Different Stages of Primary Sjogren's Syndrome Involving Lymphotoxin and Type 1 IFN

Primary Sjogren'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-alpha) and lymphotoxin alpha (LT alpha) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-alpha in pSS using an animal model, the IL-14 alpha (IL14 alpha TG) transgenic mouse. IL14 alpha TG mice lacking the type 1 IFNR (IL14 alpha TG.IFNR-/-) had the same submandibular gland and lacrimal gland injury as did the IL14 alpha TG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14 alpha TG.IFNR-/- mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14 alpha TG mice was inhibited in IL14 alpha TG.IFNR-/- mice. Production of LTa was identified in both IL14 alpha TG mice and IL14 alpha TG.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 LTa; 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.