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Alsalem, Sultan

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Alsalem, Sultan

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    Antigens in the Pathogenesis of Immunoglobulin G4 - Related Disease
    (2017-06-07) Alsalem, Sultan; Pillai, Shiv S.; Perugino, Cory A.; Mahajan, Vinay S.; Della-Torre, Emanuel
    Immunoglobulin G4-Related Disease (IgG4-RD) is a chronic, fibroinflammatory disorder capable of affecting every organ system. Under the umbrella of IgG4-RD, many poorly characterized eponymous disorders such as Kuttner’s tumor, Mikulicz disease, and Ormond’s disease have been unified based on shared serologic and histopathological features. The pathogenesis of IgG4-RD is thought to involve plasmablasts (circulating antibody secreting cells), CD4+ cytotoxic T cells (CD4+ CTLs) and IL-4 secreting follicular helper T cells. What antigen or collection of antigens these cells are responding to remains unknown. Similarly, whether such antigens are of a self or an exogenous source has not been clarified. In this work, we aim to investigate such questions pertaining to the presence and identify of the antigenic stimulus behind IgG4-RD. Firstly, to re-define what has previously been published in the setting of AIP (now largely considered to be a stereotypic manifestation of IgG4-RD), we examine six established autoantigens associated with AIP in the setting of a large and clinically diverse cohort of systemic IgG4-RD. Thirdly, to better understand the possibility of a chronic viral source of antigen, we study the frequency of Cytomegalovirus and Epstein-Barr virus B cell reactivity among our cohort of IgG4-RD subjects. Lastly but most germane to the issue of disease relevance, we utilize next generation sequencing (NGS) to identify dominant plasmablasts clones, clone and purify the respective monoclonal antibody and determine which antigen each is binding to. The need for discovery of novel, disease-relevant rather than disease-associated antigens is perhaps the item of greatest importance in the current paradigm of what we consider to be IgG4-RD. Such a finding will allow for further validation of the cells we posit to be centrally involved in this disease – CD4+ CTLs and Tfh cells – and help unify the hypothesized disease mechanism. If occurring at any significant frequency and specificity, the finding of disease-relevant antibodies may also develop into clinical importance. Here, we present the most common clones of monoclonal antibodies derived from IgG4-RD patients, and look at their reactivity against human tissues and our approach at arriving at the antigens involved in this disease and show how numerous AIP-associated antigens are actually not universally involved in IgG4-RD, and reveal that the majority of patients with a high CD4-CTL counts have a concomitant history of CMV or EBV exposure. This thesis hopes to offer beneficial insight on the pathological process that drives IgG4-RD.