Cross-Reactivity of Antiphospholipid Antibodies with Gut Commensal Proteins in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies (aPL), mainly targeted against β2 glycoprotein 1 (β2GP1). The autoimmune response to β2GP1 is aimed at several B-cell and T-cell epitopes. Molecular mimicry of these epitopes by gut commensal proteins, so-called mimotopes, causing cross-immunization, might contribute to the formation of aPL.

To study the potential role of gut microbiome cross-immunization in APS by examining cross-reactivity of aPL with gut commensal mimotope-containing proteins.

Fecal microbial metagenome of APS patients was determined using shotgun sequencing. An in-house developed in silico pipeline was used to identify gut commensal proteins that show sequence homology with known β2GP1 B and T cell epitopes in the metagenomic data. An enzyme-linked immunosorbent assay was used to test the identified microbial proteins for IgG cross-reactivity, with plasma of 21 APS patients and 17 control participants.

The in silico pipeline resulted in the identification of six gut commensals with a B cell and T cell β2GP1 epitope homologue. Of these, YjjG family noncanonical pyrimidine nucleotidase, one of the candidate-β2GP1 B cell mimicking proteins, showed significantly increased IgG reactivity in APS patients compared to control participants, as well as higher binding of a specific anti-β2GP1 monoclonal antibody than a negative control.

Our study shows reactivity of IgG antibodies to YjjG family noncanonical pyrimidine nucleotidase from Roseburia amylophila in APS patients. Insights into the origins of antibody formation may yield new therapeutic targets for improvement of APS treatment.