F2F Poster 21st Lancefield International Symposium for Streptococci and Streptococcal Diseases 2022

IgG2 and Th17/Th1 cooperation promote the autoimmune pathogenesis of acute rheumatic fever (#151)

Christine A Kirvan 1 , Kathy Alvarez 2 , Andria Hedrick 2 , Susan E Swedo 3 , Kent Ward 4 , Harry Hill 5 , Stanley Kosanke 6 , David Jankelow 7 , Madeleine W Cunningham 2
  1. Biological Sciences, California State University, Sacramento, CA, USA
  2. Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
  3. Pediatrics and Developmental Neuropsychiatry Branch, National Institute of Mental Health, Bethesda, MD, USA
  4. Pediatric Cardiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
  5. Pathology, University of Utah School of Medicine, Salt Lake City , UT, USA
  6. Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
  7. Cardiology, University of Witwatersrand, Johannesburg, South Africa

Antecedent group A streptococcal pharyngitis is a well-established cause of acute rheumatic fever (ARF) where rheumatic valvular heart disease (RHD) and Sydenham chorea (SC) are major manifestations.  In ARF, crossreactive antibodies and T cells respond to streptococcal antigens, and through molecular mimicry target heart and brain tissues.  In this translational human study, we further address questions regarding specific pathogenic mechanisms leading to streptococcal sequelae which target the heart and brain. We investigate the immunoglobulin G (IgG) subclasses to better understand pathogenesis and how a streptococcal antigen, N acetyl-beta-D-glucosamine (GlcNAc), the immunodominant epitope of the group A carbohydrate, contributes to disease. In RHD and SC, we found serum IgG2 reacted significantly with the group A streptococcal carbohydrate epitope, GlcNAc, and separated ARF from uncomplicated pharyngitis.  In SC, IgG2 in cerebrospinal fluid (CSF) selectively targeted human neuronal cells as well as GlcNAc demonstrating crossreactivity.  In rheumatic carditis, the IgG2 subclass preferentially deposited in valve tissues despite elevated concentrations of IgG1 and/or IgG3 to group A streptococcal M protein and/or GlcNAc in RHD sera.  IgG2 was associated with a IFNg+ and IL-17A+ cell mediated immune response.  The evidence herein suggests Th17 and Th1 cell subsets infiltrate tissues where IgG2 deposition dominated in heart valves with rheumatic carditis.  Our novel human study of ARF/RHD demonstrates a strong IgG2 autoantibody response which targeted heart valves concomitantly with a strong IL-17A/IFNg cooperative signature in the valves. GlcNAc-specific IgG2 appears to be an important autoantibody in pathogenesis of group A streptococcal sequelae and may serve as a biomarker for risk or development of rheumatic valvular heart disease.