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MEDICEL – Bologna April 5th 2011

MEDICEL – Bologna April 5th 2011. Environmental and Genetic Risk Factors for Coeliac Disease. Luigi Greco, European Laboratory for Food Induced Disease Naples, Italy.

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MEDICEL – Bologna April 5th 2011

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  1. MEDICEL – Bologna April 5th 2011 Environmental and Genetic Risk Factors for Coeliac Disease Luigi Greco, European Laboratory for Food Induced Disease Naples, Italy ELFID-UNINA

  2. PREVENT CD (EUFP6) “Nutritionalriskfactors in CoeliacDisease : possibleinductionoftolerancetogluten in geneticallypredisposedinfantsduringbreastfeeding ELFID-UNINA

  3. Israel ELFID-UNINA PREVENT CD PARTNERS

  4. PREVENT CELIAC DISEASE ??? • 1319 infants from families with a first degree relative with CD were recruited. • 905 of them, who were HLADQ2 and /or DQ8 positive, were prospectively followed-up for the development of CD. • Biopsies were performed if symptoms appeared and/or if two or three consecutive samples were positive for anti-tissue transglutaminaseor anti-gliadin ELFID-UNINA

  5. Intervention : 100 mg gluten at 4 mon. Till December 2010, 787, 450, and 207 infants were older than 12, 24 and 36 months respectively. 48 biopsies were performed in 47 children 31 diagnosis of CD diagnosis were made ELFID-UNINA

  6. Prevention or infection ? Of the 207 children who reached the age of 36 mo, 14 were diagnosed with CD between the 2nd and 3rd year (prevalence = 6,76%). Expected < 5% Of the 243 children aged 12-24 mo 15 new cases occurred (6,17%). Two more infants were diagnosed before the age of 12 mo. Expected < 2,5% ELFID-UNINA

  7. The great Swedish Epidemic ELFID-UNINA

  8. Just a stimulation of the phenotype to unveal ELFID-UNINA

  9. Breast feeding in cases and controls ELFID-UNINA

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  13. PROFILE OF CD CANDIDATE GENESan alternative point of view • COMMON TO OTHER AUTOIMMUNE DISEASES • CELL STRUCTURE AND SHAPE • MOLECULAR RECEPTION OF VIRAL (?) PARTICLES • NATURAL IMMUNITY AND INFLAMMATION • THE NF-kB SYSTEM • HLA SPECIFIC RECOGNITION AND PRESENTATION • T-CELL STIMULATION AND ACTIVATION ELFID-UNINA

  14. MOLECULAR RECEPTION OF VIRAL (?) PARTICLES • Molecular mimicry between Gluten fractions and Viral Antigen is likely and may suggest the alternative use of the same pathway • Double stranded RNA viruses naturally link to Toll Like receptor (TLR3) and then they can activate Transglutaminase. • Tissue Transglutaminase is activated by viral or bacterial polysaccarides (poly-C) , through Toll Like Receptors CD CANDIDATE GENES • TLR7 and TLR8: Key players in the antiviral response • TNFRSF14 also engages the herpes virus entry mediator. ELFID-UNINA

  15. Viral (& Gluten?) Receptors • TNFRSF14 gene Function: This receptor was identified as a cellular mediator of herpes simplex virus (HSV) entry. • TNFSF14 gene Function: Binding to the decoy receptor TNFRSF modulates its effects. Activates NFKB, stimulates the proliferation of T-cells, and inhibits growth of the adenocarcinoma HT-29. Acts as a receptor for Herpes simplex virus • TLR 7 gene & TLR 8 gene Function : play afundamental role in pathogen recognition and activation of innate immunity. They recognize pathogen-associated molecular patterns (PAMPs) GLUTEN??? and mediate the production of cytokines necessary for the development of effective immunity. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. ELFID-UNINA

  16. TNFSF14 with its receptor TNFRSF14 ELFID-UNINA

  17. TLR7/TLR8 receptors • Two of these orphan receptors TLR7/TLR8 act as sensors for single stranded RNA. • Activation of TLRs leads to the generation of an adaptive immune response resulting in the eradication of pathogens. ELFID-UNINA

  18. An important contribution by A. Fasano , Baltimora! J Immunol. 2006 Feb 15;176(4):2512-21. Gliadinstimulationof murine macrophageinflammatory gene expression and intestinalpermeability are MyD88-dependent: roleof the innate immune response in Celiacdisease. Thomas KE, Sapone A, Fasano A, Vogel SN. DepartmentofMicrobiology and Immunology, Universityof Maryland Schoolof Medicine, Baltimore, 21201, USA. Unfortunately they are not able to identify the specific Toll Like Rec. involved : they try with TLR2 and TLR4 and find that they are not stimulated by gliadin ELFID-UNINA

  19. TLR7 and TLR8: Key players in the antiviral response gluten NuclearActivation ELFID-UNINA

  20. Is Rotavirus Infection a Risk Factor ? • Rotavirus infection has been reported marginally increased in CD cases vs controls (Stene & Norris 2007) • In Celiac Disease, a Subset of Autoantibodies against Transglutaminase Binds Toll-Like Receptor 4 and Induces Activation of Monocytes (Zanoni et al., XX) • A subset of TGASeAb recognize the viral protein VP-7, suggesting a possible involvement of rotavirus infection through a mechanism of molecular mimicry. • Rotavirus Infection was not increased in CD vs controls (Rostami-Nejad M. et al , 2010) ELFID-UNINA

  21. EPIDEMIOLOGY DOES NOT SUPPORT THIS !Trend of infective Gastro Enteritis vs Celiac Disease ELFID-UNINA

  22. Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial InfectionThe American Journal of Human Genetics (2010), doi:10.1016/j.ajhg.2010.05.004 • The improved response to bacterial ligands, followed by positive selection of different SH2B3 gene variants suggest: • a possible mechanism of how this polymorphism contributes to the increased risk of developing immune-related diseases • that the cause of the signature of positive selection should be sought in improved host defense against infections. ( … We observed a dose-response relationship of the risk-allele A with IL1b production (p = 0.034 for trend)… ELFID-UNINA

  23. PROFILE OF CD CANDIDATE GENESan alternative point of view • COMMON TO OTHER AUTOIMMUNE DISEASES • CELL STRUCTURE AND SHAPE • MOLECULAR RECEPTION OF VIRAL (?) PARTICLES • NATURAL IMMUNITY AND INFLAMMATION THE NF-kB SYSTEM • HLA SPECIFIC RECOGNITION AND PRESENTATION • T-CELL STIMULATION AND ACTIVATION ELFID-UNINA

  24. TNFAIP3 gene - OR = 1,26(Trynka G et al., GUT 2009) • Inhibits NF-kappa B activation as well as TNF-mediated apoptosis. • Interacts with NAF1 and inhibits TNF-induced NF-kappa-B-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal. • Has deubiquitinating activity that is directed towards 'Lys-48' or 'Lys-63'-linked polyubiquitin chains • The A20 gene product is required for termination of the NF-kB signal mediated by innate immune receptors via de-ubiquitination of several NF-kB signalling factors. ELFID-UNINA

  25. Where TNFAIP3 works ELFID-UNINA

  26. African-Derived Genetic Polymorphisms in TNFAIP3 Mediate Risk for AutoimmunityJames P. Lodolce,*,1 Lauren E. Kolodziej,*,1 Lesley Rhee,*The Journal of Immunology, 2010, 184, 7001 -7009 • In African-American SLE patients a novel African-derived risk haplotype (odds ratio = 1.6; p = 0.006) wasidentified in TNFAIP3 gene • In addition, a rare protective haplotype was defined by A125V(odds ratio = 0.31, p = 0.027). • Although A125V was associatedwith protection from SLE, surprisingly the same allele was associatedwith increased risk of inflammatory bowel disease. • Functional activity: the A125V coding-change variantalters the DUB activity of the protein. ELFID-UNINA

  27. Structure of a NF-kB/DNA complex.  The NF-kB consists of two subunits: p50 (green) and p65 (red). NF-kB works only when two members form a dimer. ELFID-UNINA

  28. We pubblished 10 years ago! • NF-κB is the specific molecular mechanism by which inflammation is activated in celiac mucosa • NF-κB activation in mucosal tissue culture from healed celiac patients exposed to gluten peaks very early at 6 hour after exposition and fades after 24 hours • NF-κB is costituvely activated in celiac mucosa ELFID-UNINA

  29. NF-KB c-Rel Pathway GLUTEN ? NF_kBNuclearActivationComplex ELFID-UNINA

  30. Candidate Gene in the NF-kB domain REL gene Function • The REL gene encodes c-Rel, a transcription factor that is a member of the Rel/NFKB family . • Functionally, the gene participates in several processes: • positive regulation of I-kappaBkinase/NF-kappaB cascade, • cytokine production, • positive regulation of interleukin-12 biosynthetic process, • positive regulation of transcription, DNA-dependent, • transcription from RNA polymerase II promoter). ELFID-UNINA

  31. NF-kB include 5 genes .Three subunits, c-Rel, p65 o RelA, e RelB, have a transactivation domain. These members of the NF-kB family assemble homo- or heterodimers to produce gene regulatory complexes with specific properties C-Rel is a main candidate gene in CD ELFID-UNINA

  32. Family Study Improving the recurrence risk in sibs 180 FAMILIES WITH PROBANDS AND UNKNOWN PHENOTYPE OF SIBS ELFID-UNINA

  33. Genotypic TDT based on three pseudo-controls *statistically significant results ELFID-UNINA

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  35. HLA only and HLA + 3 genes BS classifications ELFID-UNINA

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  37. RiskRanksforeach DQ class ELFID-UNINA

  38. What we learn from these studies ? EARLY NUTRITION : very difficult, it may act on the individual case. Breast feeding and gluten work on the phenotype. • INFECTIONS : we do have anecdotical experience that infections unveil the disease, but … risk factor ? ELFID-UNINA

  39. GENETIC PROFILE • Certainly the most interesting and promising domain • Susceptibility to infections is important • Genes regulating autoimmunity • Possible population differences ELFID-UNINA

  40. THEN : WHAT WE DO ? • Start or continue a good collection of data and files • Whole Families are very important • A center based BIOBANK is the next step • Serum, DNA, Saliva : different methods to reinforce your own collection • Apply for research projects ELFID-UNINA

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