Autoimmune diseases are a class of diseases caused by the immune system mistakenly attacking the body's own tissues. In cases of autoimmune diseases such as lupus and rheumatoid arthritis, women account for about 80%. How to explain this gender difference has been a mystery.
Recently, researchers have discovered that a "molecular coating" on the female X chromosome may be related to the immune response [1].
女性X染色体上“分子涂层”——XIST RNP
这一“分子涂层”即长链非编码RNA(long non-coding RNA,LncRNA)——X染色体失活特异转录本（X in-active specific transcription factor,XIST）蛋白质复合物。
In the human genome, non-coding RNA accounts for about 99% of the total RNA of cells, and lncRNA, as a non-coding RNA, participates in the process of inflammation, abnormal proliferation, migration, invasion and apoptosis in autoimmune diseases, promotes the release of inflammatory factors, and aggravates or reduces the severity of the disease.
XIST is an important regulator of cell growth and development, which can regulate cell proliferation, differentiation, apoptosis, migration and invasion, and plays an important role in various types of tumors and diseases such as brain tumors, leukemia, lung cancer, breast cancer, pulmonary fibrosis, inflammation, neuropathic pain, and cardiomyocyte hypertrophy.
Molecular coatings can "seal" genes on the X chromosome
In most mammals, including humans, male cells usually have only one X chromosome, while female cells usually carry two X chromosomes. X chromosome inactivation inhibits the activity of one X chromosome in most XX cells, making the "dose" of their X-linked gene equal to that of male XY cells.
LncRNA XIST is located in the X chromosome inactivation center, winding around the chromosome, attracting dozens of proteins to form complexes, effectively sealing genes in the chromosome, causing genetic silencing of one X chromosome during female cell development, affecting fibroblast-like synovial cell proliferation and pro-inflammatory cytokine production.
Molecular coatings are expressed in patients with autoimmune diseases
Lupus nephritis is one of the serious complications of systemic lupus erythematosus. It has been reported that the expression of the XIST gene is overexpressed in SLE patients, and the X-linked allele variants in the patient's lymphocytes are increased, while the X-linked alleles in the lymphocytes that knock out XIST are restored to balance.
Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovitis and vasculitis, and the main clinical manifestations are symmetrical deformity and loss of function of the distal joints.
XIST was overexpressed in fibroblast-like synovial cells and osteoclasts in patients with rheumatoid arthritis, promoting the up-regulation of the expression of inflammatory and proliferative signaling pathway factors. It is speculated that the increased expression of XIST in peripheral serum exosomes in patients with rheumatoid arthritis may be related to the pathogenesis of patients with rheumatoid arthritis.
The XIST molecule itself can trigger an inflammatory immune response, and many of the proteins that interact with XIST are able to attack tissues and organs, leading to chronic inflammation and damage characteristic of autoimmune diseases.
Since XIST is typically expressed only in female cells, autoantibodies that attack XIST-associated proteins may have a greater effect on women than on men. The XIST RNP complex, which encloses certain X chromosomes, is prevalent in women with autoimmune diseases.
Defective gene regulation on sex hormones and the X chromosome is a driver of autoimmune differences. The discovery that the core protein of X chromosome inactivation itself can trigger an immune alarm may provide new diagnostic and therapeutic opportunities for autoimmune diseases.
Resources:
1.Diana R. Dou, Yanding Zhao, Julia A. Belk, Yang Zhao, Kerriann M. Casey, Derek C. Chen, Rui Li, Bingfei Yu, Suhas Srinivasan, Brian T. Abe, Katerina Kraft, Ceke Hellström, Ronald Sjöberg, Sarah Chang, Allan Feng, Daniel W. Goldman, Ami A. Shah, Michelle Petri, Lorinda S. Chung, David F. Fiorentino, Emma K. Lundberg, Anton Wutz, Paul J. Utz, Howard Y. Chang,
Xist ribonucleoproteins promote female sex-biased autoimmunity,Cell,Volume 187, Issue 3,2024,Pages 733-749.e16,ISSN 0092-8674,https://doi.org/10.1016/j.cell.2023.12.037.
2. Zhao Lin, Ni Chenghua, Li Jie, Liang Bo, Fu Dongdong. Expression and clinical application value of LncRNA XIST and miR-101-3p in peripheral blood mononuclear cells of SLE patients, Anhui Medicine, 2024, 45(01), 28-33
3. Xiao Hui, Han Xing, Jin Hongjie, Liu Xiao. Study on the regulation of mesangial cell proliferation and apoptosis of lupus nephritis by long non-coding RNA XIST targeting miR-150-5p, Journal of Hebei Medical University, 2023, 44(07), 760-766
4. Yu Juan, Sun Ning, Song Shusheng, Zhang Li, Zhang Jian, Li Xiaojun. Expression and significance of serum exosome long non-coding RNAHotair and XIST in patients with rheumatoid arthritis, Journal of Clinical Laboratory Medicine, 2023, 41(08), 586-590 DOI:10.13602/j.cnki.jcls.2023.08.06