Meghan E Free1, Katherine G Stember2, Jacob J Hess3, Elizabeth A McInnis3, Olivier Lardinois3, Susan L Hogan3, Yichun Hu3, Carmen Mendoza3, Andrew K Le3, Alex J Guseman4, Mark A Pilkinton5, Dante S Bortone6, Kristen Cowens6, John Sidney7, Edita Karosiene7, Bjoern Peters7, Eddie James8, William W Kwok8, Benjamin G Vincent9, Simon A Mallal5, J Charles Jennette2, Dominic J Ciavatta10, Ronald J Falk2. 1. UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel Hill, NC, 27599, USA. Electronic address: meghan_free@med.unc.edu. 2. UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel Hill, NC, 27599, USA; UNC Department of Pathology and Laboratory Medicine, CB #7525, Brinkhous-Bullitt Building, Chapel Hill, NC, 27599, USA. 3. UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel Hill, NC, 27599, USA. 4. UNC Department of Chemistry, CB #3290, Chapel Hill, NC, 27599, USA. 5. Vanderbilt Center for Translational Immunology and Infectious Diseases, A2200 MCN, 1161 21st Avenue South, Nashville, TN, 37232, USA. 6. UNC Lineberger Comprehensive Cancer Center, CB #7295, Chapel Hill, NC, 27599, USA. 7. La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA, 92037, USA. 8. Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA, 98101, USA. 9. UNC Lineberger Comprehensive Cancer Center, CB #7295, Chapel Hill, NC, 27599, USA; UNC Division of Hematology/Oncology, Department of Medicine, Physician's Office Building, 3rd Floor, 170 Manning Drive, CB #7305, Chapel Hill, NC, 27599, USA; UNC Curriculum in Bioinformatics and Computational Biology, CB #7264, Chapel Hill, NC, 27599, USA. 10. UNC Kidney Center, Department of Medicine, 7024 Burnett-Womack, CB #7155, Chapel Hill, NC, 27599, USA; UNC Department of Genetics and Molecular Biology, Coker Hall, 120 South Road, CB #3280, Chapel Hill, NC, 27599, USA.
Abstract
BACKGROUND: Treatment of autoimmune diseases has relied on broad immunosuppression. Knowledge of specific interactions between human leukocyte antigen (HLA), the autoantigen, and effector immune cells, provides the foundation for antigen-specific therapies. These studies investigated the role of HLA, specific myeloperoxidase (MPO) epitopes, CD4+ T cells, and ANCA specificity in shaping the immune response in patients with anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. METHODS: HLA sequence-based typing identified enriched alleles in our patient population (HLA-DPB1*04:01 and HLA-DRB4*01:01), while in silico and in vitro binding studies confirmed binding between HLA and specific MPO epitopes. Class II tetramers with MPO peptides were utilized to detect autoreactive CD4+ T cells. TCR sequencing was performed to determine the clonality of T cell populations. Longitudinal peptide ELISAs assessed the temporal nature of anti-MPO447-461 antibodies. Solvent accessibility combined with chemical modification determined the buried regions of MPO. RESULTS: We identified a restricted region of MPO that was recognized by both CD4+ T cells and ANCA. The autoreactive T cell population contained CD4+CD25intermediateCD45RO+ memory T cells and secreted IL-17A. T cell receptor (TCR) sequencing demonstrated that autoreactive CD4+ T cells had significantly less TCR diversity when compared to naïve and memory T cells, indicating clonal expansion. The anti-MPO447-461 autoantibody response was detectable at onset of disease in some patients and correlated with disease activity in others. This region of MPO that is targeted by both T cells and antibodies is not accessible to solvent or chemical modification, indicating these epitopes are buried. CONCLUSIONS: These observations reveal interactions between restricted MPO epitopes and the adaptive immune system within ANCA vasculitis that may inform new antigen-specific therapies in autoimmune disease while providing insight into immunopathogenesis.
BACKGROUND: Treatment of autoimmune diseases has relied on broad immunosuppression. Knowledge of specific interactions between human leukocyte antigen (HLA), the autoantigen, and effector immune cells, provides the foundation for antigen-specific therapies. These studies investigated the role of HLA, specific myeloperoxidase (MPO) epitopes, CD4+ T cells, and ANCA specificity in shaping the immune response in patients with anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. METHODS:HLA sequence-based typing identified enriched alleles in our patient population (HLA-DPB1*04:01 and HLA-DRB4*01:01), while in silico and in vitro binding studies confirmed binding between HLA and specific MPO epitopes. Class II tetramers with MPO peptides were utilized to detect autoreactive CD4+ T cells. TCR sequencing was performed to determine the clonality of T cell populations. Longitudinal peptide ELISAs assessed the temporal nature of anti-MPO447-461 antibodies. Solvent accessibility combined with chemical modification determined the buried regions of MPO. RESULTS: We identified a restricted region of MPO that was recognized by both CD4+ T cells and ANCA. The autoreactive T cell population contained CD4+CD25intermediateCD45RO+ memory T cells and secreted IL-17A. T cell receptor (TCR) sequencing demonstrated that autoreactive CD4+ T cells had significantly less TCR diversity when compared to naïve and memory T cells, indicating clonal expansion. The anti-MPO447-461 autoantibody response was detectable at onset of disease in some patients and correlated with disease activity in others. This region of MPO that is targeted by both T cells and antibodies is not accessible to solvent or chemical modification, indicating these epitopes are buried. CONCLUSIONS: These observations reveal interactions between restricted MPO epitopes and the adaptive immune system within ANCA vasculitis that may inform new antigen-specific therapies in autoimmune disease while providing insight into immunopathogenesis.
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