Amelioration of Mercury-Induced Autoimmunity by 4-1BB

Abstract

In certain strains of mice, subtoxic doses of HgCl2 (mercuric chloride; mercury) induce a complex autoimmune condition characterized by the production of antinucleolar IgG Abs, lymphoproliferation, increased serum levels of IgG1/IgE Abs, and deposition of renal immune complexes. 4-1BB is an important T cell costimulatory molecule that has been implicated in T cell proliferation and cytokine production, especially production of IFN-γ. To elucidate T cell control mediated by the 4-1BB signaling pathway in this syndrome, we assessed the effect of administering agonistic anti-4-1BB mAb on mercury-induced autoimmunity. Groups of A.SW mice (H-2s) received mercury/control Ig or mercury/anti-4-1BB or PBS alone. Anti-4-1BB mAb treatment resulted in a dramatic reduction of mercury-induced antinucleolar Ab titers, serum IgG1/IgE induction, and renal Ig deposition. These effects may be related to the present finding that anti-4-1BB mAb decreases B cell numbers and function. The anti-4-1BB mAb-treated mercury group also showed a marked reduction in Th2-type cytokines but an increase in Th1-type cytokines and chemokines. Increased IFN-γ production due to anti-4-1BB mAb treatment appears to be responsible for the observed B cell defects because neutralization of IFN-γ in vivo substantially restored B cell numbers and partly restored IgG1/IgE. Collectively, our results indicate that 4-1BB mAb can down-regulate mercury-induced autoimmunity by affecting B cell function in an IFN-γ-dependent manner and thus, preventing the development of autoantibody production and tissue Ig deposition.

4-1BB signaling beyond T cells

“…7 Much progress has been made in understanding the basis of the biased in vivo 4-1BB effects, and several causative molecules have been indentified, the main players being interferon (IFN)-c, [8][9][10] tumor necrosis factor (TNF)-a, 8 transforming growth factor-b, 11,12 and indoleamine 2,3-dioxygenase. 13,14 Nearly a decade after the discovery of 4-1BB, two groups demonstrated functional expression of 4-1BB on DCs, 4,15 an attribute somewhat conflicting with its proposed role as a T cell-activating molecule.…”

The effect of activating and inhibiting Fc-receptors on murine mercury-induced autoimmunity

“…Furthermore, like many other autoimmune responses the Hg-induced ANoA reaction is dependent on T-cells [20], the T-cell costimulatory pathways CD28/B7 and CD40/CD40L [21], and IFNg [22]. Susceptibility is linked to the H-2A locus [18], and IgG isotypes dominate [26], which makes it similar to an adaptive immune response. Using adoptive cell transfer it has been shown that regulatory CD4þCD25þ cells from Hg-treated mice causes a long-lasting suppressive effect on ANA formation in Hg-treated recipients, while transfer of CD8þ cells had no effect [27].…”

How can a chemical element elicit complex immunopathology? Lessons from mercury-induced autoimmunity

“…For example, antibody stimulation of 4-1BB, a molecule belonging to the tumor necrosis factor receptor (TNFR) superfamily, downregulates HgIA disease manifestations significantly [77]. Similarly, blockade of signaling by the negative regulatory molecule CTLA-4 both increases disease severity in susceptible rodents and results in antinucleolar autoantibody production in genetically resistant DBA/2 mice [78].…”