The diverse genetic backgrounds of lupus-prone murine models, which produce both quantitative and qualitative differences in disease expression, may be a valuable resource for studying the influence of environmental exposure on autoimmune disease in sensitive populations. We tested this premise by exposing autoimmune-prone BXSB and the nonautoimmune C57BL/6 mice to the heavy metal mercury. Although both strains express a nonsusceptible H-2 haplotype, exposure to mercury accelerated systemic autoimmunity in both male and female BXSB mice, whereas the C57BL/6 mice were resistant. The subclasses of antichromatin antibodies elicited in BXSB mice by mercury exposure were more consistent with the predominant Th1-type response of idiopathic disease than with the Th2-type response found in mercury-induced autoimmunity (HgIA). The appearance and magnitude of both humoral and cellular features of systemic autoimmunity correlated with the mercury dose. Furthermore, environmentally relevant tissue levels of mercury were associated with exacerbated systemic autoimmunity. These studies demonstrate that xenobiotic exposure can accelerate spontaneous systemic autoimmunity, and they support the possibility that low-level xenobiotic exposure enhances susceptibility to systemic autoimmunity in genetically susceptible individuals.

Although evidence indicates that environmental factors play a major role in precipitating systemic autoimmunity in genetically susceptible individuals, little is known about the mechanisms involved. Certain heavy metals, such as mercury, are potent environmental immunostimulants that produce a number of immunopathologic sequelae, including lymphoproliferation, hypergammaglobulinemia, and overt systemic autoimmunity. Predisposition to such metal-induced immunopathology has been shown to be influenced by both MHC and non-MHC genes, as well as susceptibility to spontaneous lupus, in mice and other experimental animals. Among the various mouse strains examined to date, the DBA/2 appears to uniquely lack susceptibility to mercury-induced autoimmunity (HgIA), despite expressing a susceptible H-2 haplotype (H-2d). To define the genetic basis for this trait, two genome-wide scans were conducted using F2 intercrosses of the DBA/2 strain with either the SJL or NZB strains, both of which are highly susceptible to HgIA. A single major quantitative trait locus on chromosome 1, designated Hmr1, was shown to be common to both crosses and encompassed a region containing several lupus susceptibility loci. Hmr1 was linked to glomerular immune complex deposits and not autoantibody production, suggesting that DBA/2 resistance to HgIA may primarily involve the later stages of disease pathogenesis. Identification and characterization of susceptibility/resistance genes and mechanisms relevant to the immunopathogenesis of mercury-induced autoimmunity should provide important insights into the pathogenesis of autoimmunity and may reveal novel targets for intervention.

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.

No abstract

Background: CD4 T cells help B cells produce antibodies following antigen challenge. This response classically occurs in germinal centers (GC) located in B-cell follicles of secondary lymphoid organs (SLO), a site of immunoglobulin isotype switching and affinity maturation. GC formation requires specialized CD4 T cells, T-follicular helper (Tfh) cells, which localize to follicles and provide B cells with survival and differentiation signals that are essential for B-cell maturation into memory and long-lived plasma cells. Pathogenic autoantibodies in human and murine lupus arise in a like manner. Although Tfh cells are critical for GC development, their genesis in humans, role in promotion of autoimmunity, and potential as therapeutic targets in SLE are incompletely understood. To address these issues, we dissected Tfh cell development and function, defining their transcriptional regulation, migration, and function in vivo in normal and lupus-prone mice and ex vivo in normal humans and patients with SLE. Methods: We used a combination of approaches-flow cytometry, confocal microscopy, microarrays, quantitative chromatin immunoprecipitation and DNA sequencing (ChIP-seq), retroviral overexpression, and T-cell-B-cell helper assays-to characterize Tfh cells in normal mice and in lupus-prone strains, and from the tonsils of normal humans and the blood of patients with SLE. Results: We found that the transcription factor Bcl6 (B-cell CLL/lymphoma 6) is necessary and sufficient for Tfh development and function, via genetic control of Tfh proteins that are essential for their migration to B-cell follicles and GC and subsequent B-cell maturation. We dissected steps in Tfh development within SLO, beginning with their genesis in the T-cell zone followed by emigration to sites of B-cell interaction outside the B-cell follicle, where we have shown that B cells serve to provide signals for continued Tfh expansion and follicular migration. We have now begun to tease apart the factors that mediate T-cell-B-cell collaboration in the follicle; these represent therapeutic targets in SLE. Finally, we have shown that patients with SLE have expansion of Tfh cells in the blood, a finding that highlights their potential role in the pathogenesis of SLE and as likely therapeutic targets. Conclusion: These studies help define the developmental pathways for Tfh cells, and the steps that enable these cells to function in the B-cell follicle to promote immunoglobulin and autoantibody production. They have also helped define markers of Tfh cells in normals and autoimmune individuals, and suggest that they are a promising therapeutic target in patients.