Primary Sjgren's syndrome (SS) is a systemic autoimmune disorder characterized by the presence of circulating autoantibodies, inflammation of lacrimal and salivary glands (SG), and a debilitating dryness of the eyes and mouth. The long term goal of our research is to understand a critical question in SS pathogenesis: how do autoantibodies targeting intracellular proteins exert pathogenic effects in SS? This proposal will focus on Ro52-reactive autoantibodies. Almost 70% of SS patients are positive for anti-Ro52 and their presence is associated with higher disease severity. However, the precise role of Ro52-reactive autoantibodies in SS pathogenesis remains unknown. By using unique patient material available to us in the Oklahoma Sjgren's Syndrome Center of Translational Research and novel experimental mouse model systems developed in our laboratory this proposal will investigate the pathogenic role of anti-Ro52 autoantibodies in SS. Work from our laboratory has firmly established that systemic activation of innate immunity is directly involved in different facets of SS pathogenesis. Our recently published work demonstrates for the first time that Ro52- generated antibody responses are directly involved in SG dysfunction. Based on our substantial published and preliminary data, this proposal will test the overall hypothesis that interactions between activated innate immunity and anti-Ro52 autoantibodies play a critical role in SS pathogenesis.
In Aim 1, we will assess innate immune mechanisms responsible for autoantibody deposition in SG. We will test the hypothesis that in vivo activation of innate immunity upregulates Ro52 expression within the SGs, and influences deposition of anti-Ro52 antibodies within the tissue.
In Aim 2, we will test the hypothesis that IgG deposition in SGs of SS patients is associated with SS pathogenesis. Using our novel Ro52-immunization model we will also test the hypothesis that antibody deposition and glandular dysfunction represent the early stage of SS, which is followed by lymphocytic infiltration in salivary glands.
In Aim 3, we will evaluate the mechanisms of anti-Ro52 antibody mediated modulation of type I IFN response in SS. Based on our preliminary data we will test the hypothesis that cell penetrating anti-Ro52 antibodies interfere with the cellular functions of Ro52 and cause a dysregulated type I IFN response in salivary gland and plasmacytoid dendritic cells. This proposal brings together a diverse team of experts; immunologists, geneticists, molecular biologist, biostatisticians and clinical researchers to address the pathogenic mechanisms of one of the most prevalent autoimmune disorder. By integrating multiple expertise, a novel mouse model system and unique SS patient material, this proposal will define the mechanism(s) responsible for innate immunity and autoantibody-mediated SG pathology in SS.
Sjgren's syndrome is a chronic autoimmune disorder mainly affecting salivary glands and lacrimal glands and causes severe dry mouth and dry symptoms. This proposal seeks to understand how antibodies reactive with certain self-proteins cause dry mouth. This work will lead to better understanding of pathogenic mechanisms in Sjgren's syndrome and help in devising new diagnostic tests and treatments for the disease.
|Sroka, Magdalena; Bagavant, Harini; Biswas, Indranil et al. (2018) Immune response against the coiled coil domain of Sjögren's syndrome associated autoantigen Ro52 induces salivary gland dysfunction. Clin Exp Rheumatol 36 Suppl 112:41-46|
|Trzeciak, Marta; Bagavant, Harini; Papinska, Joanna et al. (2018) Immune Response Targeting Sjögren's Syndrome Antigen Ro52 Suppresses Tear Production in Female Mice. Int J Mol Sci 19:|
|Bagavant, Harini; Trzeciak, Marta; Papinska, Joanna et al. (2018) A Method for the Measurement of Salivary Gland Function in Mice. J Vis Exp :|
|Papinska, J; Bagavant, H; Gmyrek, G B et al. (2018) Activation of Stimulator of Interferon Genes (STING) and Sjögren Syndrome. J Dent Res 97:893-900|
|Sima, Corneliu; Montero, Eduardo; Nguyen, Daniel et al. (2017) ERV1 Overexpression in Myeloid Cells Protects against High Fat Diet Induced Obesity and Glucose Intolerance. Sci Rep 7:12848|