Celiac Disease: The Quintessential Autoimmune Disease Ivor D. Hill, MB, ChB, MD.

Celiac Disease: The Quintessential Autoimmune Disease Ivor D. Hill, MB, ChB, MD.....

Celiac Disease Autoimmune Diseases What are they? How do you get them? Why does it matter?

Celiac Disease Autoimmune diseases - what are they? A disease in which the body produces antibodies that attack its own tissues, leading to the deterioration and in some cases to the destruction of such tissue.

Celiac Disease Autoimmune diseases - how do you get them? Predisposition (genetics) Environmental factor Disease

Celiac Disease What do we know about celiac disease? Immunologic cascade Genetic component Dietary factor Trigger factor?

Celiac Disease The role of the diet Dietary factor Samuel Gee 1888: a kind of chronic indigestion.. errors in the diet might be the cause Concluded:- But if the patient can be cured at all it must be by means of diet. Herter 1908: fats better tolerated than carbohydrates Still 1918: poor tolerance of bread Howland 1921: increased tolerance to carbohydrates Haas 1928: banana based diet that excluded cereals

Celiac Disease The role of the diet Willem-Karel Dicke 1950: Dietary factor Exclusion of wheat and rye led to dramatic improvement of the general condition of the child Wheat starch did not have the same damaging effect Willem-Karel Dicke

Celiac Disease Dietary factor Gluten protein fraction in wheat, barley and rye Prolamines high in proline and glutamine

Gliadin (alcohol soluble) Celiac Disease Gluten Glutenin (alcohol insoluble) 33 MER

The role of genetics Celiac Disease Genetic component Historical Family members Monozygotic twins HLA identical siblings Genetic studies HLA Non-HLA

Celiac Disease A polygenic disorder! Genetic component HLA DQ2 - DQA1*05/DQB1*02 HLA DQ8 - DQA1*03/DQB1*0302 DR3-DQ2 DQB1*0201 DQA1*0501 DQB1*X DQA1*0505 DQB1*0202 DR5-DQ7 DR7-DQ2 DQ2 - inherited in cis DQ2 - inherited in trans

Relative risk DQ2 homozygous Celiac Disease The Gene Dose Effect* DQA1*0501 DQB1*0201 DQA1*0501 DQB1*0201 DQ2 + DQB1*02 DQ2 + DQ/X DQA1*0501 DQA1*0501 DQB1*0201 DQB1*02 DQB1*0201 - Increased peptide binding & gluten specific T cell response # * Greco L, et al. Frontiers in celiac disease. Karger 2008;12:46-56. # Vader W, et al, PNAS 2003;100:12390-12395.

The role of genetics Celiac Disease Genetic component HLA DQ2/8 is necessary but not sufficient!

Celiac Disease The role of genetics Genetic component A polygenic disorder! Non-HLA genes - SNP s & GWAS - Immunochip (refined search) 40 non-hla loci 58 SNP s Immune regulation genes Autoimmune disease overlap

Celiac Disease Possible role of other factors Trigger factor? Questions? Variability Age of onset Disease progression Increasing prevalence Infections Rotavirus*, Adenovirus Stress (pregnancy) MICROBIOME *Clin Gastroenterol Nutr 2017;15694-702

Celiac Disease The immune process Innate & Adaptive Systems Immunologic cascade CXCR3 Zonulin With permission from Stefano Guandalini, MD.

Celiac Disease Why does it matter? Potential Alternative Therapies!

Celiac Disease Current treatment Strict gluten free diet for life! Problems: Hidden sources Constant vigilance Increased costs A skilled nutritionist should be involved in every case!

Treatment QOL issues Celiac Disease Are patients with celiac disease seeking alternative therapies to a gluten-free diet? J Gastrointestin Liver Dis 2011;20:27-31 Patient Perception of Treatment Burden Is High in Celiac Disease Compared With Other Common Conditions Am J Gastroenterol 2014; 109:1304 1311 Gluten-free diet or alternative therapy: a survey on what parents of celiac children want. Int J Food Sci Nutr 2015;66:590-594 59.5% of parents surveyed expressed the need for alternative therapies

Treatment - the future Celiac Disease Potential targets for intervention. Gluten detoxification Peptide transport blockade Immune pathway inactivation Genetic grain modification Enzymatic digestion Zonulin inhibition of tight junction opening Peptide binding polymers TTG antibody HLA DQ binding block Cytokine antibody Vaccination

Celiac Disease Treatment - the future Gluten free diet Villi Regular diet Crypts 4 EC Peptide IEL Gliadin 2 3 1 Gluten 4 TG2 TG2 DGP APC 5 6 TCR DQ2/8 IFNg IFNa CD4+ T cell 8 CCR9 autoantibodies 7 Plasma cell IL-15

Treatment - the future Celiac Disease Gluten detoxification Genetic modification of wheat - problematical! V 1 R V P V P 6 Q L Q P Q N P S Q Q Q P Q 19 - positive? G Peptide IEL Gliadin 20 4Q V P L V Q Q Q Q F 30 Gluten 2 3 L 31 G Q Q Q P F P P Q Q P Y 43 EC P 44 Q P Q P F P S Q Q P Y 55 TG2 L 56 Q L 5Q P IFNg F P Q P Q L P Y TG2 68 IFNa autoantibodies S 69 Q P Q P F R P Q Q P Y 80 DGP 6 Q 82 P Q P Q Y S Q P Q Q P I S 95 IL-15 CD4+ T cell Plasma cell APC Q TCR 96................. CCR9............ N DQ2/8 8 266 1 - negative - positive - positive 7 - negative - positive 4

Treatment - the future Celiac Disease Gluten detoxification Complete digestion of toxic peptides Glutenase - ALV003 Peptide IEL Gliadin ALV001 4- (barley derived Gluten cysteine EC endoprotease) plus IFNa TG2 5 IFNg TG2 ALV002 - bacterial DGP 6 derived prolyl- CD4+ T cell APC TCR endopeptidase) DQ2/8 8 2 3 CCR9 1 autoantibodies Challenges - Acid inactivation - Complete digestion Potential role 7 - Highly sensitive Plasma cell IL-15 4 cases - Just-in-case med

Treatment - the future Celiac Disease Peptide transport blockade Peptide binding polymers Gluten binder DGP 4 EC TG2 Polymers TG2 APC Peptide- IEL Reduces Gliadin 5 BL-7010 2 3 IFNg IFNa autoantibodies - Prevents mucosal 6 absorption of Gluten wheat and barley gluten damage in mice CD4+ T cell Plasma cell TCR CCR9 DQ2/8and 8 on biopsies 1 7 Challenges - Peptide specific? - Possible binding 4 of other proteins - Potential nutrient IL-15 deficiencies - Binding capacity unknown

Treatment - the future Celiac Disease Peptide transport blockade Tight Junction Control Zonulin antagonist Zonulin receptor DGP 4 EC TG2 TG2 APC Peptide 5 6 IEL TCR DQ2/8 Zonulin IFNg Gliadin IFNa CD4+ T cell 8 2 3 Tight junction CCR9 AT-1001 (larazotide) - 1Prevents opening of tight junction - Safety profile4 - Duration of action ~ 90 mins Gluten - Does 7 not affect transcellular IL-15 uptake Potential role Plasma cell - For possible exposure autoantibodies

Treatment - the future Celiac Disease Immune pathway inactivation Antibody Blockers TTG inhibitor 4 EC Peptide IEL Gliadin 2 3 1 Gluten 4 HLA inhibitor DGP TG2 Peptide TG2 APC 5 6 TCR DQ2/8 Deamidated peptide IFNg IFNa CD4+ T cell 8 CCR9 TTG inhibitor autoantibodies 7 Plasma cell IL-15 T cell receptor HLA blocker HLA DQ2/DQ8

Treatment - the future Celiac Disease Immune pathway inactivation Antibody Blockers Monoclonal antibodies EC Peptide TG2 5 Anti IL-15 TG2 antibody DGP 4 APC IL-15 6 IEL TCR DQ2/8 IFNg Gliadin IFNa CD4+ T cell 8 2 3 CCR9 1 Gluten autoantibodies Plasma cell 4 7 IL-15 TNF-a antibody INF-g antibody INF-g TNF-a

Treatment - the future Celiac Disease Immune pathway inactivation Promote gluten tolerance Gluten peptide Vaccination Nexvax2 - targets 3 peptides HLA-DQ2.5 individuals Challenges - Duration of effect unknown - Unknown frequency of administration - Role of other peptides to be determined

Gluten-free Alternatives? Celiac Disease Much desired! Several potential possibilities Challenges remain Role to be determined Complete replacement of the GFD? Rescue from minor exposure? Any alternative therapy must be as effective and safe as the gluten free diet!

Celiac Disease What about the future? New genes Geno/phenotype Genetic component Immunologic cascade Specific pathways Potential therapies Dietary factor Trigger factor? Specific peptides Modified wheat Microbiome manipulation

Celiac Disease Questions