Title: Autoantigens Underlying IgG4 Related Disease
Description: Immunoglobulin G4-related disease (IgG4-RD) is a newly emerging immune-mediated condition that can affect over a dozen organs. The systemic nature of this disease allows it to exhibit a plethora of diverse disorders, including malignancies, infections and also inflammatory diseases. This diversity is evident in the highly heterogeneous patient population, from pancreatic cancer patients to patients with Mikulicz’s disease. Such disorders were often diagnosed as isolated, single-organ diseases until the early 21st century, when IgG4-RD was identified by a set of histopathological characteristics seen across patient biopsies. The three hallmark pathological features —lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis— are vital today for a definitive diagnosis. The ability to accurately diagnose IgG4-RD has transformed the outlook for patients, as it is treatable, with patients generally responsive to immunosuppressive therapies.

Over the past decade, we have gained great insight into the widespread immune dysregulation that takes place in IgG4-RD, such as elevated levels of IgG4 antibodies and the presence of characteristic CD4+ cytotoxic T lymphocytes in tissue lesions. However, the etiology of the disease is still unknown and it is unclear whether the IgG4 autoantibodies are drivers of the disease or a mere consequence of a robust inflammatory response.

My thesis aims to address these critical questions by identifying the target antigen(s) of these autoantibodies. Essentially, this would provide insight into the pathogenesis in IgG4-RD and help elucidate possible drivers of the dysregulated immune response.

In this paper, I discuss the twenty likely antigenic targets of IgG4 autoantibodies in patient serum, which were identified elegantly by the parallel analysis of translated ORF’s (PLATO). These antigens were then synthesized via large-scale transfection of 293F cells. Lastly, the specificity of patient antibodies against these recombinant proteins was then evaluated using ELISA, testing sera from over 100 IgG4-RD patients.