Secondary exposure to heavy metal in genetically susceptible mice leads to acceleration of autoimmune response.

Exposure to mercury (Hg) and silver (Ag) has been shown to induce autoimmune diseases in genetically susceptible rodents. Here, A.SW mice were initially exposed to HgCl, AgNO or tap water (control) for 3 weeks.

Autoantibodies in outbred Swiss Webster mice following exposure to gold and mercury.

Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored.

Mechanisms of Environment-Induced Autoimmunity.

Although numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating persistent inflammation.

Lipid membranes accelerate amyloid formation in the mouse model of AA amyloidosis.

Introduction: AA amyloidosis develops as a result of prolonged inflammation and is characterized by deposits of N-terminal proteolytic fragments of the acute phase reactant serum amyloid A (SAA). Macrophages are usually found adjacent to amyloid, suggesting their involvement in the formation and/or degradation of the amyloid fibrils. Furthermore, accumulating evidence suggests that lipid membranes accelerate the fibrillation of different amyloid proteins.

Mercury-induced inflammation and autoimmunity.

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.

Bank1 and NF-kappaB as key regulators in anti-nucleolar antibody development.

Systemic autoimmune rheumatic disorders (SARD) represent important causes of morbidity and mortality in humans. The mechanisms triggering autoimmune responses are complex and involve a network of genetic factors. Mercury-induced autoimmunity (HgIA) in mice is an established model to study the mechanisms of the development of antinuclear antibodies (ANA), which is a hallmark in the diagnosis of SARD.

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN.

Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus, with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA).

HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity.

The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies.

Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice.

Background: Following human mercury (Hg) exposure, the metal accumulates in considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg have been studied extensively, factors responsible for interindividual variation in humans are largely unknown. Differences in accumulation of renal Hg between inbred mouse strains suggest a genetic interstrain variation regulating retention or/and excretion of Hg.

A tandem repeat in decay accelerating factor 1 is associated with severity of murine mercury-induced autoimmunity.

Decay accelerating factor (DAF), a complement-regulatory protein, protects cells from bystander complement-mediated lysis and negatively regulates T cells. Reduced expression of DAF occurs in several systemic autoimmune diseases including systemic lupus erythematosus, and DAF deficiency exacerbates disease in several autoimmune models, including murine mercury-induced autoimmunity (mHgIA). Daf1, located within Hmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate.

MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1.

Background: Urinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors.

Immunohistochemical evaluation of cell cycle regulators: impact on predicting prognosis in stage t1 urinary bladder cancer.

Background and Objective. The cell cycle is regulated by proteins at different checkpoints, and dysregulation of this cycle plays a role in carcinogenesis. Matrix metalloproteinases (MMPs) are enzymes that degrade collagen and promote tumour infiltration.

Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies.

Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours.

Objective: Stage T1 urothelial carcinoma of the bladder (UCB) exhibits heterogeneous clinical behaviour, and the treatment is controversial. The aim of this study was to evaluate prognostic factors for UCB in a defined, population-based cohort comprising patients with a first time diagnosis of primary stage T1 UCB.

Material And Methods: The study population initially consisted of 285 patients with primary stage T1 UCB reported to the regional Bladder Cancer Registry in the Southeast Healthcare Region of Sweden from 1992 to 2001.

Definition of IFN-γ-related pathways critical for chemically-induced systemic autoimmunity.

IFN-γ is essential for idiopathic and murine mercury-induced systemic autoimmunity (mHgIA), and heterozygous IFN-γ(+/-) mice also exhibit reduced disease. This suggests that blocking specific IFN-γ-related pathways that may only partially inhibit IFN-γ production or function will also suppress autoimmunity. To test this hypothesis, mice deficient in genes regulating IFN-γ expression (Casp1, Nlrp3, Il12a, Il12b, Stat4) or function (Ifngr1, Irf1) were examined for mHgIA susceptibility.

HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder.

Objective: The HER2 receptor is involved in pathways essential for cell proliferation, and is an important predictive and prognostic factor in breast cancer. HER2 probably plays a critical role in many types of cancer, including urothelial carcinoma of the bladder (UCB). Stage T1 UCB exhibits heterogeneous clinical behaviour, and the frequency of HER2 expression in such disease has not been thoroughly examined.

β2-microglobulin is required for the full expression of xenobiotic-induced systemic autoimmunity.

Mercury exposure in both humans and mice is associated with features of systemic autoimmunity. Murine HgCl₂-induced autoimmunity (mHgIA) requires MHC Class II, CD4⁺ T-cells, co-stimulatory molecules, and interferon-γ (IFN-γ), similar to spontaneous models of systemic lupus erythematosus (SLE). β₂-microglobulin (B2m) is required for functional MHC Class I molecules and the neonatal F(c) receptor (F(c)Rn).

Deficiency of activating Fcγ-receptors reduces hepatic clearance and deposition of IC and increases CIC levels in mercury-induced autoimmunity.

Background: Inorganic mercury (Hg) induces a T-cell dependent, systemic autoimmune condition (HgIA) where activating Fcγ-receptors (FcγRs) are important for the induction. In this study we examined the influence of activating FcγRs on circulating levels and organ localization of immune complexes (IC) in HgIA.

Methods And Principal Findings: Mercury treated BALB/c wt mice showed a significant but modest increase of circulating IC (CIC) from day 12 until day 18 and day 35 for IgG2a- and IgG1- CIC, respectively.

Toxicology of autoimmune diseases.

Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators.

T cells are required for the production of blister-inducing autoantibodies in experimental epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita is a prototypical organ-specific autoimmune disease caused by autoantibodies against type VII collagen of the dermal-epidermal junction. Although mechanisms of autoantibody-induced blister formation were extensively characterized, the initiation of autoantibody production in autoimmune blistering diseases is still poorly defined. In the current study, we addressed the role of T cells for the production of blister-inducing autoantibodies in mice immunized with type VII collagen.

Mercury toxicokinetics--dependency on strain and gender.

Mercury (Hg) exposure from dental amalgam fillings and thimerosal in vaccines is not a major health hazard, but adverse health effects cannot be ruled out in a small and more susceptible part of the exposed population. Individual differences in toxicokinetics may explain susceptibility to mercury. Inbred, H-2-congenic A.

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

Fc-receptors for IgG (FcgammaR) link cellular and humoral immune responses, controlling the balance between activating and inhibitory immune responses, and are involved in autoimmune diseases. Mercury (Hg) induces an autoimmune condition in genetically (H-2(s,q,f)) susceptible mice characterized by lymphoproliferation, hypergammaglobulinemia and IgG antinucleolar antibodies (ANoA). Here we investigate the role of activating (FcgammaRI, FcgammaRIII) and inhibitory (FcgammaRIIb) Fc-receptors on mercury-induced autoimmunity (HgIA) using DBA/1 mice (H-2(q)) with targeted FcgammaR mutations and wild type (wt) mice.

Mercury species in lymphoid and non-lymphoid tissues after exposure to methyl mercury: correlation with autoimmune parameters during and after treatment in susceptible mice.

Methylmercury (MeHg) is present in the environment as a result of the global cycling of mercury, although anthropogenic sources may dramatically increase the availability in confined geographical areas. Accumulation of MeHg in the aquatic food chain is the dominating way of exposure in mammals, which accumulate MeHg in all organs, including the brain. Demethylation has been described in the organs, especially in phagocytic cells, but mainly in the flora of the intestinal tract.