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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 PREVENT CD (EUFP6) “Nutritional risk factors in Coeliac Disease : possible induction of tolerance to gluten in genetically predisposed infants during breast feeding ELFID-UNINA Israel ELFID-UNINA PREVENT CD PARTNERS 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 transglutaminase or antigliadin ELFID-UNINA 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 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 The great Swedish Epidemic ELFID-UNINA Just a stimulation of the phenotype to unveal ELFID-UNINA Breast feeding in cases and controls ELFID-UNINA ELFID-UNINA Delay from symptoms to diagnosis in months Milk N Latency (mt) Breast 26,0 6,3 Bottle 120,0 4,0 F p 5,15 0,025 0,708 0,552 Age at gluten introduction (mt) 1° 7,0 6,0 2° 18,0 5,7 3° 79,0 4,1 4° 37,0 3,8 >5° 5,0 6,1 ELFID-UNINA Mean age at first symptoms Milk N Mean (mt) Breast 26,0 8,91 Bottle 120,0 6,30 F p 6,64 0,01 0,604 0,60 Age at gluten introduction (mt) 1° 7,0 7,4 2° 18,0 6,0 3° 79,0 6,9 4° 37,0 6,9 >5° 5,0 4,2 ELFID-UNINA PROFILE OF CD CANDIDATE GENES an 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 MOLECULAR RECEPTION OF VIRAL (?) PARTICLES 1. Molecular mimicry between Gluten fractions and Viral Antigen is likely and may suggest the alternative use of the same pathway 2. Double stranded RNA viruses naturally link to Toll Like receptor (TLR3) and then they can activate Transglutaminase. 3. 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 Viral (& Gluten?) Receptors 1. TNFRSF14 gene Function: This receptor was identified as a cellular mediator of herpes simplex virus (HSV) entry. 2. 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 3. TLR 7 gene & TLR 8 gene Function : play a fundamental 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 TNFSF14 with its receptor TNFRSF14 ELFID-UNINA 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 An important contribution by A. Fasano , Baltimora! J Immunol. 2006 Feb 15;176(4):2512-21. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease. Thomas KE, Sapone A, Fasano A, Vogel SN. Department of Microbiology and Immunology, University of Maryland School of 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 TLR7 and TLR8: Key players in the antiviral response gluten Nuclear Activation ELFID-UNINA 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 EPIDEMIOLOGY DOES NOT SUPPORT THIS ! Trend of infective Gastro Enteritis vs Celiac Disease 7 6 5 4 Enteritis 3 Celiac 2 1 0 50 55 60 65 70 75 80 YEARS ELFID-UNINA 85 90 95 100 Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection The 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 immunerelated 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 ELFID-UNINA risk-allele A with IL1b production (p = 0.034 for trend)… PROFILE OF CD CANDIDATE GENES an 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 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-Bdependent 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 ELFID-UNINA de-ubiquitination of several NF-kB signalling factors. Where TNFAIP3 works ELFID-UNINA African-Derived Genetic Polymorphisms in TNFAIP3 Mediate Risk for Autoimmunity James 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) was identified in TNFAIP3 gene In addition, a rare protective haplotype was defined by A125V (odds ratio = 0.31, p = 0.027). Although A125V was associated with protection from SLE, surprisingly the same allele was associated with increased risk of inflammatory bowel disease. Functional activity: the A125V coding-change variant ELFID-UNINA alters the DUB activity of the protein. 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 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 NF-KB c-Rel Pathway GLUTEN ? NF_kB Nuclear Activation Complex ELFID-UNINA 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-kappaB kinase/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 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 ELFID-UNINA C-Rel is a main candidate gene in CD Family Study Improving the recurrence risk in sibs 180 FAMILIES WITH PROBANDS AND UNKNOWN PHENOTYPE OF SIBS ELFID-UNINA Genotypic TDT based on three pseudo-controls SNP Gene Model Risk Allele OR (95% CI) p-value rs1464510* LPP Additive A 2.36 (1.64-3.41) 3∙10-6 rs2816316* RGS1 Dominant A 1.75 (1.07-2.86) 0.025 rs842647* REL Dominant A 1.66 (1.04-2.65) 0.034 rs2327832 OLIG3 Additive G 1.35 (0.90-2.03) 0.150 rs6441961 CCR1/CCR3 Additive A 1.24 (0.89-1.72) 0.189 rs6822844 IL2/IL21 Additive C 1.43 (0.82-2.49) 0.210 rs1738074 TAGAP Dominant A 1.31 (0.79-2.16) 0.293 rs3184504 SH2B3 Additive A 1.19 (0.86-1.63) 0.294 rs17810546 IL12A Additive G 1.10 (0.80-1.51) 0.572 rs9811792 IL12A/SCHIP1 Dominant G 1.10 (0.59-2.05) 0.753 *statistically significant results ELFID-UNINA ELFID-UNINA HLA only and HLA + 3 genes BS classifications HLA groups from 1 to 3 VS HLA groups 4-5 HLA-BS Healthy CD Healthy CD Test + 105 31 55 24 Test - 111 2 161 9 Considered at risk 136 (55%) 69 (28%) Sensitivity (95% CI) 0.94 (0.86-0.95) 0.73 (0.58-0.88) Specificity (95% CI) 0.51 (0.44-0.58) 0.75 (0.69-0.80) ELFID-UNINA Risk BY HLA HAPLOTYPE 0.25 0.20 0.15 0.10 0.05 0.00 DQ- DQ8 DQ2 ELFID-UNINA DQ2T DQ22 Risk Ranks for each DQ class INCREASING RISK BY A ALLELES IN 3 GENES 0.25 0.20 0.15 RISK DQ22 DQ2T DQ2 DQ8 0.10 DQ- 0.05 0.00 AA Min AAA 0,25 AAAA 0,5 AAAAA 0,75 ELFID-UNINA AAAAAA Max 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 GENETIC PROFILE • Certainly the most interesting and promising domain • Susceptibility to infections is important • Genes regulating autoimmunity • Possible population differences ELFID-UNINA 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