Dr Priya Bowry MBBS MRCGP DFFP DIC MSc (Allergy)

1. Is it Wheat or Gluten Allergy? A MISNOMER!!!Adverse Reactions to Wheat (Triticum estivum) and Gluten Dr Priya Bowry MBBS MRCGP DFFP DIC MSc (Allergy)

3. Structure of talk • Classification of Adverse Reactions to Foods • What makes Wheat so special? • The Wheat Grain & Gluten • Classification of adverse reactions to wheat and gluten ie Wheat allergy, Coeliac Disease and Non Coeliac Wheat Intolerance(NCWI, prev NCGI) • Conclusion

5. Wheat – Triticum estivum • Wheat is one of the most important food crops, and is grown on about 220 million hectares worldwide • It is the 2nd oldest cultivated plant after barley, used for food for humans and fodder for livestock since 7500 BC. 3rd most planted crop after rice and corn. • Is eaten by 2.5 billion people in 89 countries • Starch accounts for nearly 60% of the grain's weight, the proteins (13-15%) are also of considerable nutritional importance • Used as a flour for baked goods

6. The baking properties of a flour are determined by its content of gluten, a water-binding, elastic substance that forms on contact with moisture from a mixture of proteins (namely Glutenin and Gliadin), lipids and carbohydrates. • In wheat, gluten comprises about 80% of the protein contained. It gives the dough its elasticity and makes leavening possible by retaining the carbon dioxide bubbles produced by yeast or synthetic leaveners such as baking powder, thus causing the dough to rise. When the protein coagulates during baking, it stabilises the shape of the resulting product

7. Wheat is also an ingredient of numerous processed foods. Wheat starch is a common food thickener in soups and sauces. Gluten is frequently used as an emulsifier, gelling- or stabilizing-agent in products such as ice-cream or ketchup. • Wheat can also be found in cosmetics including toothpaste, lipsticks and vitamin E which can be derived from wheat germ • Whole wheat and other grains are rich in fibre, nutrients, minerals and vitamins and have numerous health benefits

8. What makes Wheat SO Special? • One of the MOST controversial foods i.e. debates about healthy versus unhealthy. The phenomenon is fuelled by the media and exploited by the food industry. Health fads by ‘Health Gurus’ (non experts) influence society and eating habits • Gluten has been the media's most popular nutrition topic - the ‘BAD BOY ON THE BLOCK’ apparently causing everything from obesity to depression • Wheat is one of the Top 10 allergens worldwide

9. The Wheat Grain • Bran: the outer edible protective layer of the seed, rich in fibre and vitamins • Endosperm: holds the plant supply for food to grow, rich in starch and protein • Germ: reproductive part of the plant, rich in minerals, vitamins, protein and fat

11. Wheat Proteins – 18% of dry matter • Water-soluble Albumins and Salt-soluble Globulins: (15-20%) • Beta amylase • alpha amylase/trypsin inhibitor, proteinases • Non specific Lipid Transfer Proteins • Puroindolines (tryptophan rich proteins) • Water Insoluble 80% • Alcohol soluble prolamins – alpha, beta, gamma and omega Gliadins (monomeric proteins) • Alcohol insoluble Glutenins – low molecular weight and high molecular weight

12. } Gluten, mainly found in endosperm • Albumins-smallest wheat proteins • Globulins- larger than albumins • Gliadins (prolamin) • Glutenins • Physiologically active proteins (enzymes) in wheat grains are found in the albumin and globulin groups. • Cereal grains store energy in the form of starch. Starch is basically a polymer of glucose. at least two types of polymers are distinguishable: amylose and amylopectin.

13. Gluten • Gluten is a protein complex comprised of 2 components: gliadin (the water-soluble component) and glutenin (the water-insoluble component). Gliadin directly affects the induction of an innate immune response via the proline and glutamine peptide-rich sequences • Is found in wheat and grains such as rye and barley Synthetic gliadin peptide (cyan) complex with HLA class II histocompatibility antigen (α chain in magenta, β chain in green) and ethylene glycol (PDB code 1s9v)

14. BAD BOY ON THE BLOCK - GLUTEN Commonest

15. Wheat Allergy (WA) • A food allergy to wheat is characterized by T helper type 2 activation which can result in immunoglobulin E (IgE) and non-IgE mediated reactions. Requires immune system to be activated by specific immunological responses: • IgE mediated (majority of kids with food allergy) • Non-IgE mediated – immunoglobulin, immune complex or cell-mediated immunity (less well understood). Key role of T cells, with the secretion of pro‐inflammatory cytokines that may influence intestinal permeability. The vast majority of these responses are characterized by an eosinophilic infiltration in the gastrointestinal (GI) tract, and are called eosinophilic gastrointestinal diseases • Both antibody and cell-mediated • May be immediate (usually IgE mediated) or delayed (non-IgE mediated) • Wheat allergy has a prevalence of <0.5%

16. The route of sensitization appears to be important in the development of wheat allergy. Could be inhalant eg Bakers asthma or rhinitis, ingestant (sensitized to heat-treated and digested wheat proteins absorbed through the gastrointestinal epithelium) or contact (eg wheat‐containing cosmetics). • A large variety of wheat grain proteins have been identified as allergens in all pathologies studied. The type of IgE-binding profile in patients with wheat food allergy is correlated to age and symptoms that manifest

17. Sensitization and Memory at First allergen exposure after crossing epithelial barrier • Early phase responses (Acute/ Immediate) at subsequent allergen exposure • Chronic Inflammation – late phase responses

18. Sensitization and Memory at First allergen exposure after crossing epithelial barrier ALLERGEN-SPECIFIC IgE ANTIBODIES. Allergen specific IgE B cells (plasma cells with memory) proliferate B cells switch from producing IgM,G,A to IgE antibodies T-B cell cooperation to promote class switching (IL 4,5,10,13) SENSITIZATION TH 2 DIFFERENTIATION AND MEMORY T cell differentiation (IL 4 ) to TH 2 cell Antigen taken up and processed by APC then presented to Tø via MCH Class 2 receptor Interleukins are cytokines produced by leucocytes to act on cellular receptors and mediate how cells differentiate and behave

19. Early phase responses (Acute/ Immediate) at subsequent allergen exposure Allergen + two allergen specific IgE-Abs crosslink and bind with high affinity IgE receptors (FcεR1) on mast cells and basophils Mast cell degranulation – release of histamine, leukotrienes, tryptase, prostaglandins, cytokines responsible for symptoms Allergen crosses epithelial barrier

20. Chronic Inflammation – late phase responses Eosinophils proliferate in bone marrow, are recruited & migrate via chemoattraction to tissues (IL5, leukotrienes, chemokines, eotaxin produced by TH 2 cells) Eo in target tissue release major basic protein, eo peroxidase, eo derived neurotoxin, eo cationic protein: severe inflammatory response & mass tissue destruction

21. Immediate Symptoms of WA • Immediate symptoms of wheat allergy affecting: • GI (OAS, nausea, vomiting, abdominal pain, diarrhoea, bloody stools), • Skin (urticarial, maculopapular rashes, flushing, angioedema), • Respiratory (acute upper and lower airways), usually with other GI/skin manifestations. • Eye allergies • Anaphylaxis (rarely), wheat -induced anaphylaxis provoked by exercise • Occupational – Bakers asthma and rhinitis

22. Delayed Symptoms (non IgE and mixed) • Delayed wheat allergy: can occur one hour to several days after ingestion. • GI (constipation, GERD-like symptoms, Eosinophilic eosophagitis, Food Protein-Induced Enterocolitis Syndrome (FPIES), enteropathy, proctocolitis, malabsorbtion, FTT, severe colic and others) • Skin (eczema – over 33% have food allergy) • Respiratory (upper and lower) • Eyes

24. Baker's asthma: • gliadins have been implicated. • Subjects with baker's asthma as well as the food‐allergic subjects had the most intense IgE‐reactivity to the albumin/globulin fraction. • A novel cross reactive cereal allergen family, the wheat thioredoxins • Wheat‐dependent, exercise‐induced anaphylaxis (WDEIA) • Omega‐5 gliadin is implicated in severe immediate‐type reactions in children • LMW and HMW glutenins also cause WDEIA • Atopic Dermatitis in kids with or without asthma: • a/b- and g-gliadins • some proteins of water/salt-soluble fraction • Anaphylaxis in adults and children: • B-type LMW glutenin subunits • Wheat lipid transfer proteins (LTPs) have been identified as a major allergen for all above

25. Diagnosis • Careful medical history, especially occupation. • when the offending food is eaten almost on a daily basis, as is the case with wheat and other cereals, a causal relationship may not be suspected. • SPT remains the most commonly used diagnostic procedure. In some cases, serum wheat‐specific IgE (sIgE) can be a substitute, indicates merely sensitization • Confirmation requires well‐designed, graded oral challenge by an experienced physician, or bronchial provocation for bakers asthma

26. Management • Avoidance of wheat containing products • For occupational allergy, minimise inhalant exposure • Adrenaline autoinjector for anaphylaxis • Follow up to assess tolerance • Oral Immunotherapy – potential role in future

27. Coeliac Disease (CD) • CD is an autoimmune malabsorption disorder resulting in villous atrophy, linked to ingestion of prolamins ie gluten in wheat, secalin in rye, and hordein in barley by inducing an inflammatory response. 40% associated with HLA phenotypes (HLADQ2 90% and HLADQ8 10%) • Gluten markedly enhances zonulin activity in the intestinal epithelium leading to damage of the intestinal epithelial tight junction. IL15 causes gut inflammation. • Comorbid autoimmune disorders include type 1 diabetes, autoimmune thyroiditis, arthritis, and primary biliary cirrhosis

28. 1.The enzyme‐resistant proline‐rich gluten fragment penetrates into the lamina propria 2.Becomes deamidated by transglutaminase3. Deamidated gluten becomes recognized by the antigen‐presenting cells bearing HLA‐DQ2 and HLA‐DQ8 4. Is re-presented to T‐helper cells, which in turn produce IFN‐g by a Th1 pathway5. Antibodies are produced to transglutaminase and gliadin by plasma cells through a Th2 pathwayIL15 – key mediator in inflammation

29. During wheat ingestion for 6-12 weeks Villous atrophy seen

30. Management • Strict avoidance of wheat, barley, and rye. Some patients may not tolerate oat • Type 1 refractory CD – no response to GFD but respond to corticosteroids • Type 2 refractory CD – no response to GFD and partial or no response to corticosteroids, poorer prognosis, higher risk for premalignant condition Enteropathy associated T-cell lymphoma (EATL) • Trial of monoclonal anti-IL15

31. Non Coeliac Wheat Sensitivity (NCWS) • Previously ‘Non Coeliac Gluten Sensitivity (NSGS) • Prevalence 30%. Poorly understood, predominantly Innate immune responses play a role • Besides gluten, other wheat proteins and the poorly absorbed fermentable oligo‐, di‐, and monosaccharides and polyols, trypsin inhibitors, and wheat germ agglutinins can contribute to the symptoms, hence expansion of term NCGS to NCWS • Resemblance of Irritable bowel symptoms and overlap between the two. Intestinal and systemic symptoms – lethargy, fatigue, anxiety, brain fog • Diagnosis of exclusion, and wheat elimination-rechallenge

32. Causes of NCWS

34. In Conclusion • Wheat is a popular and important part of human diet across many cultures • It has been very controversial in recent times especially in regards to gluten, which plays an important role in disease together with other wheat proteins and components such as fructans • Understanding the wheat related diseases allows for better diagnosis and management • Currently, for all the conditions, cornerstone of management remains dietary avoidance • Knowledge of hidden sources of wheat and gluten are important for patients in foods and cosmetics • Primary prevention: early introduction during weaning between 4-12m may prevent WA & CD

35. Is it Wheat or Gluten Allergy? Correct nomenclature is important! Non Coeliac Wheat Sensitivity NCWS & FODMAPS

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