Article

Censoring of autoreactive B cell development by the pre-B cell receptor.

Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, UK.
Science (Impact Factor: 31.48). 07/2008; 321(5889):696-9. DOI: 10.1126/science.1157533
Source: PubMed

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.

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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. "
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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 . "
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