Sjogren's Syndrome (SS) is an autoimmune disease, characterized by widespread inflammation in the exocrine glands and other organs resulting in dryness of the lining surfaces of the body, most notably, dry mouth and dry eyes. In addition it can involve numerous other organs such as the joints, skin and nervous sytem. Under this project, the GTTB- SS Clinic conducts clinical investigations and clinical trials, and collaborates with laboratory investigators in GTTB, other NIH laboratories and Institutions outside the NIH in order to understand the mechanisms underlying this disease. The ultimate goal of our research is to find treatments for Sjogren?s Syndrome (SS) that are safe, effective and target specific steps in the pathogenesis of SS. To achieve this goal, we focus our research in two broad categories. Natural history studies include observational and retrospective studies with the goal to expand our knowledge about the pathogenesis of SS, to improve our diagnostic and prognostic tools and to identify targets for new therapies. The other major area involves the evaluation of novel treatments in patients with Sjogren's Syndrome. The period since the last reporting was marked by the appointment of a new Head and expansion of the Sjogren's Syndrome Clinic leading to considerable changes in the organization of the SS Clinic. Clinical activities have increased gradually with arrival of two excellent rheumatology reseach fellows during the year. The clinical activities focused primarily on the natural history studies and on the develoment of new protocols. In collaboration with other laboratories in GTTB we established a program to sytematically evalute the effect of immunomodulation in both patients and animal models of Sjogren's Syndrome. The goal of this collaborative effort is to narrow the gap between basic science and clinical practice. To achieve this, it is essential to have well characterized, high quality clinical data from patients. To this effect we have started a program to transform the large amount of patient-related research data available primarily in hardcopies and in various small electronic formats into a single flexible, powerful, user-friendly electronic relational database. The final system will also enable direct entry of data by patients and health care providers into the electronic database, significantly improving efficacy. On the laboratory side we have continued on-going collaborations and started some new projects. To identify biomarkers of Sjogren?s Syndrome (SS) in the saliva,we analyzed protein expression profiles of 39 SS patients and 19 controls by by proteomic methods, in collaboration with the laboratory of Human Craniofacial Genetics (NIDCR). We identified significant increases of beta 2-microglobulin, lactoferrin, immunoglobulin light chain and polymeric Ig receptor in the SS group. Increases were present in all stages of disease. Two unmatched proteins, presumably proline-rich proteins, and amylase were reduced in the patient groups. The salivary proteomic profile of Sjogren?s Syndrome patients reflected both increased inflammatory activity and acinar damage when compared to controls. These results indicate that high-throughput proteomic approaches can be used to discover biomarkers of SS in parotid saliva. The other major area of our efforts focuses on evaluating novel treatments for Sjogren's Syndrome. The ultimate aim is to develop safe and effective treatments that target specific steps in the pathogenesis of SS. Our general approach is to start with early stage clinical studies (Phase I/II) to establish the safety of an intervention, and at the same time, collect data about its possible efficacy. Our goal is to understand why a particular drug targeting specific components of the immune system may or may not work. Therefore, we will combine these clinical trials with thorough basic science evaluations to learn more about the pathogenesis of SS and the biologic effects of the intervention. The main goal of the Sjogren?s Clinic is to perform translational research that can be best achieved in smaller studies including mechanistic studies that may be impractical in a multicenter setting. We have identified several drugs that may be available for these studies and plan to start several clinical trials in the next year.