The immunology of allergy and allergic predisposition

1. The immunology of allergy and allergic predisposition Efrem Eren efrem.eren@uhs.nhs.ac.uk

2. The role of our immune system • Protect us from infection BUT • Do not damage self • Autoimmune disease • Recognising what is a pathogen or not • Bacteria vs food • Allergy! • Difficult job!

3. What you need to cause an allergic reaction • Allergen (what you are allergic to) • Food, pollen, drug • IgE antibody specific for above • Mediator cells • Mast cells or basophils

4. The process Mast Cell Histamine

5. Food allergy in children • Foods are an important component of childhood allergy • Common causes: cow's milk protein, eggs, peanut, soy, tree nuts, fish, and wheat. • Clinical manifestations • Urticaria/angioedema, anaphylaxis, atopic dermatitis, respiratory symptoms, or a gastrointestinal (GI) disorder. • GI allergic manifestations • Immunoglobulin E (IgE) mediated (immediate GI hypersensitivity and oral allergy syndrome) • "mixed" GI allergy syndromes (involving some IgE components and some non-IgE or T-cell-mediated components) include eosinophilic esophagitis and eosinophilic gastroenteritis. • Non-IgE-mediated or T-cell-mediated allergic GI disorders include dietary protein enteropathy, protein-induced enterocolitis, and proctitis

6. Antibodies • How do we make IgE? • IgE antibodies are key to the development of an allergic reaction • We make different types of antibody IgG, IgM, IgA and IgE • Randomly created (shuffling a pack of cards) • Most do not work or cause damage to self and are removed • Those that are functional and are safe survive • We have the potential to produce antibodies to most pathogens out there! • Sometimes it goes wrong • Autoimmune disease (IgG) • Allergy (IgE)

7. Antibodies

8. Where do antibodies come from • Lymphocytes are a subgroup of white cells • B cells, T cells • We make millions of different B and T cells • B cells make antibody with the help of T cells • Individually recognise a slightly different shape • Shape is “non self” • If they recognise “self” they usually die • When a B cell sees/recognises non self it changes into an antibody factory (plasma cells) A plasma cell

9. More on IgE • Important in our immune response to parasites • The same mast cell and basophil chemicals released via IgE can help kill parasites • In modern society the role of IgE is overtaken by allergy • Allergy and IgE • You are not born with allergies, they develop • IgE; very low levels at birth (cord blood) • We can measure IgE specific for allergens, pollen, food, drugs etc. • Specific IgE (RAST) • Blood test for allergy • Allergen specific IgE difficult to detect at birth

10. How and why allergies develop • Knowing how IgE antibodies are made can help to understand why people develop allergies? • Explain what goes wrong • Why are allergies increasing

11. How does your immune system make IgE? • IgE is made by B cells (type of white cell) • External factors influence the “decision” for a B cell to • Make an antibody to a non pathogen e.g. pollen or food • Make IgE , not IgG, IgA or IgM • Important external factors: • T cells: Important accessory cells in generating IgE • Chemicals (cytokines) produced by the T cells

12. How are T cells important? • Need T cell help (helper T cells) • Helper cells add level of control • Important in helping B cells make antibody • Types of Helper T cells (TH) • TH1 important in immune response to viruses and bacteria • Cytokines Interferon Gamma • TH2 important in generating IgE • Cytokines IL-4, IL-13, • Too much TH2 influence =allergy T cell (TC) influences the type of antibody the B cell (BC) makes by direct contact and chemicals (cytokines) they produce

13. Other types of cells • Regulatory T cells • Prevent immune system from recognising “self” prevent autoimmunity and allergy • Antigen presenting cells • Important in TH cell function • Present small fragments of pathogens e.g. bacteria or viruses to T cells to activate them • Also present allergens to TH cells=allergy T Cell in close contact with larger antigen presenting cell. This is essential for the T cell to function

14. Now the basic immunology has been covered: • Allergy in the developing infant • A few points • Why our immune system goes wrong and allergies develop • Genetics • Environmental factors • Hygiene hypothesis • Mother’s influence

15. A few points: You can develop allergy at any age Your immune system has to have “seen” the agent you are allergic to at some point previously Allergies can resolve e.g. egg and milk Modification of immune response (regulatory T cells, IgG4 antibodies?) Role of allergy in the developing infant

16. Why our immune system goes wrong and allergies develop • Genetics • Allergic predisposition does run in families • But no clear inheritance pattern recessive , dominant X-linked • HLA: • Some autoimmune disorders have a strong genetic link e.g. HLA B27 and ankylosing spondylitis • No such HLA association with allergy • Allergy most likely polygenetic multiple factors genetic and environmental

17. Environmental factors • Hygiene hypothesis: Why is childhood allergy increasing? • Environment is too clean • Most responses to viruses and bacteria are TH1, generating IgG, • If infants immune system is shielded from pathogens is there and increased propensity for TH2 to dominate? • Will the immune system to make IgE inappropriately?

18. Hygiene hypothesis evidence: • Individuals who were exposed to a farming environment in childhood are less likely to develop allergies • Mainly livestock farming and exposure to pathogens • TH1 biased immune response • Raised number of regulatory T cells in cord blood (protect against TH2 pro allergic responses)

19. Alterations to DNA • DNA methylation • Biochemical modification of DNA affecting cellular function • DNA methylation has been described in immune cells, particularly • Regulatory T cells • Helper T cells (TH1 and TH2) • Role of environmental factors influencing immune function at a genetic level

20. Studies on DNA methylation • Farmers (hygiene hypothesis) • Different DNA methylation patterns in children exposed to farming environment • Particularly influencing IL-13 and IL-4 (TH2 cytokines) • Mothers influence • Mothers living in farming environment have different placental immune cell DNA methylation (CD14) • Vitamin B12 and folic acid levels influence DNA methylation • Role of mothers diet?

21. Diet and nutrition • Maternal diet • Reduced tobacco exposure and increased intake of oily fish during pregnancy and early childhood may be effective in reducing the incidence of asthma at 2 years of age • Maternal diet of fresh foods rich in vitamin C is associated with reduced risk of infant wheeze • Antigen avoidance diet to a high-risk woman during pregnancy is unlikely to reduce substantially her child's risk of atopic diseases

22. Childhood nutrition: • Vitamin D supplements • Vitamin D deficiency is common! • Role of nutrition and lack of sun exposure • Immune modulator (influences B and T cell function) • Vitamin D deficiency common in allergy • Asthma • Urticaria • Rhinitis • Should we supplement vitamin D? • Allergen avoidance in high risk groups: Carina

23. Summary • Key components of an allergic response • IgE, mast cells/basophils, mediators (histamine) • What is IgE and how it’s made • Clinical features of allergic reactions • Possible explanations for why individuals develop allergies • Many questions still not many answers!

24. Any questions?