Dataset Information

Restricted myeloperoxidase epitopes drive the adaptive immune response in MPO-ANCA vasculitis.

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-MPO_447-461 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⁺CD25^intermediateCD45RO+ 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-MPO_447-461 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.

SUBMITTER: Free ME

PROVIDER: S-EPMC6930338 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Restricted myeloperoxidase epitopes drive the adaptive immune response in MPO-ANCA vasculitis.

Free Meghan E ME Stember Katherine G KG Hess Jacob J JJ McInnis Elizabeth A EA Lardinois Olivier O Hogan Susan L SL Hu Yichun Y Mendoza Carmen C Le Andrew K AK Guseman Alex J AJ Pilkinton Mark A MA Bortone Dante S DS Cowens Kristen K Sidney John J Karosiene Edita E Peters Bjoern B James Eddie E Kwok William W WW Vincent Benjamin G BG Mallal Simon A SA Jennette J Charles JC Ciavatta Dominic J DJ Falk Ronald J RJ

Journal of autoimmunity 20190802

<h4>Background</h4>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<sup>+</sup> T cells, and ANCA specificity in shaping the immune response in patients with anti-neutrophil cytoplasmic autoantibody (ANCA) vasculit ...[more]

PMID: 31383567

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Project description:Our understanding of immune recognition and response to infection and non-infectious forms of cell damage and death is rapidly increasing. The major focus is on host immunity and microbiological invasion. However, it is also clear that these same pathways are important in the initiation and maintenance of autoimmunity and the damage caused to targeted organs. Understanding the involvement of cell death in autoimmune disease is likely to help define critical pathways in the immunopathogenesis of autoimmune disease and new therapeutic targets. An important immune responder cell population in host defense and autoimmunity is the neutrophil. One autoimmune disease where neutrophils play important roles is MPO-ANCA Microscopic Vasculitis. This a severe disease that results from inflammation to small blood vessels in the kidney, the glomeruli (high blood flow and pressure filters). One of the best studied ways in which neutrophils participate in this disease is by cell death through NETosis resulting in the discharge of proinflammatory enzymes and nuclear fragments. In host defense against infection this process helps neutralize pathogens however in auto immunity NETosis results in injury and death to the surrounding healthy tissues. The major autoimmune target in this disease is myeloperoxidase (MPO) which is found uniquely in the cytoplasm of neutrophils. Although the kidney is the major organ targeted in this disease MPO is not expressed in the kidney. Autoantibodies target surface MPO on activated circulating neutrophils resulting in their lodgment in glomerular capillaries where they NETose releasing extracellularly MPO and nuclear fragments initiating injury and planting the key autoantigen MPO. It is the cell death of neutrophils that changes the kidney from innocent bystander to major autoimmune target. Defining the immunopathogenesis of this autoimmune disease and recognizing critical injurious pathways will allow therapeutic intervention to block these pathways and attenuate autoimmune injury. The insights (regarding mechanisms of injury and potential therapeutic targets) are likely to be highly relevant to many other autoimmune diseases.

Dataset Information

Restricted myeloperoxidase epitopes drive the adaptive immune response in MPO-ANCA vasculitis.

Background

Methods

Results

Conclusions

Publications

Restricted myeloperoxidase epitopes drive the adaptive immune response in MPO-ANCA vasculitis.

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