The main immunological event in the pathogenesis of SLE is B cell hyperactivity, and several lines of evidence demonstrate that B cells are essential for development of autoimmunity and disease expression (Lu and Cyster, 2002; Zouali, 2005). Transfer of cultured pre-B cells derived from (NZB x NZW) F1 fetal liver into SCID mice is sufficient to generate a lupus-like syndrome (Reininger et al., 1992). Since T cells do not develop from these donor cells, it appears that B-lineage-intrinsic defects play a primary role in the pathogenesis of the autoimmune disorder. It is also clear that, before disease development, (NZB x NZW) F1 mice have large numbers of B cells spontaneously producing low-affinity, IgM anti-DNA antibodies (Steward and Hay, 1976). In human lupus, the number of B cells that secrete Igs spontaneously is dramatically increased (Zouali et al., 1991). Characterization of autoantibody genes shows that pathogenic, high-affinity IgG anti-DNA antibody (Ab) result from an Ag-driven process (Demaison et al., 1994; Radic and Weigert, 1994), implying that the adaptive immune branch underlies their production. However, other evidence suggests that B cells with innate-like functions may play a role in autoim-munity (Viau and Zouali, 2005). In humans, increased numbers of B-1 cells are found in patients with certain autoimmune diseases. In experimental models, early studies recognized that B-1 cells exhibit binding to self-Ags and that they can potentially produce high-affinity autoantibodies typical of autoimmune disease. The autoimmune NZB mouse has an expanded B-1 population that could be linked to the Sle2 lupus susceptibility locus. In mice homozygous for the lpr mutation, B-1 cells produce anti-erythrocyte autoantibodies responsible for autoimmune hemolytic anemia and their elimination reverses autoim-munity. Studies of B-1 cell trafficking also support their role in autoimmunity. While B-1 cells are known to preferentially migrate toward the chemoattractant CXCL13 (BLC), they fail to home to the peritoneal cavity in aged (NZB x NZW) F1 mice, developing lupus nephritis (Ishikawa et al., 2001). When injected intravenously, they are preferentially recruited to the target organs that show ectopic expression of CXCL13, namely the kidney, the lung, and the thymus. This aberrant homing of B-1 cells in aged (NZB x NZW) F1 mice may favor autoantibody production.
Studies of MZ B cells also suggest that they can potentially play a role in the spontaneous development of autoantibodies (Viau and Zouali, 2005). In humans, infiltrating cells exhibiting a MZ B cell phenotype have been described in Grave's disease and in Sjogren's syndrome (Segundo et al., 2001; Groom et al., 2002). In the autoimmune NZB mouse model, several findings suggest that MZ B cell function is abnormal. There is an enhanced proliferation following stimulation with anti-Ig and -MHC class II Abs. Additionally, NZB mice have an increased proportion of MZ B cells exhibiting an "activated" phe-notype, with increased levels of costimulatory molecules, as compared with non-autoimmune mouse strains. Like its parental NZB strain, the lupus-prone (NZB x NZW) F1 mouse model demonstrates increased numbers of CD1high
B cells, a phenotype of MZ B cells. Importantly, this MZ B cell expansion is detectable as early as 4 weeks of age and is responsible for production of large amounts of anti-DNA Abs, as compared with FO B cells (Zeng et al., 2000; Schuster et al., 2002).
Studies of longevity factors (APRIL and BAFF) that influence B cell maturation and survival at several levels also point to a link of MZ B cells with autoimmunity. Mice overexpressing BAFF spontaneously develop an SLE-like syndrome associated with a dramatic increase in MZ B cells (Mackay et al., 1999; Batten et al., 2000). More recently, it was found that the salivary glands of BAFF transgenic mice contain a subpopulation of B cells with an MZ-like phenotype (B22O+HAS+ CD21highCD1high) that could derive from the expanded MZ population present in the spleen of BAFF transgenic mice (Groom et al., 2002). Importantly, MZ-like B cells also have been detected in the thyroid gland of patients with Graves's disease. It is possible that these cells have aberrantly acquired trafficking receptors, enabling them to circulate and home to other lymphoid locations, as occurs in aged (NZB x NZW) F1 mice whose B-1 cells abnormally migrate to ectopic target organs (Ito et al., 2004).
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