Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice

Abstract

Inhalational exposure to crystalline silica is linked to several debilitating systemic autoimmune diseases characterized by a prominent humoral immune component, but the mechanisms by which silica induces autoantibodies is poorly understood. To better understand how silica lung exposure breaks B cell tolerance and unleashes autoreactive B cells, we exposed both wildtype mice of healthy C57BL/6 and lupus-prone BXSB, MRL, and NZB strains and mice carrying an autoantibody transgene on each of these backgrounds to instilled silica or vehicle and monitored lung injury, autoimmunity, and B cell fate. Silica exposure induced lung damage and pulmonary lymphoid aggregates in all strains, including in genetically diverse backgrounds and in autoantibody transgenic models. In wildtype mice strain differences were observed in specificity of autoantibodies and site of enhanced autoantibody production, consistent with genetic modulation of the autoimmune response to silica. The unique autoantibody transgene reporter system permitted the in vivo fate of autoreactive B cells and tolerance mechanisms to be tracked directly, and demonstrated the presence of transgenic B cells and antibody in pulmonary lymphoid aggregates and bronchoalveolar lavage fluid, respectively, as well as in spleen and serum. Nonetheless, B cell enumeration and transgenic antibody quantitation indicated that B cell deletion and anergy were intact in the different genetic backgrounds. Thus, silica exposure sufficient to induce substantial lung immunopathology did not overtly disrupt central B cell tolerance, even when superimposed on autoimmune genetic susceptibility. This suggests that silica exposure subverts tolerance at alternative checkpoints, such as regulatory cells or follicle entry, or requires additional interactions or co-exposures to induce loss of tolerance. This possibility is supported by results of differentiation assays that demonstrated transgenic autoantibodies in supernatants of Toll-like receptor (TLR)7/TLR9-stimulated splenocytes harvested from silica-exposed, but not vehicle-exposed, C57BL/6 mice. This suggests that lung injury induced by silica exposure has systemic effects that subtly alter autoreactive B cell regulation, possibly modulating B cell anergy, and that can be unmasked by superimposed exposure to TLR ligands or other immunostimulants.

Demonstration of Subclinical Early Nephrotoxicity Induced by Occupational Exposure to Silica among Workers in Pottery Industry

“…22 More recently, some reports and studies are associating autoimmune renal diseases and silica exposure where autoantibodies against nuclear and other self-antigens deposit in and damage kidneys. 23,24 The results revealed that there was a highly significant positive correlation between the duration of occupational exposure to silica and the elevated levels of the measured urinary biomarkers among silica-exposed workers. Additionally, the linear regression analysis showed that the duration of silica exposure could be considered a highly significant predicting factor for the glomerular and tubular subclinical affection.…”

Perspective: The Lung, Particles, Fibers, Nanomaterials, and Autoimmunity

“…A significant outcome of the chronic pulmonary inflammation induced by crystalline silica, in animal models, is the formation of TLS (59). These structures comprise accumulations of B and T cells as well as follicular dendritic cells (FDC) and plasma cells (59)(60)(61). The presence of immunoglobulin including autoantibodies in the BALF of silica-exposed mice (60,61) suggests that the lung is a site of autoantibody production.…”

“…These structures comprise accumulations of B and T cells as well as follicular dendritic cells (FDC) and plasma cells (59)(60)(61). The presence of immunoglobulin including autoantibodies in the BALF of silica-exposed mice (60,61) suggests that the lung is a site of autoantibody production. A variety of autoantibody specificities are found in both humans (62) and experimental models (59,60,63) after silica exposure.…”

“…The presence of immunoglobulin including autoantibodies in the BALF of silica-exposed mice (60,61) suggests that the lung is a site of autoantibody production. A variety of autoantibody specificities are found in both humans (62) and experimental models (59,60,63) after silica exposure. These include anti-DNA, -SS-A/Ro, -SS-B/La, -Scl70, -Sm, and -RNP.…”

Silica Induction of Diverse Inflammatory Proteome in Lungs of Lupus-Prone Mice Quelled by Dietary Docosahexaenoic Acid Supplementation

“…Notably, crystalline silica dust (cSiO 2 ) exposure in construction, mining, and ceramics industries has been epidemiologically associated with lupus and other autoimmune diseases (6)(7)(8)(9). Induction of autoimmunity can be recapitulated at the preclinical level by introduction of cSiO 2 dust particles into the lungs of mice predisposed to lupus (10)(11)(12)(13)(14). Our laboratory has found in lupus-prone female NZBWF1 hybrid mice that, following four repeated weekly intranasal instillations with cSiO 2 , latency of glomerulonephritis onset is reduced by three months (15,16).…”