A common gut bacterium can trigger antiphospholipid syndrome

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What causes the immune system, designed to protect us, to turn on the body and attack healthy cells?

Common bacteria that reside in the human gut may be partly to blame, say Yale researchers, who studied the origins of a serious autoimmune disease that frequently affects young women.

For their study, the research team focused on cells from patients with antiphospholipid syndrome, an immune system disorder that raises the risk of blood clots.

This chronic condition can lead to lung clots, strokes, heart attacks, and in pregnant women, miscarriages or stillbirths.

Using patient immune cells and antibodies, as well as animal models of the disease, the investigators did several experiments to explore the phenomenon.

They found that a common gut bacterium, Roseburia intestinalis, can trigger the disease in individuals who have a genetic predisposition.

Risultati immagini per Roseburia intestinalis

In those patients, the immune system’s defender T and B cells react to a blood protein involved in clotting, and also to the bacteria, in certain amino acids found in the bacteria.

Over time, this ongoing “cross-reactive” response leads to tissue damage and chronic disease.


Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia. It is characterized by the presence of antiphospholipid antibodies (APL) that are directed against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI).

Its main manifestations are recurrent vascular thromboses (so-called “thrombotic APS”) and pregnancy complications (“obstetric APS”).

According to the current consensus criteria, a persistently positive functional lupus anticoagulant (LA) assay and/or the presence of anti-b2GPI and/or anti-cardiolipin antibodies, together with clinical symptoms, is mandatory for the diagnosis of APS. Other clinical features, such as thrombocytopenia, Coombs-positive haemolytic anaemia, heart valve disease, renal microangiopathy and neurologic disorders are also common in APL-positive patients.

APS can be associated with other autoimmune disorders, such as systemic lupus erythematosus. In rare cases, catastrophic APS (CAPS) occurs, with the development of excessive thrombosis at multiple sites, usually affecting small vessels and leading to multi-organ dysfunction and organ failure.

Treatment usually comprises antithrombotic therapy using antiplatelet and anticoagulant agents. However, there is no consensus concerning the intensity or duration of therapy. Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high.

For patients with CAPS, a combined therapeutic approach that includes anticoagulation, glucocorticoids, plasma exchange and/or intravenous immunoglobulin seems to be the best treatment option.


By identifying a gut bacterium, instead of the immune system, as the target for treatment, the study could lead to new drugs for these patients, according to the scientists.

The research was also the first to show cross-reactivity of gut bacteria in humans with this disease, said senior author Dr. Martin Kriegel of Yale — a finding that could impact the understanding and treatment of other autoimmune diseases.

This shows tissue samples

Images of heart tissue from a mouse model of antiphospholipid syndrome.

The animals’ gut was either colonized with the human gut bacterium Roseburia intestinalis that led to heart attacks and inflammation (left) or pretreated with an antibiotic that left the heart uninflamed (right).

The image is credited to Ruff et al, Cell Host Microbe 2019.

The full study is published in Cell Host & Microbe.

Other authors are William E. Ruff, Carina Dehner, Woo J. Kim, Odelya Pagovich, Cassyanne L. Aguiar, Andrew T. Yu, Alexander S. Roth, Silvio Manfredo Vieira, Christina Kriegel, Olamide Adeniyi, Melissa J. Mulla, Vikki M. Abrahams, William W. Kwok, Ruth Nussinov, Doruk Erkan, and Andrew L. Goodman.

Funding: This work was supported by grants from the National Institutes of Health (K08AI095318, R01AI118855, T32AI07019, andT32DK007017-39), Yale Rheumatic Diseases Research Core, Women’s Health Research at Yale, O’Brien Center at Yale, Arthritis National Research Foundation, Arthritis Foundation, and Lupus Research Alliance, as well as the American Heart Association, and Lupus Research Institute.

Source:
Yale
Media Contacts: 
Ziba Kashef – Yale
Image Source:
The image is credited to Ruff et al, Cell Host Microbe 2019.

Original Research: Closed access
“Pathogenic Autoreactive T and B Cells Cross-React with Mimotopes Expressed by a Common Human Gut Commensal to Trigger Autoimmunity”. Martin Kriegel Perola et al.
Cell Host & Microbe. doi:10.1016/j.chom.2019.05.003

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