Imunološki mehanizmi u bolestima gastrointestinalnog trakta

master's thesis

• Title (english): Immunological mechanisms in gastrointestinal diseases
• Author: Iva Topalušić
• Mentor: Asja Stipić-Marković (mentor)
• Committee member: Danka Grčević (predsjednik povjerenstva)
• Committee member: Jasenka Markeljević (član povjerenstva)
• Committee member: Asja Stipić-Marković (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Internal Medicine); Zagreb
• Defense date and country: 2014-07-15, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine

Abstract

Imunološki sustav gastrointestinalnog trakta organiziran je u limfno tkivo pridruženo sluznici probavne cijevi-GALT (od engl. gut associated lymphoid tissue). Nedavno je prepoznata i imunološka uloga epitelnih stanica koje luče antimikrobne peptide, produciraju crijevni glikokaliks i imaju predočnu funkciju. Dendritičke stanice (CD 103+ DS) glavne su predočne stanice crijevne imunosti. Potiču imunoregulatorne mehanizme, kojima se prema antigenima hrane i crijevne mikrobiote normalno uspostavlja imunotolerancija. Glavni je mehanizam uspostave imunotolerancije poticanje diferencijacije naivnih limfocita T prema regulatornim limfocitima (T reg). T reg lučenjem antiinflamatornih citokina IL-10 i TGFß (transformirajući čimbenik rasta β), inhibiraju proinflamatornu imunološku kaskadu (Th1, Th2, Th17). U uspostavi imunotolerancije ulogu imaju i sekretorna IgA antitijela koja smanjuju imunogenost antigena, okružuju ih i odvajaju od sluznice, te sprječavaju kontakt s imunološkim stanicama. Pravilna diferencijacija limfocita T ovisi o interakciji stanica nespecifične imunosti i crijevne mikrobiote. U sluznici probavnog sustava nalazi se oko 1013 bakterija, od kojih 85% čine laktobacili i bifidobakterije. Za mnoge je pripadnike crijevne mikrobiote (B. fragilis, F. prauznitsii) pokazano da stimuliraju upravo diferencijaciju T reg. Poremećaj diferencijacije T reg i promjene crijevne mikrobiote smatraju se važnima u razvoju alergijskih reakcija na hranu. Stoga se proučava terapijska uloga probiotika i specifične imunoterapije, s ciljem poticanja imunotolerancije. Kod bolesnika s upalnim bolestima crijeva, nađeno je niz promjena nespecifične i specifične imunosti. Najčešće se spominju polimorfizmi NOD2 (od od engl. Nod-like receptor) i TLR4 (od engl. Toll-like receptor) te dominacija Th17 limfocitnog odgovora. Niz je novosti vezanih uz patogenezu celijakije koja je povezana s Th1 i Th2 obrascima preosjetljivosti na gluten i njegove frakcije. Otkrivena je značajna uloga IL-15 u patogenezi refraktorne celijakije, što otvara mogućnost uspješnijem liječenju ovih bolesnika. Sindrom iritabilnog crijeva također se povezuje s imunološkim promjenama te se postižu dobri terapijski rezultati probioticima. Eozinofilni ezofagitis i gastroenteritis u posljednje su vrijeme u porastu te se povezuju s alergijama na hranu. Ipak, potrebna su daljnja istraživanja njihove patogeneze.

Abstract (english)

The mucosal immune system includes diffuse lymphoid cells and organized lymphoid structures that form gut associated lymphoid tissue-GALT. The immunological role of epithelial cells has also been confirmed. They produce glycocalyx and antimicrobial peptides that control different classes of microorganisms. Dendritic cells (DC) have the main role in antigen presenting. Under steady-state conditions, CD 103+ DC are specialized in driving mucosal tolerogenic responses. They induce T regulatory cell development. T reg produce IL-10 and TGFß (transforming growth factor β), that have an antiinflamatory effect and inhibit Th1, Th2 and Th17 cell development. IgA are also important to control intestinal immune homeostasis via two actions. They reduce the expression of inflammatory bacterial epitopes by opsonization and inhibit their contact with immune cells. The intestinal microbiota is composed of 1013 microorganisms. Lactobacilli and Bifidobacteria dominate (> 85% of total bacteria). Microbiota has diverse effect on immune cells. For instance, B. fragilis and F. prauznitsii are able to promote T reg differentiation. The role of gut microbiota dysbiosis and deviation in T reg cells differentiation has been well studied in the pathogenesis of food allergy. Further studies are needed to investigate therapeutic effects of probiotics and speciffic imunotherapy. There are many disorders in adaptive and innate immunity whitch are thought to have a role in the pathogenesis of inflammatory bowel disease. Mutations of NOD2 (Nod- like receptor) and TLR4 (Toll- like receptor), as well as increased activity of Th17 pathway, have been studied in the context of inflammatory bowel disease. New pharmacological approaches due to these mechanisms are needed to be studied. Coeliac disease is both Th1 and Th2 disorder caused by a gluten hypersensitivity. The role of IL-15 in refractory coeliac disease has recently been highlighted. Irritable bowel syndrom has also been explained by some immunological mechanisms. Recent studies have shown that probiotics have good results in treatment of these patients. Eosinophilic esophagitis and eosinophilic gastroenteritis have receantly been recognised as increasing disorders, at least partly connected with food allergy. Further studies are needed to explain pathogenesis of these disorders.

• Keywords: imunoregulacija; nespecifična i specifična imunost; crijevna mikrobiota; probiotici; gastrointestinalne bolesti
• Keywords (english): immunoregulation; adaptive immunity; innate immunity; gut microbiota; probiotics; gastrointestinal diseases
• Language: croatian
• URN:NBN: urn:nbn:hr:105:727514
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2015-10-12 07:01:26