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

2. MSc Allergy 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. MSc Allergy 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. MSc Allergy The process Histamine Mast Cell

5. MSc Allergy 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. MSc Allergy 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. MSc Allergy Antibodies

8. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy Role of allergy in the developing infant 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?)

16. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy 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. MSc Allergy Any questions?