Naturally occurring autoimmune disease in (NZB X NZW) F1 mice is correlated with suppression of MZ B cell development due to aberrant B Cell Receptor (BCR) signaling, which is exacerbated by exposure to inorganic mercury.

Autoimmune diseases are multifactorial and include environmental as well as genetic drivers. Although much progress has been made in understanding the nature of genetic underpinnings of autoimmune disease, by comparison much less is understood regarding how environmental factors interact with genetics in the development of autoimmunity and autoimmune disease. In this report, we utilize the (NZB X NZW) F1 mouse model of Systemic Lupus Erythematosus (SLE).

At low levels, inorganic mercury interference with antigen signaling is associated with modifications to a panel of novel phosphoserine sites in B cell receptor pathway proteins.

Epidemiological studies indicate that human and animal exposure to environmental mercury (Hg) disrupts normal immune system function, but the molecular mechanism responsible for this is still unresolved. We have previously utilized phospho-proteomic mass spectrometry to demonstrate that in the absence of B Cell Receptor (BCR) stimulation, exposure of B cells to Hg induces significant changes to a great many elements of the BCR signaling pathway in a concentration dependent manner. In this report, we have extended those initial findings by utilizing mass spectrometry to evaluate in detail the effect of low-level Hg exposure on BCR induced phospho-proteomic changes.

Elements of the B cell signalosome are differentially affected by mercury intoxication.

It has been suggested that environmental exposures to mercury contribute to autoimmune disease. Disruption of BCR signaling is associated with failure of central tolerance and autoimmunity, and we have previously shown that low levels of Hg(2+) interfere with BCR signaling. In this report we have employed multiparametric phosphoflow cytometry, as well as a novel generalization of the Overton algorithm from one- to two-dimensional unimodal distributions to simultaneously monitor the effect of low level Hg(2+) intoxication on activation of ERK and several upstream elements of the BCR signaling pathway in WEHI-231 B cells.

A systems toxicology approach identifies Lyn as a key signaling phosphoprotein modulated by mercury in a B lymphocyte cell model.

Network and protein-protein interaction analyses of proteins undergoing Hg²⁺-induced phosphorylation and dephosphorylation in Hg²⁺-intoxicated mouse WEHI-231 B cells identified Lyn as the most interconnected node. Lyn is a Src family protein tyrosine kinase known to be intimately involved in the B cell receptor (BCR) signaling pathway. Under normal signaling conditions the tyrosine kinase activity of Lyn is controlled by phosphorylation, primarily of two well known canonical regulatory tyrosine sites, Y-397 and Y-508.

HLA Immune Function Genes in Autism.

The human leukocyte antigen (HLA) genes on chromosome 6 are instrumental in many innate and adaptive immune responses. The HLA genes/haplotypes can also be involved in immune dysfunction and autoimmune diseases. It is now becoming apparent that many of the non-antigen-presenting HLA genes make significant contributions to autoimmune diseases.

T-cell receptor signaling is mediated by transient Lck activity, which is inhibited by inorganic mercury.

Genetically susceptible rodents exposed to low nontoxic levels of inorganic mercury (Hg(2+)) develop idiosyncratic autoimmune disease associated with defective T-cell function. However, the molecular mechanisms underlying this phenomenon remain mostly unexplained. Brief exposure of T cells to micromolar concentrations of Hg(2+) leads to physiologically relevant nontoxic cellular mercury burdens, and as we have previously reported, attenuates T-cell receptor (TCR) signal strength by approximately 50%.

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells.

The heavy metal mercury (Hg) is known to have immunomodulatory properties affecting lymphocyte signal transduction, death receptor signaling and autoimmunity. In this study we tested the hypothesis that Hg exposure would attenuate T-cell activation and caspase 8 and 3 activity in response to antigenic stimuli. To test this hypothesis, BALB/cJ mice were exposed to 10 mg/l mercuric chloride (HgCl(2)) in their drinking water for 2 weeks followed by injection with 20 microg of the Staphylococcal aureus enterotoxin B (SEB) superantigen.

Low and nontoxic inorganic mercury burdens attenuate BCR-mediated signal transduction.

The ubiquitous environmental heavy metal contaminant mercury (Hg) is a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease. However, the mechanism(s) whereby Hg initiates or perpetuates autoimmune responses, especially at the biochemical/molecular level, remain poorly understood. Recent work has established a relationship between impaired B-cell receptor (BCR) signal strength and autoimmune disease.

Inorganic mercury inhibits the activation of LAT in T-cell receptor-mediated signal transduction.

Little is known as to the molecular mechanisms involved with mercury intoxication at very low levels. Although the mechanism is not known, animal studies have nevertheless shown that low levels of mercury may target the immune system. Inorganic mercury (Hg2+) at very low (but non-toxic) levels can disrupt immune system homeostasis, in that genetically susceptible rodents develop idiosyncratic autoimmune disease, which is associated with defective T-cell function.

Inorganic mercury dissociates preassembled Fas/CD95 receptor oligomers in T lymphocytes.

Genetically susceptible rodents exposed to low burdens of inorganic mercury (Hg2+) develop autoimmune disease. Previous studies have shown that low, noncytotoxic levels of Hg2+ inhibit Fas-mediated apoptosis in T cells. These results suggest that inhibition of the Fas death receptor pathway potentially contributes to autoimmune disease after Hg2+ exposure, as a consequence of disruption of peripheral tolerance.

Gene expression influences on metal immunomodulation.

Heavy metals in the environment originate from both human activities and natural processes. Exposure to these metals can result in important changes to immune activity. Depending on the metal and dose, these changes can result in enhanced immune function, diminished immune responses, or altered responses that produce autoimmune disease.

Real-time control of neutrophil metabolism by very weak ultra-low frequency pulsed magnetic fields.

In adherent and motile neutrophils NAD(P)H concentration, flavoprotein redox potential, and production of reactive oxygen species and nitric oxide, are all periodic and exhibit defined phase relationships to an underlying metabolic oscillation of approximately 20 s. Utilizing fluorescence microscopy, we have shown in real-time, on the single cell level, that the system is sensitive to externally applied periodically pulsed weak magnetic fields matched in frequency to the metabolic oscillation. Depending upon the phase relationship of the magnetic pulses to the metabolic oscillation, the magnetic pulses serve to either increase the amplitude of the NAD(P)H and flavoprotein oscillations, and the rate of production of reactive oxygen species and nitric oxide or, alternatively, collapse the metabolic oscillations and curtail production of reactive oxygen species and nitric oxide.

Attenuation of CD95-induced apoptosis by inorganic mercury: caspase-3 is not a direct target of low levels of Hg2+.

Exposure to environmental mercury may be a factor that contributes to idiosyncratic autoimmune disease. Studies have demonstrated that inorganic, ionic mercury (i.e.

Inorganic mercury attenuates CD95-mediated apoptosis by interfering with formation of the death inducing signaling complex.

Inorganic mercury (Hg2+) modulates several lymphocyte signaling pathways and has been implicated as an environmental factor linked to autoimmune disease. From the standpoint that autoimmune diseases represent disorders of cell accumulation, in which dysregulated apoptosis may be one mechanism leading to the accumulation of autoreactive lymphocytes, we have been investigating the influences of Hg2+ on CD95-mediated apoptosis. We demonstrate here that low and noncytotoxic concentrations of Hg2+ impair CD95 agonist-induced apoptosis in representative Type-I and Type-II T cell lines.

Cutting edge: fever-associated temperatures enhance neutrophil responses to lipopolysaccharide: a potential mechanism involving cell metabolism.

Although much progress has been made in elucidating the mechanisms underlying the physiological regulation of fever, there is little understanding of the biological utility of fever's thermal component. Considering the evolutionary co-conservation of fever and innate immunity, we hypothesize that fever's thermal component might in general augment innate immune function and, in particular, neutrophil activation. Accordingly, we have evaluated the effect of febrile temperatures on neutrophil function at the single-cell level.