A common gut commensal as a cross-reactive candidate in antiphospholipid syndrome (HUM3P.250)

Abstract

Abstract Antiphospholipid syndrome (APS) is an autoimmune clotting disease characterized by autoantibodies interfering with coagulation. Given the vast antigenic potential of the gut microbiota, we hypothesized that adaptive immune responses to gut commensals may sustain chronic autoreactivity via cross-reactivity. We identified in in silico searches the common, gram-positive gut commensal Roseburia intestinalis as a prime candidate for molecular mimicry, containing peptide sequences highly homologous to both T and B cell immunodominant epitopes of the major autoantigen in APS, the plasma protein b2-glycoprotein I (b2GPI). PBMCs from APS patients proliferated significantly more to R. intestinalis protein extracts compared to phylogenetically closely related Eubacterium rectale, which lacks homologous peptides. We therefore cloned b2GPI-specific CD4 memory T cells and tested cross-reactivity with peptides in vitro. Preliminary data supports that IL-2 but not IL-4, IL-10 or IL-17 secretion can be elicited from an autoantigen-specific Th1 clone in response to a R. intestinalis peptide. Furthermore, Western blotting using patient plasma samples revealed specific bands for R. intestinalis including a potential cross-reactive protein at 24 kDa. Pre-adsorption using recombinant b2GPI prior to Western blotting showed a decrease in this candidate band. These data support a working model whereby autoreactive T and B cell responses are sustained by cross-reactivity with a common gut commensal.