title: Silica Triggers Inflammation and Ectopic Lymphoid Neogenesis in the Lungs in Parallel with Accelerated Onset of Systemic Autoimmunity and Glomerulonephritis in the Lupus-Prone NZBWF1 Mouse.
abstract: Genetic predisposition and environmental factors influence the development of human autoimmune disease. Occupational exposure to crystalline silica (cSiO2) has been etiologically linked to increased incidence of autoimmunity, including systemic lupus erythematosus (SLE), but the underlying mechanisms are poorly understood. The purpose of this study was to test the hypothesis that early repeated short-term cSiO2 exposure will modulate both latency and severity of autoimmunity in the lupus-prone female NZBWF1 mouse. Weekly intranasal exposure to cSiO2 (0.25 and 1.0 mg) for 4 wk beginning at 9 wk of age both reduced latency and increased intensity of glomerulonephritis. cSiO2 elicited robust inflammatory responses in the lungs as evidenced by extensive perivascular and peribronchial lymphoplasmacytic infiltration consisting of IgG-producing plasma cells, and CD45R+ and CD3+ lymphocytes that were highly suggestive of ectopic lymphoid tissue (ELT). In addition, there were elevated concentrations of immunoglobulins and the cytokines MCP-1, TNF-α and IL-6 in bronchoalveolar lavage fluid. cSiO2-associated kidney and lung effects paralleled dose-dependent elevations of autoantibodies and proinflammatory cytokines in plasma. Taken together, cSiO2-induced pulmonary inflammation and ectopic lymphoid neogenesis in the NZBWF1 mouse corresponded closely to systemic inflammatory and autoimmune responses as well as the early initiation of pathological outcomes in the kidney. These findings suggest that following airway exposure to crystalline silica, in mice genetically prone to SLE, the lung serves as a platform for triggering systemic autoimmunity and glomerulonephritis.
authors.affiliation: Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, United States of America; Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Bates
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States of America; Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Brandenberger
authors.affiliation: Department of Pathobiological Studies, School of Veterinary Medicine, Louisiana State University, Baton Rogue, Louisiana, United States of America.
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Langohr
authors.affiliation: Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, United States of America; Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, United States of America; Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
authors.affiliation: Center for Environmental Health Sciences, University of Montana, Missoula, Montana, United States of America.
authors.forename: Andrij
authors.initials: A
authors.lastname: Holian
authors.affiliation: Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan, United States of America; Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Pestka
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008297:Male; D051379:Mice; D012822:Silicon Dioxide / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide