β2-glycoprotein I (β2GPI) is a major autoantigen in antiphospholipid syndrome (APS). New findings implicate the human gut commensal Roseburia intestinalis in the development and maintenance of chronic autoimmune responses to this antigen in APS via cross-reactivity.
“To our knowledge, the human gut microbiome has not previously been linked with APS,” says corresponding author Martin Kriegel. “Our study highlights the gut as a potential chronic trigger in patients with APS.”
Kriegel and colleagues found that R. intestinalis contains amino acid sequences that are highly homologous to sequences found in B cell and T cell epitopes within β2GPI. Although the prevalence of this commensal was similar in individuals with anti-β2GPI antibodies (including individuals with APS) and healthy individuals, anti-β2GPI antibody-positive individuals had signs of chronic subclinical intestinal inflammation and systemic adaptive immune responses to R. intestinalis.
Furthermore, compared with healthy individuals, patients with APS had higher levels of antibodies that were cross-reactive with a bacterial DNA methyltransferase expressed by R. intestinalis, and levels of these antibodies correlated with levels of anti-β2GPI antibodies in patients with APS.
Mice immunized with R. intestinalis lysates had higher levels of serum antibodies that could cross-react with human β2GPI compared with sham-immunized mice. Importantly, oral administration of R. intestinalis in a mouse model of spontaneous APS triggered the development of anti-human-β2GPI antibodies, as well as APS-related morbidity and mortality.
administration of R. intestinalis… triggered the development of anti-human-β2GPI antibodies
“An important finding was that an otherwise harmless bug, that is often considered beneficial, can be dangerous in patients who are genetically or otherwise prone to over-react to particular pieces of this gut microbe,” explains Kriegel. “Selecting those patients who show reactivity to the bacterium and who have predisposing genes will be essential to identify who could possibly benefit in the future from attempts to remove this and similar cross-reactive triggers from the gut.”
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Original article
Ruff, W. E. et al. Pathogenic autoreactive T and B cells cross-react with mimotopes expressed by a common human gut commensal to trigger autoimmunity. Cell Host Microbe. https://doi.org/10.1016/j.chom.2019.05.003 (2019)
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McHugh, J. Gut commensal implicated in APS. Nat Rev Rheumatol 15, 452 (2019). https://doi.org/10.1038/s41584-019-0268-9
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DOI: https://doi.org/10.1038/s41584-019-0268-9
