Sjogren's syndrome (SS) is an autoimmune disease characterized by the progressive destruction of the secretory acinar cells in exocrine glands.  Treatments used to date in advanced cases have not been successful in reversing or preventing disease progression.  Due to the lack of reliable biomarkers, it is currently not possible to make a positive diagnosis in the early stages of the disease.  The diagnosis of SS currently relies on either the appearance of lymphocytic infiltration in labial minor salivary glands or of autoantibodies against Ro and La in the serum.  However, disease severity, i.e. saliva production by the major salivary glands, frequently does not correlate with these clinical findings.  In the early stages of this disease, salivary gland morphology can be essentially normal and Ro and La autoantibodies can be absent, yet fluid secretion is often compromised.  These markers are neither particularly sensitive nor specific for SS.  Because saliva contains most of the same proteins found in serum, saliva can be used to diagnose and monitor local as well as systemic health status.  Saliva collection is easy, rapid and non-invasive.  Recent advances in high-throughput proteomics approaches have made it feasible to identify the proteins expressed in human fluids.  It is important to identify that subset of proteins whose expression is modified in saliva of SS patients relative to normal subjects.  There is a need to identify novel antibody markers.  The salivary glands of SS patients are enriched for memory B-cells that have presumably homed and established residence there on the basis of antigenic drive, chemokine attraction and adhesion molecule retention.  Using hypothesis-driven models of the pathogenesis of this disease, we propose to identify a dependable set of biomarkers in blood and saliva linked with early SS.  Specifically: In Aim 1, we will identify salivary proteins associated with SS.  In Aim 2, we will identify an autoantibody signature characteristic of SS.  In Aim 3, we will identify and validate biomarkers for the diagnosis and evaluation of SS.  Taken together, the results of these studies will address gaps in our understanding of the correlation between blood and saliva SS-specific biomarkers, salivary gland function, and disease progression, and will allow us to better understand the pathogenic processes resulting in the salivary infiltration by autoimmune memory B-cells and to develop a practical approach for the measurement of autoantibodies as SS biomarkers in the clinic.