Basic and Clinical Immunology for the Busy Clinician

Basic and Clinical Immunology for the Busy Clinician

Issue: April 2020
Disclosures: Silverman reports no relevant financial disclosures.
February 29, 2020
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Lupus Gut Dysbiosis, High Disease Activity a 'Vicious Cycle'

Issue: April 2020
Disclosures: Silverman reports no relevant financial disclosures.
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Gregg J. Silverman, MD
Gregg Silverman

SCOTTSDALE, Ariz. — Characteristic microbiome imbalances in patients with lupus could potentially act as both the cause and effect of high lupus disease activity, according to Gregg Silverman, MD, of the New York University School of Medicine.

Due to this “vicious cycle,” lupus remission may require treating autoimmunity and rebalancing the microbiome, he added.

“The point is that this shift in the microbiome, we think, contributes to higher disease activity, and higher disease activity may shift the environment in the bowel, so these bacteria expand,” Silverman told attendees at the annual Basic and Clinical Immunology for the Busy Clinician symposium. “An effective immune therapy may require both treating the autoimmunity and rebalancing the microbiome.”

Evidence suggests that 30% or more of lupus patients have leaky gut.

Discussing his previous research in the Annals of the Rheumatic Diseases, Silverman noted that patients with systemic lupus erythematosus in an NYU cohort demonstrated decreased species richness diversity compared with the control group. For example, patients with SLE had an overall 5-fold greater level of Ruminococcus gnavus (RG) of the Lachnospiraceae family.

This, Silverman said, provides an early biomarker, as the highest levels of serum anti-RG strain-restricted antibodies were found in patients with active nephritis in the discovery cohort. In addition, IgG anti-RG2 levels have identified lupus nephritis in two other independent cohorts, at Temple University, in Philadelphia, and Ohio State University, he told attendees.

The NYU lupus also found evidence of impaired gut barrier among patients, with high fecal calprotectin, as well as high hepatic production of acute phase reactants such as soluble CD14 and alpha 1 acid glycoprotein.

Extrapolating on this previous research, Silverman told attendees that these findings contribute to a “mechanistic hypothesis” of lupus nephritis, in which the gut acts as a bioreactor and leaky gut releases a nephritogenic bacterial antigen.

“We have actually shown in the laboratory — we haven’t published it yet — that, in fact, the Ruminococcus gnavus expansions make lots of superantigen in the leaky gut,” Silverman said. “It gets out, and we think that is contributing to lupus.”

According to Silverman, evidence suggests that 30% or more of lupus patients have leaky gut, based on increases in this neutrophil protein in their feces, or that soluble CD14 or alpha 1 acid glycoprotein that represent actually protein markers if there is bacterial leakage that stimulates the liver.

“The idea is that we think that expansion of this particular bacterial species escaping the bowel wall through a leaky gut stimulates the immune system, and this actually cross reacts with anti-DNA antibodies,” Silverman said. “We think it is all part of a vicious circle.” – by Jason Laday

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Disclosure: Silverman reports no relevant financial disclosures.