Using large scale B cell receptor repertoire sequencing to further understand human autoimmune disease
High-throughput B cell receptor (BCR) repertoire sequencing has been applied to gain insights into immune responses in individuals with a range of diseases, including autoimmunity. Two recent studies that highlight such investigations will be presented in this webinar. Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction mediated by the actions of autoantibodies directed against proteins expressed on the post-junction muscle membrane. There is a well-known association between abnormalities in the thymus and MG. Notably, the MG thymus can serve as a reservoir of autoantibody-producing B cells. Thus, thymectomy is provided as a treatment. However, many patients fail to improve, and the causes of poor responses are not understood. The first part of this seminar will address why that might be. Using BCR repertoire sequencing, we demonstrated that disease-associated B cell clones mature in the thymus before emigrating to the circulation. These B cell clones are present in the circulation after thymectomy, and their persistence correlates with less favorable changes in clinical symptoms after thymectomy. These findings provide mechanistic insight into the immunopathology associated with a diminished clinical response to thymectomy. The second part of this webinar will cover studies performed to understand why MG relapses can occur after B cell–depleting therapy. It is known that autoantibody-producing B cells are present during relapses; it is not understood whether these B cells emerge from the failed depletion of pre-existing B cells or are generated de novo. We carried out single-cell transcriptional profiling and BCR repertoire sequencing on longitudinal samples. B cell clones present before therapy that persisted during relapse were identified. Persistent B cell clones included both antibody-secreting cells and memory B cells characterized by gene expression signatures associated with B cell survival. A subset of these clones was specific for MG autoantigen targets. These results demonstrate that B cell–depleting therapy is not fully effective at eliminating autoantibody-producing B cells and provide a mechanistic understanding of post-treatment relapse in MG. Please join us after the webinar for an opportunity to engage in discussion and ask questions of the experts. Thursday, April 29th 1:00 PM EDT
Kevin C. O’Connor, Ph.D.,
Associate Professor of Neurology and Immunology
Yale School of Medicine
Dr. O’Connor earned his undergraduate degree in Chemistry from the University of Massachusetts at Amherst and his Ph.D. in Biochemistry at Tufts University. He completed his post-doctoral training in Immunology at Harvard Medical School where he also spent several years on the faculty as an Assistant Professor. He is now on the faculty at Yale School of Medicine. He is a neuroimmunologist with a special interest in human translational immunology. His laboratory focuses on studying the roles of B cells, T cells, and autoantibodies in human autoimmune neurologic diseases. He and his team have sought to further define the mechanisms underlying autoimmunity in a number of disorders. Most recently, he has formed a coordinated, multidisciplinary program that aims to answer fundamental questions related to the immunopathology of myasthenia gravis (MG). They have developed new assays, fostered clinical collaborations, and built a biorepository to underpin and enable innovative research that aims to both further our mechanistic understanding of the causality of MG and improve therapeutic intervention. Specifically, they have sought to move the field forward by focusing their study on the rare B cell subsets that produce pathogenic MG autoantibodies and by generating human recombinant autoantibodies from these cells. The resulting studies have provided insight into the details of MG autoimmune mechanisms. This includes identifying MG patients expected to respond to B cell depletion therapy, detailing the unique molecular mechanisms of autoantibody-mediated pathology in patients with an IgG4-mediated subtype of MG, and providing an understanding for the persistent disease in MG patients who have had a thymectomy.
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