Autoimmune rheumatologic diseases
Antiphospholipid syndrome (APS) is an HLA-DR53-associated autoimmune clotting disorder targeting the plasma protein b2-glycoprotein I (b2GPI). The gut microbiota provides an enormous antigenic challenge to the mucosal adaptive immune system. We thus hypothesized that a homeostatic adaptive immune response to commensals can trigger and sustain autoreactive T cells via cross-reactivity with autoantigens in an HLA-susceptible host. We have identified in silico a human gut commensal, Roseburia intestinalis, as a cross-reactive candidate with highly homologous peptide sequences to the immunodominant b2GPI T and B cell epitopes. R. intestinalis is abundant in human microbiomes including APS patients based on a species-specific fecal PCR. HLA-DR53-positive APS PBMCs proliferated significantly more to R. intestinalis protein extracts compared to phylogenetically closely related Eubacterium rectale, lacking homologous sequences. We next synthesized an MHCII tetramer for a major T cell epitope in b2GPI that is conserved in R. intestinalis. Tetramer-positive CD45R0+ CD25- CD4+ memory T cells from APS patients showed significant and dose-dependent proliferation to heat-killed R. intestinalis compared to controls. Cytokine measurements revealed a heterogeneous but pathogen-associated phenotype including GM-CSF, TNF-α, IL-21, and IL-9. We further cloned b2GPI-specific memory CD4+ T cells using a T cell library assay, confirmed clonality by TCR Vbsequencing, and were able to also demonstrate cross-reactivity to the mimic sequence in R. intestinalis. In summary, we have identified human b2GPI autoepitope-specific CD4+ memory T cells, which have a pathogen-associated phenotype and cross-react to R. intestinalis. We propose that ubiquitous gut commensals could represent persistent triggers for autoreactive lymphocytes in human autoimmunity.
Yale University, Department of Immunobiology