The work was reported in Immunity on Aug. 22.
Autoimmune diseases such as rheumatoid arthritis and type 1 diabetes result when the body’s immune system mistakenly attacks its own tissue. Many of these diseases disproportionately affect females. In lupus, for example, more than 90 percent of diagnosed patients are women. Previous studies have shown that intestinal bacteria are involved this effect, but their precise role has thus far been opaque.
To shed light on this mechanism, Alexander Chervonsky, MD, PhD, professor of pathology at the University of Chicago, studied a mouse model of type 1 diabetes, a disease in which immune cells attack healthy islet cells — insulin-producing cells found in the pancreas. In these mice, the incidence of type 1 diabetes is 1.4 to 4.4 times higher in females than in males.
This gender bias disappeared when mice were raised under special conditions to be free of germs, including intestinal bacteria. Germ-free females and males were equally susceptible to the disease. When these mice were exposed to intestinal bacteria prevalent in males, Chervonsky and his team found that males exhibited a lower incidence of type 1 diabetes, but females did not. In addition, the team found that bacteria in the gut of males and females were similar before puberty or as adults if the male had been castrated and thus unable to produce testosterone.
“Taken together, our research shows that to establish protection against type 1 diabetes in male mice, both male hormones and bacterial influence are needed,” Chervonsky said.
The team ran gene-expression arrays to shed light on the genetic pathways at play, focusing on interferon gamma, a signaling molecule involved in the inflammatory response. In mice lacking the ability to produce interferon gamma, gender bias in type 1 diabetes disappeared. Males also produced higher levels of the molecule, leading the team to hypothesize that it plays a central role in how gender bias in autoimmunity arises.
The team plans to further elucidate the molecular pathways responsible for this phenomenon, as well as the role of hormones in this interaction. They also plan on testing if other disease models, such as lupus, are driven by the same mechanisms.
“We hope that studying the molecular pathways activated by hormones and gut microbe interaction will someday allow us to find targeted therapeutics based on small molecules or other biologics, rather than use actual microbes or hormones, which can have wide side-effects,” Chervonsky said.
The work was supported by the National Institutes of Health, Juvenile Diabetes Research Foundation, the National Institute of Diabetes and Digestive and Kidney Diseases and the University of Chicago.
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