Session Title: B Cell Biology and Targets in Autoimmune Disease I
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Autoantigen-specific T Cell and Antibody Reactivity to a Human Gut Commensal in Antiphospholipid Syndrome
William Ruff1, Carina Dehner1, Alex Roth1, Silvio M. Vieira1, Cassyanne L. Aguiar2, Andrew Goodman3, Doruk Erkan2, Martin A. Kriegel1,4
1Department of Immunobiology, Yale School of Medicine, New Haven, CT
2Department of Medicine, Hospital for Special Surgery, New York, NY
3Microbial Sciences Institute, Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT
4Department of Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, CT
Background/Purpose: Antiphospholipid syndrome (APS) is a serious autoimmune clotting disorder of unknown etiology but with a well-defined major autoantigen, β2-glycoprotein I (β2GPI). Infectious triggers have been implicated in transient autoantibody production, but the persistent stimuli for anti-β2GPI antibodies remain unknown. Given the vast antigenic potential of the gut microbiota, we hypothesize that human gut commensal bacteria induce and sustain autoreactivity via cross-reactivity. To this end, we characterized APS β2GPI-specific T cell and autoantibody reactivity to in silico candidates.
Methods: NCBI BLAST was used to identify microbial protein sequences with high homology to major β2GPI epitopes. Sorting of IgA-coated fecal microbiota followed by 16S rDNA sequencing (IgA-Seq) was performed on APS and control microbiomes. Human-derived candidate and control strains were cultured anaerobically. Blood and stool samples were collected from APS patients and controls. A novel strain-specific real-time PCR strategy was developed and validated using isolated strains and defined fecal microbiomes. Memory CD4+ T cells specific to β2GPI were cloned using a T cell library assay and a monoclonal antibody specific to the RGGMR domain I epitope of β2GPI was expressed for cross-reactivity studies.
Results: Systematic in silico searches revealed Roseburia intestinalis as a major candidate with high homology to the main B and T cell epitopes of β2GPI. R. intestinalis colonization load was abundant and persistent throughout the study population. IgA-Seq showed IgA coating of the genus Roseburia. APS PBMC proliferated significantly more to protein extracts from R. intestinalis versus control subjects (p=0.0002), and also compared to the phylogenetically related, but mimic-deficient gut commensal Eubacterium rectale (p=0.02). APS memory CD4+ T cells specific for a T cell epitope in domain V cross-react with R. intestinalis mimic peptide. Further, an APS patient-derived anti-domain I β2GPI monoclonal antibody bound significantly to R. intestinalis lysates whereas a control antibody against an unrelated β2GPI epitope did not.
Conclusion: We have identified a common gut commensal, R. intestinalis, as a potential chronic cross-reactive trigger in APS. Roseburia is IgA-coated in APS microbiomes suggesting adaptive immune responses to the candidate in vivo. In vitro studies support cross-reactivity of β2GPI-specific CD4 memory T cells and a pathogenic autoantibody with R. intestinalis. This study provides a concept for common human gut commensals as chronic cross-reactive triggers in genetically susceptible autoimmune hosts such as APS patients.
To cite this abstract in AMA style:Ruff W, Dehner C, Roth A, Vieira SM, Aguiar CL, Goodman A, Erkan D, Kriegel M. Autoantigen-Specific T Cell and Antibody Reactivity to a Human Gut Commensal in Antiphospholipid Syndrome [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/autoantigen-specific-t-cell-and-antibody-reactivity-to-a-human-gut-commensal-in-antiphospholipid-syndrome/. Accessed November 25, 2020.
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