Sjögren's syndrome is a systemic autoimmune disease characterized by lymphocytic infiltrations of lacrimal and salivary glands. SS patients produce a variety of autoantibodies, including RF and ANA. Genetic factors, including HLA-DR3, predispose to primary SS. In contrast to normal SGs, the SS SG epithelial cells express high levels of HLA-DR antigens. This class II gene expression on the target organ may represent the structural basis for HLA-associated disease susceptibility. The glands are infiltrated with CD4+ T cells that can produce cytokines, including IL-2 and interferon-gamma. B cells within the SG produce autoantibodies, including RF. These SG B cells frequently use the VKIIIb subgroup of kappa light chain, a feature that SS patients share with Waldenstrom's macroglobulinemia patients. B cells undergo small clonal expansions that can be detected on Southern blot as immunoglobulin gene rearrangements, and SS patients have a markedly increased risk of developing non-Hodgkin's B-cell lymphoma involving the SGs and cervical lymph nodes. Due to accessibility of the SG for biopsy and the characteristic patterns of autoantibody production, SS provides an opportunity to study the target organ for autoimmune destruction and the transition from autoimmunity to lymphoma.