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M Bynoe

Publications and source records attributed to M Bynoe.

3 recordsLinked to original sources
PubMed1999

Crossreactive B cells are present during a primary but not secondary response in BALB/c mice expressing a bcl-2 transgene.

While it is clear that multiple genetic factors lead to autoimmune diseases such as systemic lupus erythematosus (SLE), it appears that an environmental stimulus is also required to trigger the disease in susceptible individuals. We have previously demonstrated that B cells making crossreactive antibodies that bind to both phosphorylcholine (PC), a component of pneumococcal cell wall polysaccharide, and double stranded DNA (dsDNA) can be found in BALB/c mice immunized with PC coupled to a protein carrier. While these B cells are normally eliminated in vivo by apoptosis, they can be recovered ex vivo by fusion with a cell line overexpressing the anti-apoptotic gene bcl-2. This observation led us to ask whether in vivo expression of bcl-2 might abrogate immunologic tolerance during an ongoing immune response. In the present study, we have examined BALB/c mice that constitutively express a bcl-2 transgene in the B cell compartment. Bcl-2 transgenic BALB/c mice have an expanded B cell number, but display no evidence of anti-dsDNA antibodies in the serum even following immunization with PC coupled to a protein carrier. Crossreactive anti-DNA, anti-PC B cells can be recovered by hybridoma technology late in the primary response, but do not appear in the memory B cell compartment. Thus, in vivo expression of bcl-2 can rescue B cell autoreactivity in the primary immune response, but is not sufficient for activation of these B cells or for their maintenance in the memory compartment.

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PubMed1997

Studies on the structure, regulation, and pathogenic potential of anti-dsDNA antibodies.

Studies of anti-double-stranded (anti-ds)DNA antibodies have provided insights into how and why these antibodies arise in systemic lupus erythematosus. In this review we discuss the experimental approaches that have been used by our laboratory to study these autoantibodies. Structure/function analyses including site-directed mutagenesis have helped characterize the molecular genetics of anti-dsDNA antibodies, and more recently peptide libraries have been used to define molecular motifs that these antibodies bind. Most of the pathogenic anti-dsDNA antibodies observed in lupus are somatically mutated. We demonstrated in vitro and in vivo that anti-bacterial antibodies can mutate to acquire specificity for dsDNA. Furthermore, using a fusion partner constitutively expressing bcl-2, NSO(bcl-2), we have shown the existence of anergic or preapoptotic B cells making antibodies that cross-react with both bacterial antigen and dsDNA. Whether defects in the regulation of these antibodies might contribute to serum expression of anti-dsDNA antibodies in some individuals remains unknown. A major emphasis of this review is the regulation of anti-dsDNA antibodies in a transgenic mouse model harboring the gene for the heavy chain of a pathogenic anti-dsDNA antibody. Nonautoimmune transgenic mice effectively regulate autoreactive B cells by anergy and deletion, while their autoimmune counterparts do not. The vast majority of anergic B cells expressing high-affinity transgenic anti-dsDNA antibody fail to display allelic exclusion of the heavy chain. We postulate that this may be one mechanism that allows them to escape deletion. Comparative studies on light chain usage in both the autoimmune and the nonautoimmune transgenic mouse strains have demonstrated that within the autoreactive B-cell population, there are subsets that are differentially regulated. Ultimately transgenic animals making pathogenic autoantibodies may provide us with a system for testing novel therapies for autoimmune disease.

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