New insights into the mechanism underlying lupus
A study, led by Betty Diamond at the Feinstein Institute for Medical Research, has uncovered a mechanism underlying lupus, a systemic autoimmune disease characterized by abnormal immune responses leading to autoantibody production. This study gives insights into the causes of lupus and would facilitate the development of new therapies.
The study was conducted in collaboration with researchers from the University of Texas at Austin and Roche Innovation Center Basel in Switzerland, and was described in the journal Nature Immunology.
The body's immune system normally functions to recognize and combat foreign invaders, such as bacteria, viruses, parasites, and toxins. But in lupus, the immune system fails to differentiate between foreign agents and healthy tissue. As a result, the immune system attacks healthy tissue in the joints, skin, kidneys, heart, and many other tissues, leading to systemic inflammation and damage. The cause of lupus is complex. Recent evidence supports that genetics plays a role in this autoimmune disease. To date, a limited number of susceptibility loci have been identified for lupus. One of the best-studied genetic links is the PRDM1 gene, which normally encodes a protein called PR domain zinc finger protein 1 (PRDM1) or Blimp-1 that acts as a transcription factor.
In this work, Diamond and colleagues set out to determine the exact role of Blimp-1 in regulating the immune system. They found that Blimp-1 negatively regulates the expression of the gene that encodes the protein CTSS (cathepsin S). CTSS, an enzyme that belongs to the peptidase C1 family, mainly helps the body degrade parts of a pathogen. This study showed that Blimp-1 deficiency in dendritic cells (DCs) led to increased expression of CTSS, which caused the immune system to attack healthy tissue in female mice. Furthermore, treatment with a CTSS inhibitor abolished the lupus-related phenotype in mice lacking Blimp-1. Remarkably, Blimp-1 deficiency appeared not to alter the immune system of male mice. Taken together, the results suggest that the CTSS protein may contribute to lupus in females. These findings are significant and warrant further investigation.
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