{"title":"Genetics, epigenetics and autoimmunity constitute a Bermuda triangle for the pathogenesis of rheumatoid arthritis","authors":"","doi":"10.1016/j.lfs.2024.123075","DOIUrl":null,"url":null,"abstract":"<div><div>Rheumatoid arthritis (RA), a multigene disorder with a heritability rate of 60 %, is characterized by persistent pain, synovial hyperplasia, and cartilage and bone destruction, ultimately causing irreversible joint deformity. The etiology and pathogenesis of rheumatoid arthritis (RA) are primarily influenced by specific genetic variants, particularly HLA alleles such as HLA-DRB1*01 and DRB1*04. However, other HLA alleles such as HLA-DRB1*10 and DPB*1 have also been found to contribute to increased susceptibility to RA. However, non-HLA genes also confer a comparatively high risk of RA disease manifestation. The most relevant single nucleotide polymorphisms (SNPs) associated with non-HLA genes are PTPN22, TRAF1, CXCL-12, TBX-5, STAT4, FCGR, PADI4, and MTHFR. In conjunction with genetic susceptibility, epigenetic alterations orchestrate paramount involvement in regulating RA pathogenesis. Increasing evidence implicates DNA methylation and histone protein modifications, including acetylation and methylation, as the primary epigenetic mechanisms that drive the pathogenesis and clinical progression of the disease. In addition to genetic and epigenetic changes, autoimmune inflammation also determines the pathological progression of the synovial membrane in joints with RA. Glycosylation changes, such as sialylation and fucosylation, in immune cells have been shown to be relevant to disease progression. Genetic heterogeneity, epigenetic factors, and changes in glycosylation do not fully explain the features of RA. Therefore, investigating the interplay between genetics, epigenetics, and autoimmunity is crucial. This review highlights the significance and interaction of these elements in RA pathophysiology, suggesting their diagnostic potential and opening new avenues for novel therapeutic approaches.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0024320524006659","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Rheumatoid arthritis (RA), a multigene disorder with a heritability rate of 60 %, is characterized by persistent pain, synovial hyperplasia, and cartilage and bone destruction, ultimately causing irreversible joint deformity. The etiology and pathogenesis of rheumatoid arthritis (RA) are primarily influenced by specific genetic variants, particularly HLA alleles such as HLA-DRB1*01 and DRB1*04. However, other HLA alleles such as HLA-DRB1*10 and DPB*1 have also been found to contribute to increased susceptibility to RA. However, non-HLA genes also confer a comparatively high risk of RA disease manifestation. The most relevant single nucleotide polymorphisms (SNPs) associated with non-HLA genes are PTPN22, TRAF1, CXCL-12, TBX-5, STAT4, FCGR, PADI4, and MTHFR. In conjunction with genetic susceptibility, epigenetic alterations orchestrate paramount involvement in regulating RA pathogenesis. Increasing evidence implicates DNA methylation and histone protein modifications, including acetylation and methylation, as the primary epigenetic mechanisms that drive the pathogenesis and clinical progression of the disease. In addition to genetic and epigenetic changes, autoimmune inflammation also determines the pathological progression of the synovial membrane in joints with RA. Glycosylation changes, such as sialylation and fucosylation, in immune cells have been shown to be relevant to disease progression. Genetic heterogeneity, epigenetic factors, and changes in glycosylation do not fully explain the features of RA. Therefore, investigating the interplay between genetics, epigenetics, and autoimmunity is crucial. This review highlights the significance and interaction of these elements in RA pathophysiology, suggesting their diagnostic potential and opening new avenues for novel therapeutic approaches.
期刊介绍:
Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed.
The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.