As discussed above, experimentally induced modification of receptor expression or alteration of signaling pathways may have a significant impact on B cell tolerance to self. In humans too, there are indications that abnormal B cell signaling may contribute to autoimmune disease. In lupus, stimulation of circulating B cells through their sIgM produced significantly higher Ca2+ fluxes compared with similarly induced responses of B cells from patients with other systemic rheumatic diseases (Liossis et al., 1996). The overall level of sIgM-initiated protein tyrosyl phosphorylation also was significantly enhanced, and correlated with the augmented BcR-mediated free Ca2+ responses. This aberrant BcR-mediated signaling process was not associated with disease activity, medications used, or specific clinical manifestations. It was disease-specific, suggesting a possible intrinsic SLE B cell defect that may have pathogenic implications. In further studies, the content of lupus B cells in Lyn, CD45, and SHP-1 was significantly altered in patients (Huck et al., 2001; Liossis et al., 2001). Investigation of gene polymorphisms in the Japanese population suggested that cd22 could be considered a candidate susceptibility gene for autoimmune disease (Hatta et al., 1999). Although the function of the CD22/Lyn signaling-inhibitor complex was not addressed, it is likely that decreased Lyn in SLE B cells may contribute to the B cell overactivity. In line with studies in rodents showing that CD19 overexpression by 20% induces autoAb production in normal mice, expression of CD19 and CD21 levels are 20% higher on B cells from patients with systemic sclerosis compared with healthy individuals (Saito et al., 2002). In Japanese patients with SLE, an CD19 single nucleotide polymorphism (SNP), which was rare in Caucasians, was increased (Kuroki et al., 2002).
A particular feature of human autoimmune disease is the wide variety of affected organs, the diversity of immune responses involved, the distinctive pheno-types in time course, severity, and response to medication. One possibility is that genetic predisposition contributes to determination of the pathogenic process, a view supported by the strain dependency of disease manifestations observed in mice deficient in inhibitory BcR coreceptors. Initial support to a pivotal role of FcyRIIb polymorphisms as susceptibility alleles in the pathogenesis of SLE came from mapping of a region in the telomere of human chromosome 1 (Tsao et al., 1997). This region is syntetic to a region on mouse chromosome 1 in the vicinity of the FcgRIIb1 locus (Wakeland et al., 2001) and encodes a variety of immunologically relevant molecules, including FcyRIIb and FcyRIII, and poly(ADP-ribose) polymerase (PARP). More recently, the frequency of an SNP (695T/C) coding for a nonsynonymous 232Ile/Thr substitution within the transmembrane domain of FcyRIIb was significantly increased in Japanese SLE patients compared with healthy individuals (Kyogoku et al., 2002). It is of further interest that another allele called FCGR2B-187T, which mediates a higher level of CD19 dephosphorylation and a greater degree of Ca2+ response when coengaged with the BcR than does FCGR2B-187I, is not associated with SLE in both African Americans and Caucasians (Li et al., 2003). This lack of association raises the interesting possibility that FCGR2B-187T may be interacting epistatically with background genes that differ between Japanese patients and both African American and Caucasian patients.
In mouse, PD-1 appears to inhibit immune responses in vivo, and abrogation of this inhibition could result in development of autoimmune disease. This conclusion is supported by gene mapping studies of patients wherein an intronic SNP in PD-1 was reportedly associated with SLE in 12% of Europeans and 7% of Mexicans (Prokunina et al., 2002). The identified allele alters a binding site for a transcription factor located in an intronic enhancer and could lead to aberrant regulation of PD-1 and, hence, deregulated self-tolerance. These data suggest a mechanism through which PD-1 can contribute to the development of SLE in humans (Prokunina et al., 2002).
Overall, studies of mouse models revealed that subtle alterations in overlapping signaling pathways that influence B cell responses to transmembrane and intracellular signals are sufficient to predispose mice to autoAb production. It is important to probe additional signal transduction pathways in autoimmune patients. For example, given that the lack of PKC-8 leads to autoimmunity in mice, it is possible that the activity of PKC-8 is reduced in the cells of humans with certain autoimmune diseases. Moreover, strikingly similar abnormalities of Ag-receptor signaling have previously been reported in T cells from patients with SLE (Brundula et al., 1999; Kammer et al., 2002) pointing toward potentially unifying Ag-receptor-mediated signaling defects in lupus lymphocytes (Zouali, 1998; Kammer et al., 2002). Accordingly, the signaling abnormalities encountered in SLE lymphocytes may provide a biochemical and molecular background for such diverse abnormalities as lymphocyte activation, anergy, and cell death (Hasler and Zouali, 2001; Kammer et al., 2002; Zouali and Sarmay, 2004).
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