Understanding the autoimmune mechanisms in myasthenia gravis

• Applicant: Dr. Miriam Fichtner
• Subject Area: Clinical Immunology and Allergology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428295369

• Final Report Year: 2023

Final Report Abstract

Autoimmunity is a malfunction of the immune system where an immune response develops against one’s own tissues. Myasthenia gravis is an autoimmune disease in which the immune system causes impairment of neuromuscular function by producing autoantibodies that interrupt signaling from nerves to muscles. Due to this interruption patients experience muscle weakness and fatigability. The human immune system is comprised of trillions of circulating cells. Only a tiny fraction directly contributes to autoimmune disease. In MG, those that contribute are a subset of B cells, which produce the autoantibodies. Separating those cells from the enormous population of immune cells is a highly sought-after goal because their defects can be directly investigated, and they are an extremely valuable therapeutic target. I investigated these cells to determine how the autoantibodies develop and how they behave during treatment and disease exacerbation. Overall, this work (i) furthered our understanding of how MG initiates and progresses, (ii) supported the understanding of therapeutics that specifically target disease-causing cells and evaluate the immunomechanisms of relapse after targeted therapy in MG (iii).

Publications

• Autoantibodies against Neurologic Antigens in Nonneurologic Autoimmunity. The Journal of Immunology, 202(8), 2210-2219.
  Stathopoulos, Panos; Chastre, Anne; Waters, Patrick; Irani, Sarosh; Fichtner, Miriam L.; Benotti, Erik S.; Guthridge, Joel M.; Seifert, Jennifer; Nowak, Richard J.; Buckner, Jane H.; Holers, V.Michael; James, Judith A.; Hafler, David A. & O’Connor, Kevin C.
  
• Characterization of pathogenic monoclonal autoantibodies derived from muscle-specific kinase myasthenia gravis patients. JCI Insight, 4(12).
  Takata, Kazushiro; Stathopoulos, Panos; Cao, Michelangelo; Mané-Damas, Marina; Fichtner, Miriam L.; Benotti, Erik S.; Jacobson, Leslie; Waters, Patrick; Irani, Sarosh R.; Martinez-Martinez, Pilar; Beeson, David; Losen, Mario; Vincent, Angela; Nowak, Richard J. & O’Connor, Kevin C.
  
• Fast-acting autoantibodies muscle in on encephalitis. Science Immunology, 4(42).
  Fichtner, Miriam L. & O’Connor, Kevin C.
  
• Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis. Journal of Experimental Medicine, 217(12).
  Fichtner, Miriam L.; Vieni, Casey; Redler, Rachel L.; Kolich, Ljuvica; Jiang, Ruoyi; Takata, Kazushiro; Stathopoulos, Panos; Suarez, Pablo A.; Nowak, Richard J.; Burden, Steven J.; Ekiert, Damian C. & O’Connor, Kevin C.
  
• Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology. Frontiers in Immunology, 11.
  Fichtner, Miriam L.; Jiang, Ruoyi; Bourke, Aoibh; Nowak, Richard J. & O’Connor, Kevin C.
  
• Single-cell repertoire tracing identifies rituximab-resistant B cells during myasthenia gravis relapses. JCI Insight, 5(14).
  Jiang, Ruoyi; Fichtner, Miriam L.; Hoehn, Kenneth B.; Pham, Minh C.; Stathopoulos, Panos; Nowak, Richard J.; Kleinstein, Steven H. & O’Connor, Kevin C.
  
• Eberhard Pfleiderer Myasthenie Forschungspreisträgerin. DMG Aktuell, 2-2021
  M.L. Fichtner
  
• Elevated N-Linked Glycosylation of IgG V Regions in Myasthenia Gravis Disease Subtypes. The Journal of Immunology, 207(8), 2005-2014.
  Mandel-Brehm, Caleigh; Fichtner, Miriam L.; Jiang, Ruoyi; Winton, Valerie J.; Vazquez, Sara E.; Pham, Minh C.; Hoehn, Kenneth B.; Kelleher, Neil L.; Nowak, Richard J.; Kleinstein, Steven H.; Wilson, Michael R.; DeRisi, Joseph L. & O’Connor, Kevin C.
  
• Pathogenität von LRP4/Agrin Antikörpern. DMG Aktuell, 3-2021
  M.L. Fichtner
  
• Short review: Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis. Jahrbuch der Deutschen Gesellschaft für Muskelkranke e.V. (DGM) 2021
  M.L. Fichtner
  
• Heterogeneity of Acetylcholine Receptor Autoantibody–Mediated Complement Activity in Patients With Myasthenia Gravis. Neurology Neuroimmunology & Neuroinflammation, 9(4).
  Obaid, Abeer H.; Zografou, Chryssa; Vadysirisack, Douangsone D.; Munro-Sheldon, Bailey; Fichtner, Miriam L.; Roy, Bhaskar; Philbrick, William M.; Bennett, Jeffrey L.; Nowak, Richard J. & O'Connor, Kevin C.
  
• Myasthenia gravis complement activity is independent of autoantibody titer and disease severity. PLOS ONE, 17(3), e0264489.
  Fichtner, Miriam L.; Hoarty, Michelle D.; Vadysirisack, Douangsone D.; Munro-Sheldon, Bailey; Nowak, Richard J. & O’Connor, Kevin C.
  
• Reemergence of pathogenic, autoantibody-producing B cell clones in myasthenia gravis following B cell depletion therapy. Acta Neuropathologica Communications, 10(1).
  Fichtner, Miriam L.; Hoehn, Kenneth B.; Ford, Easton E.; Mane-Damas, Marina; Oh, Sangwook; Waters, Patrick; Payne, Aimee S.; Smith, Melissa L.; Watson, Corey T.; Losen, Mario; Martinez-Martinez, Pilar; Nowak, Richard J.; Kleinstein, Steven H. & O’Connor, Kevin C.
  
• Short review: Identifizierung von Risikogenorten für AChR Myasthenia Gravis. DMG Aktuell, 1-2022
  M.L. Fichtner
  
• Features of Isoforms of Human Soluble TACI. The Journal of Immunology, 211(2), 199-208.
  Fichtner, Miriam L.; Rübsamen, Heike; Smolle, Michaela; Schaller, Jonas; Feederle, Regina; Bültmann, Andreas; Kümpfel, Tania; Schneider, Pascal; Thaler, Franziska S. & Meinl, Edgar
  
• The mechanisms of immunopathology underlying B cell depletion therapy-mediated remission and relapse in patients with MuSK MG. RRNMF Neuromuscular Journal, 4(3).
  OConnor, Kevin & Fichtner, Miriam