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Abstract: TH-PO844

Critical MPO Epitopes Drive the Adaptive Immune Response in MPO-ANCA Vasculitis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Free, Meghan E., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Stember, Katherine G., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Hess, Jacob J., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Lardinois, Olivier, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States
  • Mendoza, Carmen E., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Le, Andrew K., UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Hogan, Susan L., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Hu, Yichun, UNC Kidney Center, Chapel Hill, North Carolina, United States
  • Pilkinton, Mark A., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • James, Eddie A., Benaroya Research Institute, Seattle, Washington, United States
  • Kwok, William W., Benaroya Research Institute, Seattle, Washington, United States
  • Vincent, Benjamin, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Mallal, Simon, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Jennette, J. Charles, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Ciavatta, Dominic J., University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Falk, Ronald J., UNC Kidney Center, Chapel Hill, North Carolina, United States
Background

Autoimmune diseases, including ANCA vasculitis, rely on broad immunosuppression to treat disease. However, research to understand the interactions between human leukocyte antigen (HLA), autoantigen, and effector immune cells, would permit the development of targeted therapies to revolutionize treatment.

Methods

HLA was determined by sequence typing and peptide-HLA interactions were predicted and confirmed by in silico and in vitro binding studies. Class II tetramers were utilized to identify circulating autoreactive T cells. The clonality of anti-myeloperoxidase (MPO) T cells was determined by TCR sequencing. ELISA studies examined the temporal B cell response to MPO peptides.

Results

Patients with HLA-DPB1*04:01 and/or HLA-DRB4*01:01 exhibit CD4+ T cell reactivity to specific epitopes of MPO contained in tetramers. Autoreactive T cells are enriched for memory T cells as indicated by expression of CD25, CD45RO and CCR7. Additionally, autoreactive cells produce IL-17A upon stimulation. Tetramer positive cells are clonally restricted as evidenced by loss of TCR diversity when compared to naïve and memory T cell populations. Furthermore, this region of MPO is targeted by patient ANCA, and specific antibody reactivity is most detectable at onset of disease. These T and B cell epitopes are contained in a region of MPO that is buried and immune system recognition is dependent on secondary structure.

Conclusion

These data define the specific interactions between the autoantigen, MPO, and the adaptive immune system within ANCA vasculitis. Collectively, this study informs the development of new antigen-specific therapies in ANCA vasculitis and autoimmune disease.

Funding

  • NIDDK Support