Summary: Researchers have identified a protein they believe may cause the adverse reaction in the immune system of those suffering from Lupus. Reduced production of the Blimp-1 protein increased CTSS in females with Lupus, but not in males, the Nature Immunology study reports.
Source: Northwell Health.
Leading rheumatologist and Feinstein Institute for Medical Research Professor Betty Diamond, MD, may have identified a protein as a cause for the adverse reaction of the immune system in patients suffering from lupus. A better understanding of how the immune system becomes overactive will help lead to more effective treatments for lupus and potentially other autoimmune diseases. These findings were published in Nature Immunology.
Lupus is an autoimmune disease that causes the immune system to lose the ability to differentiate between foreign agents and healthy tissue. It becomes hyperactive and attacks healthy tissue, causing inflammation and damage to joints, skin, and internal organs. Previous studies have shown that a polymorphism or variation in the gene PRDM1 is a risk factor for lupus. PRDM1 enacts the production of a protein called Blimp-1. In this study, Dr. Diamond and her team were looking to examine how Blimp-1 regulates the immune system.
“A healthy immune system is able to identify organisms that are not normally in the body and activate cells like T-Cells to attack them,” said Dr. Diamond. “In the case of patients with an autoimmune disease like lupus, the immune system has started to identify healthy cells as something to target. Our study found that a low level of or no Blimp-1 protein in a particular cell type led to an increase in the protein CTSS which caused the immune system to identify healthy cells as something to attack – particularly in females.”
In an animal model, Dr. Diamond’s team was able to show that females with reduced production of Blimp-1 caused an increase in CTSS, a protein that helps the immune system see microbes, or a microorganisms that causes disease. This resulted in an immune system which attacked healthy cells. Male animals with the reduced production of Blimp-1 showed no change in their immune system. Though more study is required to confirm that the risk gene PRDM1 could lead to a hyperactive immune system in human females, this is a significant discovery to better understanding the causes and potential treatments for lupus.
Funding: The study was supported by Bristol Research into Alzheimer’s and Care of the Elderly, Sigmund Gestetner Trust.
Source: Heather Ball – Northwell Health
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Original Research: Abstract for “Increased cathepsin S in Prdm1−/− dendritic cells alters the TFH cell repertoire and contributes to lupus” by Sun Jung Kim, Sebastian Schätzle, S Sohail Ahmed, Wolfgang Haap, Su Hwa Jang, Peter K Gregersen, George Georgiou & Betty Diamond in Nature Immunology. Published online July 10 2017 doi:10.1038/ni.3793
Increased cathepsin S in Prdm1−/− dendritic cells alters the TFH cell repertoire and contributes to lupus
Aberrant population expansion of follicular helper T cells (TFH cells) occurs in patients with lupus. An unanswered question is whether an altered repertoire of T cell antigen receptors (TCRs) is associated with such expansion. Here we found that the transcription factor Blimp-1 (encoded by Prdm1) repressed expression of the gene encoding cathepsin S (Ctss), a cysteine protease that cleaves invariant chains and produces antigenic peptides for loading onto major histocompatibility complex (MHC) class II molecules. The increased CTSS expression in dendritic cells (DCs) from female mice with dendritic cell–specific conditional knockout of Prdm1 (CKO mice) altered the presentation of antigen to CD4+ T cells. Analysis of complementarity-determining region 3 (CDR3) regions containing the β-chain variable region (Vβ) demonstrated a more diverse repertoire of TFH cells from female CKO mice than of those from wild-type mice. In vivo treatment of CKO mice with a CTSS inhibitor abolished the lupus-related phenotype and reduced the diversity of the TFH cell TCR repertoire. Thus, Blimp-1 deficiency in DCs led to loss of appropriate regulation of Ctss expression in female mice and thereby modulated antigen presentation and the TFH cell repertoire to contribute to autoimmunity.
“Increased cathepsin S in Prdm1−/− dendritic cells alters the TFH cell repertoire and contributes to lupus” by Sun Jung Kim, Sebastian Schätzle, S Sohail Ahmed, Wolfgang Haap, Su Hwa Jang, Peter K Gregersen, George Georgiou & Betty Diamond in Nature Immunology. Published online July 10 2017 doi:10.1038/ni.3793