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User:Josiehar/Epigenetics of autoimmune disorders

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Rheumatoid arthritis (RA)

Rheumatoid arthritis is a degenerative autoimmune disease that causes damage and inflammation to a patient's joint. Global DNA hypomethylation is a hallmark of Rheumatoid Arthritis and is observed in the early stages of this disease, when joint degeneration begins.[1] Those who suffer from RA have a global decreased level of methylation on many DNA promoter regions including those associated with normal immune system and joint function. This overexpression from hypomethylation is observed in various genes such as ITGAL, CD40LG, PRF1, and more. Taking a closer glance at those who suffer from RA, it can be observed that within the synovial cells, there is a level of hypomethylation which is proposed to cause the expression and overproduction of the cytokines which perpetuate the inflammatory response causing inflammation within the synovial fluid, which is the fluid that exists between the joints.[2] Typically, healthy joints have a thin layer of synovial tissue that lines the cavities of the joints. However, as an increase number of immune cells begins to penetrate the tissue, the synovial tissue begins to form a thick lining layer that consists of different macrophages and synovial cells.[3] Hypomethylation of CD40LG, which will make the T-cells within the immune response, can lead to T-cell overexpression and becomes a contributing factor to how Rheumatoid Arthritis functions within an inflammatory response. Patients with RA often display anti-cyclic citrullinated peptide (anti-CCP) antibodies and have hypomethylation of the retrotransposon gene L1, as well as decreased methylation at the Il6 and ERa promoter.[4] TET proteins, more specifically the TET1-TET3 enzymes and TET2 in T cells can demethylate DNA which helps to set and clarify the early stages of RA.[1] The RA development from demethylation of histones in the patient can lead to expression of high levels of IL-6 which causes destruction in the joints.[1] miRNAs also play an important part in rheumatoid arthritis development as well, particularly the upregulation of miRNA-146a and miRNA-150. Although more research is needed, lncRNAs have been implicated to play a role in this disease since current treatments used for this disorder show altered expression of 85 different lncRNAs in RA patients on tocilizumab and adalimumab.[1]


Josie Edits:

Sjogren's syndrome

Sjorgen's syndrome is a dermatological autoimmune disorder that targets exocrine glands[5] and attacks lacrimal and salivary glands causing a decrease in the secretion of tears and saliva. This results in inflammation, dry eyes, and dry mouth. Patients with this condition experience a buildup of white blood cells in the salivary glands known as lymphocytic infiltrate. Current research is largely focused on the innate immune system's role in the pathogenesis of this diseases.[6] In Sjorgen's patients, miRNA-146a is upregulated in PBMCs and is associated with the pathogenesis of this disease. miRNA-146a plays an important role in regulating the immune system by providing negative feedback to toll-like receptor (TLR) signaling which is used to engage the innate immune response. When miRNA-146a is upregulated, this negative feedback to TLR signaling decreases leading to inflammation and a heightened immune response that can damage healthy cells such as those in the lacrimal and salivary gland.[7] miRNA-150 and miRNA-149 are also upregulated in the salivary glands and lymphocytes of those with Sjorgen's. These miRNAs are targeted to mRNAs that play an important role in immune function and regulating pro-inflammatory cytokine levels. The overexpression of these miRNAs thus leads to a heightened and dysregulated immune response.[8] Epigenetic alterations to the genes of CD4+ T-cell in the immune system are also observed in this condition. Specifically, research has linked hypomethylation of CD70, a T-cell costimulatory gene, to the development of Sjogren's syndrome.[9] Decreased expression of the FOXP3 gene, which leads to DNA hypermethylation, is also observed in these CD4+ T-cells. This causes CpG hypermethylation leading to the downregulation of many cells that are essential for keeping the immune system in check.[9]


Systemic lupus erythematosus (SLE)

Systemic lupus erythematosus is the most common form of lupus and is a condition in which the immune system attacks healthy bodily tissue causing wide-spread inflammation and tissue damage across many organ systems.[10] Hypomethylation is observed across the epigenome in those with systemic lupus.[11] The promoter regions of many genes including ITGAL, CD40LG, and CD70 are shown to be hypomethylated as well as the 18S and 28S ribosomal gene promoters.[12] In particular, this DNA hypomethylation is thought to alter T cells' the chromatin structure, enhancing the immune and inflammatory response observed in those with this condition.[13] Genome-wide it has been shown that when comparing the epigenomes of pairs of identical twins in which one twin is afflicted by the condition and one is not, the twin possessing the condition shows global decreases in methylation of their genomes.[14] This hypomethylation causes genes traditionally repressed by methylation to be overexpressed particularly in CD4+ T cells.[15] It has been suggested that inhibition of DNMT1 produces the loss of methylation observed in those afflicted by systemic lupus.[16] DNMT1 is a DNA methyltransferase that maintains methylation patterns across the process of DNA replication, ensuring that new copies of DNA contain the methylation pattern observed on the original parent strand.[16] Inhibition of DNMT1 causes methylation patterns to be lost across generations and epigenome-wide hypomethylation is observed. In particular, it has been observed that DNMT1 expression is lower in immune T-cells.[16]

References

  1. ^ a b c d Ciechomska M, O'Reilly S (2016-08-10). "Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases". Mediators of Inflammation. 2016: 9607946. doi:10.1155/2016/9607946. PMC 4995328. PMID 27594771.
  2. ^ Quintero-Ronderos P, Montoya-Ortiz G (2012). "Epigenetics and autoimmune diseases". Autoimmune Diseases. 2012: 593720. doi:10.1155/2012/593720. PMC 3318200. PMID 22536485.
  3. ^ Scherer, Hans Ulrich; Häupl, Thomas; Burmester, Gerd R. (2020-06). "The etiology of rheumatoid arthritis". Journal of Autoimmunity. 110: 102400. doi:10.1016/j.jaut.2019.102400. {{cite journal}}: Check date values in: |date= (help)
  4. ^ Wu H, Liao J, Li Q, Yang M, Zhao M, Lu Q (November 2018). "Epigenetics as biomarkers in autoimmune diseases". Clinical Immunology. 196: 34–39. doi:10.1016/j.clim.2018.03.011. PMID 29574040. S2CID 4357851.
  5. ^ Le Dantec, Christelle; Varin, Marie-Michele; Brooks, Wesley H.; Pers, Jacques-Olivier; Youinou, Pierre; Renaudineau, Yves (2012-08). "Epigenetics and Sjögren's syndrome". Current Pharmaceutical Biotechnology. 13 (10): 2046–2053. doi:10.2174/138920112802273326. ISSN 1873-4316. PMID 22208659. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Ciechomska M, O'Reilly S (2016-08-10). "Epigenetic Modulation as a Therapeutic Prospect for Treatment of Autoimmune Rheumatic Diseases". Mediators of Inflammation. 2016: 9607946. doi:10.1155/2016/9607946. PMC 4995328. PMID 27594771.
  7. ^ Imgenberg-Kreuz J, Rasmussen A, Sivils K, Nordmark G (May 2021). "Genetics and epigenetics in primary Sjögren's syndrome". Rheumatology. 60 (5): 2085–2098. doi:10.1093/rheumatology/key330. PMC 8121440. PMID 30770922.
  8. ^ Quintero-Ronderos P, Montoya-Ortiz G (2012). "Epigenetics and autoimmune diseases". Autoimmune Diseases. 2012: 593720. doi:10.1155/2012/593720. PMC 3318200. PMID 22536485.
  9. ^ a b Mazzone R, Zwergel C, Artico M, Taurone S, Ralli M, Greco A, Mai A (February 2019). "The emerging role of epigenetics in human autoimmune disorders". Clinical Epigenetics. 11 (1): 34. doi:10.1186/s13148-019-0632-2. PMC 6390373. PMID 30808407.
  10. ^ CDC (2023-01-31). "Systemic lupuserythematosus (SLE)". Centers for Disease Control and Prevention. Retrieved 2024-02-14.
  11. ^ XIAO, GONG; ZUO, XIAOXIA (2016-2). "Epigenetics in systemic lupus erythematosus". Biomedical Reports. 4 (2): 135–139. doi:10.3892/br.2015.556. ISSN 2049-9434. PMC 4734248. PMID 26893827. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Javierre, Biola M.; Fernandez, Agustin F.; Richter, Julia; Al-Shahrour, Fatima; Martin-Subero, J. Ignacio; Rodriguez-Ubreva, Javier; Berdasco, Maria; Fraga, Mario F.; O'Hanlon, Terrance P.; Rider, Lisa G.; Jacinto, Filipe V.; Lopez-Longo, F. Javier; Dopazo, Joaquin; Forn, Marta; Peinado, Miguel A. (2010-2). "Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus". Genome Research. 20 (2): 170–179. doi:10.1101/gr.100289.109. ISSN 1088-9051. PMC 2813473. PMID 20028698. {{cite journal}}: Check date values in: |date= (help)
  13. ^ Wu, Haijing; Chen, Yongjian; Zhu, Huan; Zhao, Ming; Lu, Qianjin (2019-09-27). "The Pathogenic Role of Dysregulated Epigenetic Modifications in Autoimmune Diseases". Frontiers in Immunology. 10: 2305. doi:10.3389/fimmu.2019.02305. ISSN 1664-3224. PMC 6776919. PMID 31611879.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  14. ^ Castillo-Fernandez, Juan E; Spector, Tim D; Bell, Jordana T (2014-07-31). "Epigenetics of discordant monozygotic twins: implications for disease". Genome Medicine. 6 (7): 60. doi:10.1186/s13073-014-0060-z. ISSN 1756-994X. PMC 4254430. PMID 25484923.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Jeffries, Matlock A; Dozmorov, Mikhail; Tang, Yuhong; Merrill, Joan T; Wren, Jonathan D; Sawalha, Amr H (2011-5). "Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus". Epigenetics. 6 (5): 593–601. doi:10.4161/epi.6.5.15374. ISSN 1559-2294. PMC 3121972. PMID 21436623. {{cite journal}}: Check date values in: |date= (help)
  16. ^ a b c Li, Jiaqi; Li, Lifang; Wang, Yimeng; Huang, Gan; Li, Xia; Xie, Zhiguo; Zhou, Zhiguang (2021-11-01). "Insights Into the Role of DNA Methylation in Immune Cell Development and Autoimmune Disease". Frontiers in Cell and Developmental Biology. 9: 757318. doi:10.3389/fcell.2021.757318. ISSN 2296-634X. PMC 8591242. PMID 34790667.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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