Mercury-induced inflammation and autoimmunity

Abstract

Background: Human exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity. This is supported by experimental animal model studies, which convincingly demonstrate the biological plausibility of mercury as a factor in the pathogenesis of autoimmune disease.

Scope of the review: In this review, we focus on ability of mercury to elicit inflammatory and autoimmune responses in both humans and experimental animal models.

Major conclusions: Although subtle differences exist, the inflammatory and autoimmune responses elicited by mercury exposure in humans and experimental animal models show many similarities. Proinflammatory cytokine expression, lymphoproliferation, autoantibody production, and nephropathy are common outcomes. Animal studies have revealed significant strain dependent differences in inflammation and autoimmunity suggesting genetic regulation. This has been confirmed by the requirement for individual genes as well as genome wide association studies. Importantly, many of the genes required for mercury-induced inflammation and autoimmunity are also required for idiopathic systemic autoimmunity. A notable difference is that mercury-induced autoimmunity does not require type I IFN. This observation suggests that mercury-induced autoimmunity may arise by both common and specific pathways, thereby raising the possibility of devising criteria for environmentally associated autoimmunity.

General significance: Mercury exposure likely contributes to the pathogenesis of autoimmunity.

Keywords: Animal model; Autoimmunity; Human; Inflammation; Mercury.

Figure 1.

The pathogenesis of inflammatory and autoimmune responses induced by subcutaneous mercury exposure in mouse models. The earliest events occurring within minutes to hours (Initiation) involve a toxic response that includes cell death and tissue damage with the release of lysosomal constituents such as cathepsin B (CatB), NETosis, and phagocytosis of cellular material. Proteolysis of self-proteins such as fibrillarin to autoantigenic forms also likely begins at this time. The ensuing Localized Inflammation occurs within hours after initial exposure and is associated with elevated CatB activity and proinflammatory cytokine expression, which is exacerbated by IL-6 and IFN-γ. Within the first 7 days, there is T Cell Activation and hypertrophy of draining Lymph Nodes dependent on co-stimulation (e.g. CD28, CD40L) and associated with concomitant reduced CD55 expression on CD4+ T cells. The subsequent B cell activation and generation of polyclonal and autoantibodies (AutoAbs) including the MHC-restricted anti-fibrillarin occurs by 7-14 days and requires IFN-γ, and likely B cell endosomal TLR signaling. Pathology, occurring within the first month, is characterized by immunoglobulin and complement deposition in the kidney. Known and Postulated events are indicated based on the literature and current understanding of inflammatory and autoimmune processes. Mouse strains that typify specific levels of response, such as resistance (DBA/2), autoAbs without pathology (C57BL/6, A/J) and autoAbs with immune deposits (B10.S, ASW, SJL) are shown.