In this project we will seek to better understand the pathogenesis of lgG4 related disease utilizing a multidisciplinary approach. Based on this knowledge we seek to influence the development of new therapies that may be applicable not just to this disease but to other autoimmune and fibrotic diseases as well. lgG4 related disease is a multisystem disorder characterized by tissue swelling/s, storiform fibrosis, obliterative phlebitis and high levels of plasma lgG4. While this disorder is likely to be autoimmune, an aberrant response to a pathogenic or commensal microbe has not been ruled out. In the principal proposal we will study in depth activated effector CD4+ T cell clones in subjects with lgG4-Related disease. We will examine the T cell receptor repertoire by Next Gen Sequencing, and obtain a detailed analysis of gene and protein expression in these clones in order to better understand how they are generated and how they function. We will perform single cell RNA seq and mass cytometry to understand the clonal origins of these effector T cells. Unique cell surface proteins found only in disease subjects will be identified. The mechanism by which these T cell clones influence fibrosis will be examined. The antibody repertoire of plasmablasts will also be identified, and novel disease related human monoclonal antibodies will be generated and the properties of clonally expanded plasmablasts will also be studied. Human ORFeome libraries will be interrogated with serum and disease related monoclonal lgG4 antibodies and disease specific antigens will be identified and used as tools to identify the antigenic peptides recognized by clonally expanded CD4+ T cells. In the Collaborative project studies will be performed to correlate oral, tissue and gut microbial communities with genetic susceptibility markers and subsets of patients with distinct functional characteristics of the clonal effector T cells in disease subjects. In the Pilot Project the glycosylation of lgG4, in subjects with active disease will be analyzed and its ability to influenc binding to different human Fc receptors will be examined.
The proposed multidisciplinary studies are designed not only to benefit patients with lgG4-related disease, but to also benefit a host of other disorders including many other autoimmune diseases and other diseases including idiopathic pulmonary fibrosis.
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