Researchers have identified a possible cause of lupus that they say could lead to a cure for the life-threatening condition, potentially stopping the immune system from mistakenly waging a nearly full-body attack on itself, reports WebMD.
In the findings published in Nature, the researchers compared and experimented with blood samples from 19 people with lupus and blood samples from 19 healthy people. The team used multiple molecular biology techniques to arrive at their conclusions, including CRISPR gene editing and a specialised approach for sequencing ribonucleic acid (RNA), which is present in all living cells and is similar to DNA in its structure.
They concluded that the blood samples from the people with lupus showed an impaired body process related to environmental pollutants, bacteria, and metabolites (substances made by chemical changes in your body that turn food into energy).
When the researchers made changes to the blood samples targeting that process, the lupus-causing cells seemed to be reprogrammed into a different type of cell that may promote protection and repair in the body.
“We’ve identified a fundamental imbalance in the immune responses made by patients with lupus, and we’ve defined specific mediators that can correct this imbalance to dampen the pathologic autoimmune response,” said co-author Deepak Rao, MD, PhD, an assistant professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital.
Lupus is an autoimmune disease, meaning the immune system attacks healthy cells of organs or tissue. Formally called systemic lupus erythematosus (SLE), the hallmark symptom is damaging inflammation that can affect the skin, blood, joints, kidneys, brain, heart and lungs.
It affects an estimated 1.5m people in the US, and current treatments typically severely impact the body’s immune system, making people more likely to get other health problems.
“Up until this point, all therapy for lupus is a blunt instrument. It’s broad immunosuppression,” said co-author Jaehyuk Choi, MD, PhD, an associate professor of dermatology at Northwestern University’s Feinberg School of Medicine and a Northwestern Medicine dermatologist.
“By identifying a cause for this disease, we have found a potential cure that will not have the side effects of current therapies.”
Study details
Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus
Calvin Law, Vanessa Sue Wacleche, Ye Cao et al.
Published in Nature on 10 July 2024
Abstract
Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13, yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarisation axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
WebMD article – Unlocking Lupus: Potential Cause and Cure Identified (Open access)
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