Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission. MG pathology is attributed to the presence of acetylcholine receptor (AChR) autoantibodies, which target the AChR at the neuromuscular junction. Many patients remain medically refractory or have intolerable adverse effects to current therapies; thus, another agent for the management of MG is needed. Several recent studies, including one performed by our group, have demonstrated the benefits of B cell depletion via rituximab treatment in MG patients. The NINDS-NeuroNEXT is conducting a multicenter randomized, double blind, placebo controlled Phase II clinical trial evaluating the therapeutic effect of rituximab for MG. We have exclusively partnered with this trial so that we can first, improve the understanding of the mechanism of action of B cell depletion in MG and second, so that fundamental questions regarding human autoimmunity can be addressed. Specimens prior to, during and after treatment are under collection for our work. This study presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that directly participate in the immunopathology of the disease. Our mechanistic studies will test the hypothesis that the mechanism underlying clinical benefit involves a reservoir of T cell-dependent, autoreactive memory B cells that supply a population of antibody secreting cells and is critical to MG autoantibody production. Rituximab eliminates this reservoir of memory B cells; then the newly formed B cell compartment is reshaped such that autoantibody production is diminished. To test this hypothesis, we have developed/applied assays to measure B cell tolerance defects, describe the repertoire of the B cell compartments and the B cell subsets that produce MG autoantibodies and characterize the antigen-specific T cells. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying the treatment of B cell-mediated autoimmune diseases with rituximab. This proposal is directly relevant to the human disease and is in clear alignment and relevance to the mission of the NIH. That is, this translational research focuses on studying the human disease with human-derived cells. Furthermore, the importance of studying MG is magnified by its service as a model for antibody-mediated disease. Innovative, novel technology such as next generation sequencing and antigen-specific T cell assays will be applied to answer fundamental questions. The study is designed to elucidate the pathogenic role of major immunological components in MG, that is the contribution of B and T cells, including an investigation of fundamental autoimmune mechanisms, namely B cell tolerance and T cell pathogenic phenotypes. Through studying MG cell-mediated immunology we will further define the events that both initiate and propagate this disease that will provide fundamental insight into the mechanisms of autoimmune disease.

Public Health Relevance

Myasthenia gravis (MG) is a chronic, disabling autoimmune neurological disease for which current treatments are ineffective in many patients. We will perform a mechanistic study linked to a clinical trial that will determine whether B cell depletion affected by the drug rituximab, is an effective treatment for MG. The mechanistic study will define the immunological events that both initiate and propagate this disease, thereby providing fundamental insight into the mechanisms of MG pathology and how the treatment affects clinical improvement.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114780-03
Application #
9378055
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2015-11-04
Project End
2020-10-31
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Vander Heiden, Jason A; Stathopoulos, Panos; Zhou, Julian Q et al. (2017) Dysregulation of B Cell Repertoire Formation in Myasthenia Gravis Patients Revealed through Deep Sequencing. J Immunol 198:1460-1473
Stathopoulos, Panos; Kumar, Aditya; Nowak, Richard J et al. (2017) Autoantibody-producing plasmablasts after B cell depletion identified in muscle-specific kinase myasthenia gravis. JCI Insight 2:
Cao, Yonghao; Amezquita, Robert A; Kleinstein, Steven H et al. (2016) Autoreactive T Cells from Patients with Myasthenia Gravis Are Characterized by Elevated IL-17, IFN-?, and GM-CSF and Diminished IL-10 Production. J Immunol 196:2075-84
Cui, Ang; Di Niro, Roberto; Vander Heiden, Jason A et al. (2016) A Model of Somatic Hypermutation Targeting in Mice Based on High-Throughput Ig Sequencing Data. J Immunol 197:3566-3574
Lee, Jae-Yun; Stathopoulos, Panos; Gupta, Sasha et al. (2016) Compromised fidelity of B-cell tolerance checkpoints in AChR and MuSK myasthenia gravis. Ann Clin Transl Neurol 3:443-54