Characterization of Potential Antigenic Triggers and Self-Reactive Lymphocytes in IgG4-Related Disease

Abstract

IgG4-related disease (IgG4-RD) is a chronic, inflammatory and fibrotic condition of suspected autoimmune etiology. The aim of this work is to explore the disease mechanism of IgG4-RD, focusing on identifying potential antigenic triggers and profiling self-reactive lymphocytes. Using assays based on the autoantibody profiles of IgG4-RD patients, several potential B cell antigens were identified, including ANXA11, AP1B1, FAM84A, and TBC1D25. Moreover, high anti-ANXA11 titer was shown to associate with increased pancreas and prostate involvement, while high anti-FAM84A reactivity was shown to associate with lacrimal and parotid gland involvement (i.e. Mikulicz phenotype). On the other hand, an activation assay was improved to better capture antigen-specific CD4+ T cell responses using COVID-19 patients’ PBMCs and SARS-CoV-2 spike protein peptides as a tool for the future validation of potential antigenic triggers in IgG4-RD from the T cell perspective. Finally, flow cytometry was used to phenotype potential self-reactive lymphocytes in IgG4-RD as part of a longitudinal clinical study. The long-term goal of this work is to use IgG4-RD as a prototype of systemic autoimmune conditions to better understand tolerance mechanisms and the break of tolerance in humans.