title: Different stages of primary Sjogren's syndrome involving lymphotoxin and type 1 IFN.
abstract: Primary Sjögren's syndrome (pSS) is a complex autoimmune disease starting in the salivary and lacrimal glands and continuing to involve the lungs and kidneys with the eventual development of lymphoma. Many studies have emphasized the role of type 1 IFN (IFN-α) and lymphotoxin α (LTα) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-α in pSS using an animal model, the IL-14α (IL14αTG) transgenic mouse. IL14αTG mice lacking the type 1 IFNR (IL14αTG.IFNR(-/-)) had the same submandibular gland and lacrimal gland injury as did the IL14αTG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14αTG.IFNR(-/-) mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14αTG mice was inhibited in IL14αTG.IFNR(-/-) mice. Production of LTα was identified in both IL14αTG mice and IL14αTG.IFNR(-/-) mice at the time that salivary gland injury was occurring. These and previous studies suggest a model for pSS that separates the disease into several stages: 1) initial injury to the submandibular and lacrimal glands via an environmental insult and LTα; 2) amplification of local injury via the production of type 1 IFN; injury to the parotid glands, lungs, and kidneys is seen; 3) progression of systemic inflammation with the eventual development of large B cell lymphoma. Understanding these different stages will help to develop strategies for treatment of patients with pSS based on the status of their disease.
authors.affiliation: Division of Allergy, Immunology and Rheumatology, Department of Medicine, State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Shen
authors.forename: Lakshmanan
authors.initials: L
authors.lastname: Suresh
authors.forename: Kishore
authors.initials: K
authors.lastname: Malyavantham
authors.forename: Przemek
authors.initials: P
authors.lastname: Kowal
authors.forename: Jingxiu
authors.initials: J
authors.lastname: Xuan
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lindemann
authors.forename: Julian L
authors.initials: JL
authors.lastname: Ambrus
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D016898:Interferon-alpha / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics*; D007674:Kidney Diseases / Q000276:immunology; D007765:Lacrimal Apparatus / Q000276:immunology / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology; D016393:Lymphoma, B-Cell; D008233:Lymphotoxin-alpha / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010306:Parotid Gland / Q000276:immunology / Q000473:pathology; D012859:Sjogren's Syndrome / Q000276:immunology*; D013363:Submandibular Gland / Q000276:immunology / Q000473:pathology; D033921:Vesicular Transport Proteins
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016898:Interferon-alpha; D007378:Interleukins; D008233:Lymphotoxin-alpha; C545985:TXLNA protein, mouse; D033921:Vesicular Transport Proteins