In individuals with lupus, the immune system turns against the body. The disease mainly affects women who, sometimes in their teens and twenties, begin to suffer from fever, renal failure, hair loss, seizures, and joint pain. Seventy percent of lupus patients have systemic lupus erythematosus (SLE), which affects the whole body, including the organs and skin, and can be fatal if left untreated.
Some people may be more susceptible to lupus based on their genetics, but what ultimately triggers the disease is unknown. New work published today (October 28) in Science Immunology offers one possible answer, finding that skin microbes can induce full-blown, systemic lupus in mice.
“The paper is really beautiful. It’s very well done and very well controlled,” says Michelle Kahlenberg, a rheumatologist and researcher at the University of Michigan who was not involved in the work.
Gut microbes likely also play a role in disease progression, with some studies showing that antibiotics can alleviate SLE symptoms in mice.
See “Do Commensal Microbes Stoke the Fire of Autoimmunity?”
Hitoshi Terui, a coauthor and dermatologist at Tohoku University School of Medicine, says that a lot of research has shown the relationship between gut microbes and autoimmune disease, but no study had linked skin microbes to autoimmune inflammation, though researchers already suspected that the epidermis—specifically keratinocytes, the skin cells that produce keratin—is involved in lupus.
Terui and his colleagues used a mouse model of Sjögren syndrome, a milder autoimmune disease that is also present in roughly 20 percent of human patients with SLE. The mice lack a functional version of a protein called IκBζ— known to help fight infection—but only in their skin. The mice develop autoantibodies similar to those of human Sjögren syndrome patients, as well as some autoantibodies associated with lupus, and have dermatitis, another symptom of SLE.
The researchers first observed that skin swabs from IκBζ knockout mice contained greater numbers of the bacterium Staphylococcus aureus than those from normal mice. qPCR revealed a possible reason for this: Compared to wildtype mice, the skin cells of IκBζ knockout mice produced less of the mRNA needed to make antimicrobial peptides (AMP), small molecules crucial for fighting infection. Mice treated with oral antibiotics against S. aureus showed less severe autoimmune symptoms. The antibiotics also brought down their autoantibody levels and ameliorated their dermatitis, hinting that S. aureus might be related to the disease.
The team then applied more S. aureus to the skin of knockout mice, and found that their levels of autoantibodies such as anti–double stranded DNA and anti-Smith antibodies (both of which are highly specific to lupus patients) increased relative to control mice. “That was the most exciting moment,” says Terui. The bacteria heightened inflammation and worsened autoimmune symptoms in knockout mice to a greater extent than in wildtype controls. The knockout mice also developed renal failure, a common complication of SLE.
The study also connected two cytokines, IL-17 and IL-23, to the worsening autoimmune symptoms. Histological experiments revealed that knockout mice had higher levels of T cells than normal mice, and these cells produced IL-17. IL-17 wasn’t just found in the epidermis—researchers detected higher levels of the cytokine circulating throughout the bodies of knockout mice. Finally, the researchers found that administering antibodies blocking IL-17 and IL-23 alleviated SLE symptoms in knockout mice exposed to the bacteria, implicating the cytokines’ activity in SLE progression.
According to Terui, these findings weren’t entirely surprising. Scientists were already “very familiar with the IL-17/IL-23 pathway because that pathway is used for the treatment of . . . psoriasis,” another autoimmune disease, he says.
Further experiments in culture showed that keratinocytes are involved in inducing autoimmune inflammation. The keratinocytes of knockout mice undergo apoptosis in response to coculture with S. aureus, which causes neutrophils to produce histone-rich, weblike structures called neutrophil extracellular traps. These structures, which can capture and kill pathogens, also induce T cells to produce IL-17 by activating dendritic cells.
See “CAR T Cells Treat Lupus in Mice”
“They did a really beautiful job teasing out the mechanism in this paper, but I think how it translates to the role of Staph aureus and human lupus is still a question that needs to be investigated,” Kahlenberg cautions. “There have been several studies that have suggested important roles for IL-17 signaling in mouse models [of lupus]. But when we look into human data, especially in the skin, we don’t see as much role for IL-17.”
The researchers also caution that dysfunctional IκBζ hasn’t been directly linked to lupus in humans and that more research is needed before these findings can be translated. They point out that patients with atopic dermatitis, a disease in which S. aureus is found in skin lesions, are at an increased risk of developing SLE. Still, Terui and study coauthor Kenshi Yamasaki, a dermatologist at Tohoku University in Japan, express hope that clinical trials of therapies using anti-IL-17 and anti-IL-23 antibodies can alleviate symptoms in SLE patients. “I believe this mechanism is working in humans too,” Yamasaki says.
