![]() As shown previously, there is no difference in IgG response to a T cell-dependent antigen between wild-type and heterozygous mutant mice ( 11). For simplicity, lpr/lpr/sIgM +/− and lpr/lpr/sIgM −/− mice are referred to as lpr and lpr/sIgM −/− mice, respectively. Thirteen breeding pairs of lpr/lpr/sIgM +/− × lpr/lpr/sIgM −/− mice were used to generate sufficient numbers of female littermates of lpr/lpr/sIgM +/− and lpr/lpr/sIgM −/− mice for various analyses. Six pairs of heterozygous double mutant mice were bred to obtain lpr mice that were heterozygous (lpr/lpr/sIgM +/−) or homozygous (lpr/lpr/sIgM −/−) for secreted IgM mutation. They were bred with MRL-lpr/lpr mice (abbreviated MRL/lpr), which were kindly provided by Suzanne Marusic of the Massachusetts Institute of Technology. Mice deficient in secreted IgM (sIgM −/−) on the mixed 129 × C57BL/6 background have been described ( 11). Mice were maintained in a specific pathogen-free facility. The resulting immune complexes are more effective in activating B cells by crosslinking B cell antigen receptor and CD19/CD21/CD81 coreceptors and/or in promoting germinal center reactions through more efficient antigen trapping on follicular dendritic cells ( 17, 18). Together, these findings suggest that secreted IgM and complement components normally can augment IgG antibody responses to foreign antigens, probably through formation of immune complexes of antigen, IgM, and activated complement component C3 ( 15, 16). The impaired IgG antibody response to suboptimal doses of antigen also was observed in mice deficient in complement component C3 or C4 or complement receptor CD21/CD35 ( 13, 14). An identical result also was obtained by another group by using an independently constructed mutant mouse strain that carried the same mutation ( 12). We showed that in the absence of secreted IgM, mutant mice had an impaired IgG antibody response to a suboptimal dose of a T cell-dependent antigen ( 11). To investigate the role of secreted IgM in various immunological processes, we previously have constructed a mutant mouse strain in which B cells are incapable of secreting IgM but still capable of expressing surface IgM and IgD and secreting IgG antibodies. The role of IgM autoantibodies in autoimmune responses and the associated organ damage remains to be elucidated. In contrast, injection of DNA-specific IgM or IgM RF rarely causes the autoimmune lesions in normal mice ( 9, 10). Similarly, transfer of IgG from T cell receptor transgenic mice that spontaneously develop rheumatoid arthritis causes the disease in immunodeficient mice ( 9). Introduction of monoclonal IgG antibody specific to DNA into normal mice, either by direct injection of purified antibodies, implantation of antibody-secreting hybridomas, or expression from Ig transgenes, induces lupus-like glomerulonephritis ( 5– 8). Evidence suggests that IgG autoantibodies are usually pathogenic whereas IgM autoantibodies are not. In rheumatoid arthritis, more than 70% of the patients develop high titers of serum IgM and IgG, referred to as rheumatoid factors (RF), specific to the Fc portion of their own IgG molecules ( 2). In systemic lupus erythematosus (SLE), a large proportion of the autoantibodies are specific to chromatin and its component DNA and histones ( 4). High levels of IgM and IgG autoantibodies are associated with many autoimmune diseases ( 1– 3). These findings suggest that secreted IgM, including IgM autoantibodies produced naturally or as part of an autoimmune response, may lessen the severity of autoimmune pathology associated with IgG autoantibodies. Similarly, the absence of secreted IgM also resulted in an accelerated development of IgG autoantibodies in normal mice. Compared with regular lpr mice, lpr mice that lack secreted IgM developed elevated levels of IgG autoantibodies to double-stranded DNA and histones and had more abundant deposits of immune complexes in the glomeruli they also suffered more severe glomerulonephritis and succumbed to the disease at an earlier age. Using mice that are unable to secrete IgM but are able to express surface IgM and IgD and to secrete other classes of immunoglobulins, we examined the effect of the absence of secreted IgM in the development of IgG autoantibodies and autoimmune disease in lupus-prone lymphoproliferative (lpr) mice. ![]() Although IgG autoantibodies often are pathogenic, the role of IgM autoantibodies in autoimmune disease is not clear. Individuals with systemic lupus erythematosus and rheumatoid arthritis are characterized by the presence of high levels of circulating IgM and IgG autoantibodies.
0 Comments
Leave a Reply. |