title: Pathogenic role of endogenous TNF-α in the development of Sjögren's-like sialadenitis and secretory dysfunction in non-obese diabetic mice.
abstract: Patients with Sjögren's syndrome (SS), an autoimmune disease primarily affecting exocrine glands, exhibit enhanced TNF-α expression in the saliva and salivary glands. However, the precise in vivo role of TNF-α during the initiation and development of SS is not clearly defined. The present study is undertaken to determine the function of endogenously produced TNF-α in the pathogenesis of SS in non-obese diabetic (NOD) mice, a model of this human disease. Administration of a neutralizing anti-TNF-α antibody to female NOD mice during the stage prior to disease onset significantly improved salivary secretion, indicating a remission of clinical symptoms of SS. TNF-α blockade also decreased the number of leukocyte foci and reduced the number of T cells and B cells in the submandibular glands (SMG). Moreover, TNF-α blockade reduced T-bet protein levels in the SMG, suggesting a decrease in T helper 1 and T cytotoxic 1 cells. These cellular changes induced by TNF-α neutralization were associated with a reduction in T- and B-cell chemoattractants CXCL9 and CXC13. In addition, TNF-α blockade markedly increased the expression level of tight junction protein claudin-1 and water channel protein aquaporin-5, two key factors required for normal salivary secretion, in the SMG. Collectively, these findings indicate that endogenous TNF-α has a pathogenic role in the development of SS in the NOD model of this disease.
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, Cambridge, MA, USA.|Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D051402:Aquaporin 5 / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000378:metabolism; D062445:Claudin-1 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016688:Mice, Inbred NOD; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012463:Saliva / Q000378:metabolism; D012793:Sialadenitis / Q000378:metabolism* / Q000473:pathology; D012859:Sjogren's Syndrome / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013363:Submandibular Gland / Q000187:drug effects / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*
chemical_list: D000974:Antibodies, Antinuclear; D057134:Antibodies, Neutralizing; D051402:Aquaporin 5; D054382:Chemokine CXCL13; D054370:Chemokine CXCL9; D062445:Claudin-1; D014409:Tumor Necrosis Factor-alpha