Study Results Indicate Potential Method of Reversing Lupus, Opening Doors to Treatment
The authors note they will continue to investigate treatments for patients with lupus as well as safe and effective methods of delivering these molecules to patients.
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According to research published in Nature, Northwestern Medicine and Brigham and Women’s Hospital scientists have discovered a molecular defect that promotes the pathologic immune response present in systemic lupus erythematosus (SLE). The researchers state that existing treatments often fail to control patients’ disease and have unintended adverse events (AEs) which reduce the immune system’s ability to fight infections; however, this discovery indicates a potential treatment by reversing the defect.1
The disease, which affects more than 1.5 million people in the US alone, can result in life-threatening damage to multiple organs, such as the kidneys, brain, and heart. It is a prototypical autoimmune disease that is driven by pathological between T cells and B cells. A prominent feature of SLE is the expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, which are 2 T cell populations that provide help to B cells. Both human TFH and TPH cells are known to produce high levels of the B cell chemoattractant CXCL13; however, the regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states are currently unclear.1,2
“Up until this point, all therapy for lupus is a blunt instrument. It’s broad immunosuppression,” said co-corresponding author Jaehyuk Choi, MD, PhD associate professor of dermatology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine dermatologist, in a news release. “By identifying a cause for this disease, we have found a potential cure that will not have the side effects of current therapies.”1
In this study, the investigators identified that 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. By using CRISPR screens, the investigators were able to identify that the aryl hydrocarbon receptor (AHR) is a potent negative regulator of CXCL13 produced by human CD4+ T cells. Further, transcriptomic, epigenetic, and functional studies demonstrate that AHR can coordinate with AP-1 family member JUN to prevent CXCL13+ TPH and TFH cell differentiation while promoting an IL-22+ phenotype. According to the investigators, type I interferon—which is a pathogenic driver of SLE—opposes AHR and JUN to promote CXCL13’s T cell production.2
“We’ve identified a fundamental imbalance in the immune responses that patients with lupus make, and we’ve defined specific mediators that can correct this imbalance to dampen the pathologic autoimmune response,” said co-corresponding author Deepak Rao, MD, PhD, assistant professor of medicine at Harvard Medical School, rheumatologist at Brigham and Women’s Hospital, co-director of Center for Cellular Profiling, in the news release.1
To demonstrate that this discovery and be leveraged for treatments, the investigators returned the molecules that activated AHR to blood samples from patients with SLE. According to the authors, this appeared to “reprogram” the cells that cause SLE, transforming them into a type of cell that instead may promote the healing of wounds that are a result of SLE. These results, according to the authors, place CXCL13+ TPH and TFH cells on a polarization axis opposite from T helper 22 cells, therefore revealing AHR, JUN, and interferon as key regulators of these differing T cell states.1,2
“We found that if we either activate the AHR pathway with small molecule activators or limit the pathologically excessive interferon in the blood, we can reduce the number of these disease-causing cells,” said Choi, in the news release. “If these effects are durable, this may be a potential cure.”1
