İnflamatuvar barsak hastalıkları ve genetik

Year 2020, Volume: 2 Issue: 3, 80 - 86, 28.06.2020

Güray Can , Hüseyin Ahmet Tezel

https://doi.org/10.38053/acmj.689278

Abstract

İnflamatuvar barsak hastalıkları gastrointestinal sistemi tutan kronik inflamatuvar bir hastalık grubudur. İnflamatuvar barsak hastalıklarının etiyolojisi hala aydınlatılamamışken, çevresel ve genetik faktörlerin kompleks etkileşimi sonucu, intestinal sistemde lüminal içeriğe karşı abartılı bir immün yanıtın oluştuğu düşünülmektedir. Bu reaksiyon, genetik olarak yatkın olanlarda lüminal antijenlere karşı immün-toleransın kaybolması sonucu meydana geliyor olabilir. Günümüzde, İnflamatuvar barsak hastalıkları için yatkınlık oluşturan, intestinal immün yanıtı etkileyebilecek çok sayıda gen tanımlanmıştır. Bunlar intestinal immün sistemin farklı basamaklarında etkili mekanizmalarla ilişkili olarak ortaya çıkmaktadır. İntestinal immün sistemin, lüminal mikrobiyota, intestinal epitelyal bariyer, antijen tanımlama, otofaji ve inflamazom, endoplazmik retikulum stresi, antijen sunumu ve kazanılmış bağışıklık sistemi ile JAK-STAT yolağını da içine alan birçok katmanında genetik olarak ortaya çıkabilecek değişiklikler sistemin işleyişinin etkilenmesine neden olacak, hastalığın gün yüzüne çıkmasına neden olacaktır. Ama maalesef son gelişmelerle birlikte hastalığın ortaya çıkmasında rol oynayan genetik değişikliklerin bunlarla sınırlı olmadığı, nonfonksiyone genler, epigenetik değişiklikler, metabolomikler ve bunun gibi birçok durumun da inflamatuvar barsak hastalıklarıyla ilişkisi gösterilmiştir. Bütün bu gelişmelere rağmen hala daha hastalığın patogenezi net birşekilde ortaya konulamamış olması, hastalığı multifaktöryel doğasından kaynaklanmaktadır.

Keywords

İnflamatuvar barsak hastalıkları, genetik, JAK-STAT yolağı

Inflammatory bowel diseases and genetic

Abstract

Inflammatory bowel diseases are a group of chronic inflammatory diseases that involve the gastrointestinal tract. While the etiology of inflammatory bowel
diseases is still not elucidated, an exaggerated immune response to luminal content is thought to occur in the intestinal tract as a result of the complex
interaction of environmental and genetic factors. This reaction may occur as a result of loss of immune-tolerance to luminal antigens in those who are
genetically susceptible. Today, a large number of genes have been identified that are susceptible to inflammatory bowel diseases that may affect the intestinal
immune response. These occur in relation to effective mechanisms at different stages of the intestinal immune system. Genetic changes that may occur in
many layers of the intestinal immune system, including luminal microbiota, intestinal epithelial barrier, antigen identification, autophagy and infamazom,
endoplasmic reticulum stress, antigen presentation and acquired immune system, and JAK-STAT pathway, will affect the functioning of the system. will cause
it to come to light. Unfortunately, with the latest developments, genetic changes that play a role in the emergence of the disease have not been limited to these;
nonfunctional genes, epigenetic changes, metabolomics and many other conditions have been shown to be associated with inflammatory bowel diseases.
Despite all these developments, the fact that the pathogenesis of the disease has not been clearly revealed is due to its multifactorial nature.

Keywords

Inflammatory bowel diseases, genetics, JAK-STAT pathway

References

• 1. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterol 1998; 115: 182-205.
• 2. Editorial: Wilhelm Fabry (1560–1624): the other fabricius. JAMA 1964; 190: 933.
• 3. Crohn B, Ginzburg L, Oppenheimer GD. Landmark article Oct 15, 1932: regional ileitis: a pathological and clinical entity, by Burril B Crohn, Leon Ginzburg, and Gordon D Oppenheimer. JAMA 1984; 251: 73–9.
• 4. Wilks S. Morbid appearances in the intestine of Miss Bankes. London Medical Times & Gazette 1859; 2: 264.
• 5. Lakatos PL, Fischer S, Lakatos L, Gal I, Papp J. Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take "toll" ? World J Gastroenterol 2006; 12: 1829-41.
• 6. Halme L, Paavola-Sakki P, Turunen U, Lappalainen M, Farkkila M, Kontula K. Family and twin studies in inflammatory bowel disease. World J Gastroenterol 2006; 12: 3668-72.
• 7. The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–78.
• 8. Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al. Mapping of a susceptibility locus for Crohn's disease on chromosome 16. Nature 1996; 379: 821-3.
• 9. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011; 474: 307-17. 10. Satsangi J, Grootscholten C, Holt H, Jewel DP. Clinical patterns of familial inflammatory bowel disease. Gut 1996: 38; 738-41.
• 11. Spehlmann ME, Begun AZ, Burghardt J, Lepage P, Raedler A, Schreiber S. Epidemiology of inflammatory bowel disease in a German twin cohort: results of a nationwide study. Inflamm Bowel Dis 2008; 14: 968–76.
• 12. Bengtson MB, Solberg C, Aamodt G, et al. Clustering in time of familial IBD separates ulcerative colitis from Crohn’s disease. Inflamm Bowel Dis 2009; 15: 1867–74.
• 13. Orholm M, Binder V,Sorensen TI, Rasmussen LP, Kyvik KO. Concordance of inflammatory bowel disease among Danish twins: results of a nationwide study. Scand J Gastroenterol 2000; 35: 1075-81.
• 14. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 2001; 411: 599-603.
• 15. Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001; 411: 603-6.
• 16. Hampe J, Schreiber S, Shaw SH, Let al. A genom wide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet 1999; 64: 808-16.
• 17. Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42: 1118-25.
• 18. Anderson CA, Boucher G, Lees CW, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 2011; 43: 246-52.
• 19. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119-24.
• 20. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science 2005; 308: 1635–8.
• 21. Burnham WR, Lennard-Jones JE, Stanford JL, Bird RG. Mycobacteria as a possible cause of inflammatory bowel disease. Lancet 1978;2(8092 Pt 1):693-6.
• 22. Chiodini RJ. Crohn's disease and the mycobacterioses: a review and comparison of two disease entities. Clin Microbiol Rev 1989; 2: 90-117.
• 23. Kallinowski F, Wassmer A, Hofmann MA, et al. Prevalence of enteropathogenic bacteria in surgically treated chronic inflammatory bowel disease. Hepatogastroenterol 1998; 45: 1552-8.
• 24. Martin HM, Campbell BJ, Hart CA, et al. Enhanced Escherichia coli adherence and invasion in Crohn's disease and colon cancer. Gastroenterol 2004; 127: 80-93.
• 25. Macpherson A, Khoo UY, Forgacs I, Philpott-Howard J, Bjarnason I. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria. Gut 1996; 38: 365-75.
• 26. Harrer M, Reinisch W, Dejaco C, et al. Do high serum levels of anti-Saccharomyces cerevisiae antibodies result from a leakiness of the gut barrier in Crohn's disease? Eur J Gastroenterol Hepatol 2003; 15: 1281-5.
• 27. Van Limbergen J, Russell RK, Nimmo ER, t al. Genetics of the innate immune response in inflammatory bowel disease. Inflamm Bowel Dis 2007; 13: 338-55.
• 28. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783-801.
• 29. Anderson KV, Bokla L, Nusslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 1985; 42: 791-8.
• 30. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085-8.
• 31. Mitchell JA, Fitzgerald KA, Coyle A, Silverman N, Cartwright N. TOLLing away in Brazil. Nat Immunol 2006; 7: 675-9. 32. Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci USA 2000; 97: 13766-71.
• 33. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413: 732-8.
• 34. Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001; 410: 1099-103.
• 35. Latz E, Schoenemeyer A, Visintin A, et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 2004; 5: 190-8.
• 36. Harton JA, Ting JP. Class II transactivator: mastering the art of major histocompatibility complex expression. Mol Cell Biol 2000; 20: 6185-94.
• 37. Inohara N, Nunez G. The NOD: a signaling module that regulates apoptosis and host defense against pathogens. Oncogene 2001; 20: 6473-81.
• 38. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 2006; 6: 9-20.
• 39. Ting JP, Kastner DL, Hoffman HM. CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 2006; 6: 183-95.
• 40. Inohara N, Nunez G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003; 3: 371-82.
• 41. Lala S, Ogura Y, Osborne C, et al. Crohn's disease and the NOD2 gene: a role for paneth cells. Gastroenterol 2003; 125: 47-57.
• 42. Girardin SE, Boneca IG, Carneiro LA, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science 2003; 300: 1584-7.
• 43. Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem 2003; 278: 8869-72.
• 39. Kaser A, Blumberg RS. Autophagy, microbial sensing, endoplasmic reticulum stress, and epithelial function in inflammatory bowel disease. Gastroenterol 2011; 140: 1738-47.
• 40. Vaishnava S, Behrendt CL, Ismail AS, Eckmann L, Hooper LV. Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface. Proc Natl Acad Sci USA 2008; 105: 20858–63.
• 41. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008; 134: 743–56.
• 42. Richardson CE, Kooistra T, Kim DH. An essential role for XBP-1 in host protection against immune activation in C. elegans. Nature 2010; 463: 1092–5.
• 43. Cadwell K, Patel KK, Maloney NS, et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 2010; 141: 1135–45.
• 44. Martinon F, Chen X, Lee AH, Glimcher LH, et al. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol 2010; 11: 411–8.
• 45. Coombes JL, Powrie F. Dendritic cells in intestinal immune regulation. Nat Rev Immunol 2008; 8: 435-46.
• 46. Johansson-Lindbom B, Svensson M, Pabst O, et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J Exp Med 2005; 202: 1063-73.
• 47. Kinnebrew MA, Buffie CG, Diehl GE, et al. Interleukin 23 production by intestinal CD103(+)CD11b(+) dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 2012; 36: 276-87.
• 48. Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 2002; 285: 1-24.
• 49. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264: 1415-21.
• 50. O'Shea JJ, Gadina M, Schreiber RD. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 2002; 109(Supp l): S121-31.
• 51. Rodig SJ, Meraz MA, White JM, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 1998; 93: 373-83.
• 52. Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93: 397-409.
• 53. Strobl B, Stoiber D, Sexl V, Mueller M. Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity. Front Biosci 2011; 17: 3214-32.
• 54. Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ. Tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene 1990; 5: 1329-36.
• 55. van Boxel-Dezaire AH, Rani MR, Stark GR. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 2006; 25: 361-72.
• 56. Ragimbeau J, Dondi E, Alcover A, Eid P, Uze G, Pellegrini S. The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. EMBO J 2003; 22: 537-47.
• 57. Karaghiosoff M, Neubauer H, Lassnig C, et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity 2000; 13: 549-60.
• 58. Shimoda K, Kato K, Aoki K, et al. Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-mediated T cell function. Immunity 2000; 13: 561-71.
• 59. Roy B, Cathcart MK. Induction of 15-lipoxygenase expression by IL-13 requires tyrosine phosphorylation of horylation of Jak2 and Tyk2 in human monocytes. J Biol Chem 1998; 273: 32023-9.