Mercury-induced autoimmunity in the absence of IL-4

After exposure to subtoxic doses of heavy metals such as mercury, H-2s mice develop an autoimmune syndrome consisting of the rapid production of IgG autoantibodies that are highly specific for nucleolar autoantigens and a polyclonal increase in serum IgG1 and IgE. In this study, we explore the role of two inhibitory immunoreceptors, CTLA-4 and FcγRIIB, in the regulation of mercury-induced autoimmunity. In susceptible mice treated with mercuric chloride (HgCl2), administration of a blocking anti-CTLA-4 Ab resulted in a further increase in anti-nucleolar autoantibodies and in total serum IgG1 levels. Furthermore, in some DBA/2 mice, which are normally resistant to heavy metal-induced autoimmunity, anti-CTLA-4 treatment leads to the production of anti-nucleolar Abs, thereby overcoming the genetic restriction of the disease. In mice deficient for the FcγRIIB, HgCl2 administration did not trigger autoantibody production, but resulted in an increase in IgE serum levels. Taken together, these results indicate that different inhibitory mechanisms regulate various manifestations of this autoimmune syndrome.

Section: Discussionsupporting

confidence: 85%

Inhibitory Signal Override Increases Susceptibility to Mercury-Induced Autoimmunity

Zheng

Monestier

2003

“…The current finding that lupus-like disease in BXSB mice does not require IL-4 is similar to what has been observed for several other humoral-mediated autoimmune diseases, including mercuryinduced systemic autoimmunity (29,35) and experimental autoimmune myasthenia gravis (EAMG) (41). In the case of EAMG, IL-4 deficiency may in fact facilitate development of disease (42).…”

Section: Discussionsupporting

confidence: 84%

“…In BXSB and MRL-Fas lpr mice, the increases in IL-4 levels and IL-4 producing cells although present are much less than the increases observed in IFN-␥ levels or IFN-␥-producing cells (27,30,34). Knockout of the IL-4 gene had no effect on disease induction in the mercury-induced model of systemic autoimmunity, which was previously considered a prototypic Th2-mediated humoral disease (29,35). Finally, expression of an IL-4 transgene by B cells in (NZW ϫ C57BL/6.Yaa)F 1 mice protected rather than enhanced the development of lupus nephritis, and this protection appeared to be due to deviation of the autoantibody response away from especially pathogenic Th1-mediated IgG subclasses such as IgG3 (36).…”

Section: D4mentioning

confidence: 98%

Development of Lupus in BXSB Mice Is Independent of IL-4

Kono

Balomenos

Park

et al. 2000

Although systemic lupus erythematosus appears to be a humorally mediated disease, both Th1 and Th2 type responses have been implicated in its pathogenesis. The Th1 response, as exemplified by IFN-γ production, has been uniformly shown in mouse lupus models to be critical for disease induction. The role of Th2 type responses, however, is more complicated, with some studies showing detrimental and others beneficial effects of IL-4 in these models. To further address this issue, we generated and analyzed IL-4 gene-deficient BXSB mice. Mice homozygous for this deletion had significantly lower serum levels of total IgG1 compared with wild-type BXSB, consistent with the lack of IL-4. However, no significant differences were observed in mortality, spleen weight, severity of glomerulonephritis, levels of anti-chromatin and anti-ssDNA Abs, or frequency of activated (CD44high) CD4+ T cells. The anti-chromatin Ab isotype response was virtually all Th1 type in both the knockout and wild-type BXSB. These findings directly demonstrate that IL-4 and, by inference, Th2 cells are not obligatory participants in the induction and maintenance of lupus in this strain.

“…This suggests that this feature of HgCl 2 -induced autoimmunity is BAFF-independent and is consistent with previous findings that mice either transgenic for BAFF or injected with BAFF showed significantly increased levels of serum IgM and IgA, but not IgG (6,34,40). Previous studies of this model have also shown that different features such as ANoA production and polyclonal activation can be individually manipulated (44,45). The present findings confirm that the various manifestations of Hg-induced autoimmunity are separately regulated.…”

Section: Discussionsupporting

confidence: 93%

A Role for B Cell-Activating Factor of the TNF Family in Chemically Induced Autoimmunity

Zheng¹,

Gallucci

Gaughan

et al. 2005

After exposure to subtoxic doses of heavy metals such as mercury, H-2s mice develop an autoimmune syndrome consisting of the rapid production of IgG autoantibodies that are highly specific for nucleolar autoantigens and a polyclonal increase in serum IgG1 and IgE. In this study, we observe that HgCl2 administration in susceptible mice results in the elevated production of B cell-activating factor of the TNF family ((BAFF) also known as BLyS, TALL-1, zTNF-4, THANK, and TNSF13B), a B cell growth factor belonging to the TNF family. A transmembrane activator and calcium-modulating and cyclophilin ligand interactor (TACI)-Ig fusion protein (which neutralizes both BAFF and a proliferation-inducing ligand (APRIL), another TNF family member) inhibited Hg-induced autoantibody or serum IgE production. These results are discussed in the context of the inhibitory effect of TACI-Ig on B cell maturation at the transitional stage.