Hide abstract]
ABSTRACT: Investigations into data storage schemes for parallel memory system of vector processing have been mainly focused on low-order interleaved schemes, skewed schemes and XOR schemes. In this paper, a new interleaved storage scheme, namely k-row interleaved scheme, is suggested and investigated. This scheme allocates k consecutive data of a vector onto one memory module sequentially and then the next k consecutive data onto the next memory module. The address mapping functions are devised and the performance of this scheme is evaluated. It is found that this scheme improves the average performance for vector access over the previous schemes. The address generation hardware is also shown to be simpleTENCON '93. Proceedings. Computer, Communication, Control and Power Engineering.1993 IEEE Region 10 Conference on; 11/1993