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. Principal Project: Studies on the Immunology of IgG4-related diseases Project Leader (PL): Shiv S. Pillai DESCRIPTION (as provided by applicant): lgG4-Related Disease is a multi-system disorder encompassing a host of previously described syndromes, all now recognized to be characterized by tumescent lesions, storiform fibrosis, obliterative phlebitis and large amounts of serum lgG4. Clinical improvement is seen with steroids in many subjects and B cell depletion is also clinically effective. Very little is known about the pathogenesis of this disorder or about th molecular and cellular basis for fibrosis in a host of apparently unrelated disorders. Studies will be performed to define T cell clonal expansions observed by Next Gen Sequencing approaches in subjects with this disease but with distinct organ involvements. Novel surface markers expressed only on effector T cell clones will be investigated as potential targets for therapy. Detailed interrogation of gene expression protein expression and metabolites will be performed by global as well as single cell RNAseq, multi-color flow cytometry, by Cytof mass cytometry, and liquid chromatography-mass spectrometry on clonally expanded T cells and will be conducted in order to understand pathways of potential therapeutic significance that contributes to the development of these T cells as well as to their effector functions in this fibrotic inflammatory disease. A possible role for lgG4 antibodies in this disordr will also be examined. Next Gen Sequencing as well as single cell cloning and sequencing strategies will be used to define plasmablast expansions and to establish specific antibody heavy-light chain pairs that may contribute to the disease. Reagents will be thus generated to identify specific antigens using human ORFeome expression libraries as source of antigen. Determining the B cell specific protein antigen and the use of recombinant proteins will be used to assist the identification of T cell specific peptides. Studies will also be performed on genetic susceptibility to lgG4-RD using Fluidigm based MHC class II genotyping and if indicated from the Immunochip analyses by Exome sequencing. Global comparisons of gene and protein expression will inform the need for epigenetic profiling studies.
Autoimmune and inflammatory diseases that cause severe tissue scarring or fibrosis can cause premature death and seriously impair the quality of life for survivors. The proposed studies may help not only patients with lgG4-related disease, but also a host of other disorders including many other autoimmune diseases and other diseases including idiopathic pulmonary fibrosis.
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