Immune-pathophysiology of lymphocytic foci in Sjogren's syndrome

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DESCRIPTION (provided by applicant): Sjogren's syndrome (SjS) is an autoimmune disease characterized by loss of exocrine function as a result of a chronic immune attack primarily against the salivary and lacrimal glands leading to xerostomia (dry mouth) and xerophthalmia (dry eyes). While a number of other tissues may become involved (e.g., the Gl tract, skin, the lungs, the vasculature and muscular systems, kidneys, bladder and vagina), of particular interest are the various sensory, peripheral, cranial and myelopathic neuropathies that develop in nearly 20% of SjS patients. Recent studies suggest that B cells and autoantibodies play a critical role in onset of exocrine glandular dysfunction. Although SjS is generally not considered a lethal disease in the absence of B cell lymphoma formation, patients have an increasingly diminished quality of life with disease progression. One feature of SjS autoimmunity in both humans and animal models is the formation of germinal-like centers in the salivary and lacrimal glands, referred to as lymphocytic foci (LF). LF and LF scores, while important diagnostic criteria for clinical disease, do not always correlate with disease severity, indicating a general lack of understanding about the nature and function of cells within LF; yet, LF must contain important information about the autoimmune response that ultimately results in exocrine glandular dysfunction and eventually destruction. Thus, the fundamental goal of the research proposed herein is to focus on defining the nature of the leukocyte populations forming within LF of the salivary glands and determine if these cell populations identify disease mechanisms involved in SjS autoimmunity. To address these issues, two specific aims are advanced: (1) Define and characterize the IL-23 secreting and CD4+ TH17 memory T cell populations infiltrating the salivary glands during development of SjS-like disease in the C57BL/6.NOD-4ecf Aec2 mouse model of SjS, and (2) Determine the possible regulatory potential of IL-27 on the CD4+ TH17 memory T cell populations for preventing development of SjS in the C57BU6.NOD-.Aecf Aec2 mouse model. The proposed research represents the core activity in preparing the principal investigator for a future career in SjS research, while the results are expected to establish the basis for future translational studies to humans by better defining factors underlying development and onset of SjS-associated manifestations. Results defining and characterizing leukocytic populations of LF in a mouse model of SjS, together with technologies developed during the conduct of the studies will establish the feasibility for transitional studies using human specimens. The present studies will further provide important data on the dynamic interactions of leukocytic populations and their products within the glands resulting in the immuno-pathophysiological manifestations and complications associated with long-term disease states.