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Abstract: FR-OR36

Association of HLA-DPB1*04:01 and Maintenance of Remission in ANCA-Associated Vasculitis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Chen, Dhruti P., University of North Carolina System, Chapel Hill, North Carolina, United States
  • McInnis, Elizabeth A., University of North Carolina System, Chapel Hill, North Carolina, United States
  • Wu, Eve, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Stember, Katherine G., North Carolina Biotechnology Center, Research Triangle Park, North Carolina, United States
  • Hogan, Susan L., University of North Carolina System, Chapel Hill, North Carolina, United States
  • Hu, Yichun, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Henderson, Candace Dione, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Blazek, Lauren N., University of North Carolina System, Chapel Hill, North Carolina, United States
  • Mallal, Simon, Vanderbilt University, Nashville, Tennessee, United States
  • James, Eddie A., Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States
  • Jennette, J. Charles, University of North Carolina System, Chapel Hill, North Carolina, United States
  • Ciavatta, Dominic J., University of North Carolina System, Chapel Hill, North Carolina, United States
  • Falk, Ronald J., University of North Carolina System, Chapel Hill, North Carolina, United States
  • Free, Meghan E., University of North Carolina System, Chapel Hill, North Carolina, United States
Background

Genome wide association studies identified HLA-DPB1*04:01 in ANCA vasculitis and observational studies suggest a biological role. We explored the interaction between HLA/PR3 peptide and association with clinical disease remission.

Methods

Peripheral blood mononuclear cells from patients with ANCA vasculitis and healthy controls with HLA-DPB1*04:01 were utilized for mRNA and protein expression assays. PR3 peptides associating with HLA-DPB1*04:01 were identified via in silico and in vitro assays. Antigen-presenting cells were analyzed for co-fluorescence of HLA-DPB1 and fluorescently tagged PR3 peptide. HLA/peptide multimers were used to identify autoreactive T cells.

Results

Carriers of HLA-DPB1*04:01 were less likely to maintain remission in PR3-ANCA vasculitis (adjusted hazard ratio for leaving remission 2.06 (1.01,4.20)), though similar effect was not observed in MPO-ANCA or the combined cohort. In silico predictions of HLA and PR3 peptide interactions showed strong affinity between PR3225-239 and HLA-DPB1*04:01 and confirmed by in vitro assays. Expression of HLA-DPB1 did not differ among patients and controls. Circulating APCs analyzed by flow cytometry demonstrated higher fluorescence overlap between peptide and HLA among patients on therapy compared to healthy controls or patients in long-term remission off therapy (Figure). We also found that there is a dynamic autoreactive CD4+ T cell response.

Conclusion

Affinity between PR3225-239 and HLA-DPB1*04:01 is reduced among patients in long-term clinical disease remission. These data suggest that the interaction is dynamic and that it could determine the subsequent immune response of T cell activation and maintenance of immunological remission. When HLA-DPB1*04:01 does present PR3225-239 as an antigen, it is recognized by autoreactive T cells. The peptide-HLA interaction may be the link explaining why patients with PR3-ANCA and HLA-DPB1*04:01 are unable to maintain disease remission.

Funding

  • NIDDK Support