1. Hypersensitivity reactions with immune team notes Prof. Mohamed Osman GadElRb. College of Medicine & KKUH.

2. Immune reactions leading to pathological damage ( intense inflammatory responses ). - Occur as : 1.Secondary heightened (increased) immune responses OR: 2.Secndary inappropriate (abnormal ) immune responses Introduction :

3. Four major categories according to Coombs and Gell classification : Type I : Immediate H/S.(allergic reaction IgE) Type II : Cytotoxic H/S.(IgM & IgG mainly) Type III : Immune – complex H/S. (antigen – antibody complex) Type IV : Delayed H/S.

4. Types I, II and III : are mediated by antibodies. ( The complement system become activated & contribute to tissue damage ). Type IV : Is generated by cell-mediated immune (mainly T helper cell ) responses. ( no complement activation ) (in chronic inflammation)

5. Time course ; Hypersensitivity reactions differ in the rate at which they occur : Type I : Can occur within minutes after exposure to allergens. Type II and III : time course, (4-8) hours to days. Type IV : require 2 - 4 days. ( delayed ). Like the tuberculin test,it is cell mediated so takes long time to arrive to site of pathogen.

6. Clinical presentation: Hypersensitivity reactions : - can occur as isolated reactions, OR : - more than one reaction may occur in the same patient. e.g. : Type I and Type III. Note: it mean the patient could have more than one type in the same time.

7. Type I Hypersensitivity. Also termed : *Immediate H/S ( can literally occur within minutes to hours ) * Anaphylactic reactions: Is a bad form of allergic reaction, this happen due to the presence of an allergen which will activate the production of certain Ig which will bind to mast cell (in tissue) & basophilic cell (in blood) so that will lead to excessive production of histamin which will cause vasodilation lead to anaphylactic shock which will kill the patient if it was systemic. OR : * Allergic reactions

8. Features : - Antibody isotype : IgE.( less frequently may be due to STS IgG.) - Cellular components: Mast cells, basophiles & eosinophils. - Antigens : termed allergens ( antigens with low molecular weight & highly soluble.) Note: the allergen differ from one person to another & from one place to another.

9. Type I H/S. Evolved as a defense against parasitic infections. ( the hygiene theory ? NEXT SLIDE ) * However, many reactions in some predisposed individuals are directed towards harmless molecules (allergens) and these individuals are said to be: “atopic” (atopy : from the Greek atopos, meaning out of place) Atopic is the person who develop an allergy to a special allergen that most of the people aren’t allergic to it,due to a special den carried out to him by his parents.

10. the hygiene theory ? If you increase the hygiene you will reduce the pathogens presence around you and that will make Th1 sleep because here is no pathogen to fight it, so no INFγ is produce so Th2 will have better chance to work and activate humoral immunity which will produce antibodies to different things lead to allergy. So for these reason the large families have less sensibility to allergy there is always one of them sick and will infect the others. The hygiene theory ?

11. Atopy. Occur in certain genetically predisposed individuals who develop one or more of the atopic diseases : allergic rhinitis, asthma, and atopic dermatitis They comprise approx. 15 – 20 % of the population Atopy tend to run in families

12. The likelihood to generate a strong IgE response is determined by : - genetic factors - environmental factors These factors depend on exposure to allergens of diverse nature : (pollens, foods, drugs fungal spores, bee - sting venoms, house dust mites and animal dander) Is a type of very small insects that live in dusty places like carpets,these insects will produce feces, the feces are highly allergic

13. Important immune notes  If you are allergic to a specific allergen and you get exposed to it,you will produce IgE.  If you exposed to allergen that is not allergic for you, you will produce IgG.

14. Response to allergens in non-atopic individuals : Adults and children without atopy mount a low – grade response, they produce allergen-specific IgG1 & IgG4.(are normal and will note develop allergy) Persons with atopy, by contrast, produce an exaggerated response characterized by production of : allergen –specific IgE antibodies(is abnormal and will develop allergy)

15. Type I Reaction occur in 2 phases: Phase I : - Sensitization phase. Allergen enter tissues, induce an immune response. B – cells transform to plasma cells & produce IgE. - IgE bind to receptors on Mast cells and basophiles ( F c ЄRI - high affinity receptors) and stay on it’s surfec individuals become: “Sensitized“ B cell Plasma cell Mast cell allergen

16. Phase II : Challenge phase. - Subsequent encounter with same allergen cross – link IgE on mast cells - This generates an intracellular signal that prompts the Mast cells to: “ Degranulate” ( release mediators into the area of reaction). note : (when the allergen came back again it will go and bind with IgE on the mast cell surface And that will lead to degranulation of histamen) Mast cell histamen

18. Degranulation : The release of a wide variety of mediators of inflammation These exert effects on surrounding target tissues. There are 2 types : 1. primary mediators 2. secondary mediators

19. Primary mediators. 1. Histamine, heparin 2. Serotonin 3. Eosinophil chemotactic factor ( ECF) 4. Neutrophil chemotactic factor (NCF ) 5. Proteases (cause tissue damage)

20. Secondary mediators : 1. Platelet activating factor 2. Leukotriens ( slow reacting substance of anaphylaxis) 3. Prostaglandins 4. Bradykinin 5. Cytokines (IL-1,TNF-a, IL-2, 3, 4, 5, 6)

21. Type 1 H/S. ( immediate hypersensitivity ). The degranulation will happen if the allergen bind to 2 IgE on the mast cell surface. The effected organs Cause etching

22. Type 1 reactions result in : * Vasodilatation and increased capillary permeability * Edema * Vasoconstriction (arteries and arterioles) * Bronchoconstriction * Increased mucus secretion

23. Symptoms of type I reactions are determined by site of location of the allergens : Inhaled allergens:  deposit in nasopharyngeal and bronchial tissues result in: - Allergic rhinitis. - Allergic asthma. Ingested allergens (oral route): food allergy (G.I.T symptoms)

24. Bee sting allergens  Injected into the blood.  Systemic inflammation.  Anaphylactic shock. (life - threatening).  Anaphylactoid reactions:- are non - IgE mediated. may result from contrast media or local anesthetics or drugs for angiogram test

25. Diagnosis:- 1. Skin prick test (SPT) (you put small drops of allergen on skin then make small cut on skin to allowed for allergen to enter and react with antiobies immediately) 2. Intra-dermal test (you inject the allergen in dermis) 3. Specific IgE measurement (RAST) (for specific allergen detection) 4. Challenge test (Nasal, Bronchial) 5. Elimination / Provocation test (Food allergy)

26. Skin prick test ( diagnosis of type 1 hypersensitivity ).

27. Type II Hypersensitivity. (Cytotoxic H/S). Features:- - IgG(mainly) - Antigens ( Bound to cell membranes or extra cellular matrix) it attack fixed receptors like - source of antigens : 1- Self - antigens. 2 - Exogenous antigens. (microbial ). Complement activation (Invariable).is the way of destruction in typeII Autoimmune disorders are type II

28. Mechanisms of tissue damage in type 11:- IgG (from blood) fix to tissue - bound antigen. - Activate complement. - Complement generate chemotactic agents (C5a). - Attract neutrophils and other inflammatory cells. destroy of antigen and tissue

29. Neutrophils bind to target through:- A. Complement receptors -(immune -adherence). B. Antibody receptors - (Opsonic - adherence). - Neutrophils secrete their enzymes to the outside (Exocytosis). - They cause direct damage

30. Complement - mediated damage (type11):- Activation of complement  C8, C9. - Membrane attack complex (MAC) - Direct lytic damage on target tissues

31. Mechanism of damage in type II H/S. Neutrophils will see antibodies on foreign body, neutrophils try to engulf it, if can't it will release it’s enzymes to lysis the foreign body.

32. Type 11 H/S.( Glomerulonephritis anti-GBM ).

33. Clinical Examples ( type 11):- 1. Incompatible blood transfusion (ABO) (massive intravascular hemolysis of RBC) It is either: o -Immediate reactions-IgM mediated o -Delayed reactions-(2-6 days ) IgG mediated 2. Hemolytic disease of the new - born (HDN) 3. Myasthenia gravis 4. Antigens of streptococcus are simillar to antigens of heart valves, so our antibodies bind to heart valves and destroy it, that called

34. Diagnosis:- - Detection of antibodies and antigens by Immunofluoresence in tissue biopsy specimens e.g. kidney, skin etc.

35. Features:- - mediated by IgG or IgM - Soluble antigens (not fixed) - Immune – Complex formation - Complement activation (invariable) Note: immune-complex mean antigen-antibody interaction, These complex will circulate in blood and activate complement system which lead to destroy the complex

36. Mechanism of tissue damage (type 111):- Immune - Complexes are continuously forming. - Depend on the nature and conc. of antigens and antibodies. - As long as they are not :- 1 - Extremely large. 2- Numerous. they are readily cleared

37. Immune complex clearance : When immune complex are normal in size and quantity : 1. The mononuclear- Phagocyte system. - Macrophages and dendritic cells degrade particles and debris 2. Erythrocytes bind complexes via FcR1 receptors and release them in the liver

38. When size and quantity over whelm the normal clearance mechanism:- 1. Complexes accumulate and deposit in blood vessels and tissues.(kidney) 2. They activate complement. Therefore : induce immune - complex disease

39. Mechanism of tissue damage (type 111): Complexes deposit in blood vessels and tissues and result in vasculitis, arthritis …et Two main types : 1. Complexes with antibody excess, (high antibody &low antigen) are termed Arthus – type reactions ( localized ) 2. Complexes with antigen excess,(low antibody &high antigen) are termed serum – sickness reactions ( systemic ), for these reason when you get snakebite the treatment by give you horse serum filled by antibodies for the venom(antigens).

40. Clinical examples (type 111) : 1. Autoimmune disease, (self – antigens ) 2.Chronic infections, (microbial antigens) 3. Cancer, (tumor antigens) 4.Drug reactions, (chemical haptens ) the interaction between drugs and carrier proteins lead to deposition of them in the tissue if they are large.

41. Diagnosis (type 111) : Demonstration of specific immune complexes in the blood or tissues by: Immunofluoresence

42. Type 111 H/S.( Glomerulonephritis ).

43. Type IV hypersensitivity ( delayed H/S ): Features : - cell-mediated (CD 4 T-cells) - activated macrophages - delayed - onset (2 – 4 days) - secondary abnormal cellular responses - granuloma formation

44. Type IV H/S. Four subtypes : 1. Basophil H/S (Jones-mote reaction) 2. Contact sensitivity (chemical antigens). 3. Tuberculin reactions (Mantoux test) 4. Granuloma formation

45. Mechanism of tissue damage (type IV ): Sensitized CD 4 Th1-cells recognize antigen Become activated and secrete cytokines Attract and activate macrophages This lead to intense inflammation that cause permanent damage

46. DTH responses to persistent antigen : Lead to formation of a granuloma This prevent spread of infection e.g. T.B. tubercle May cause local mechanical pressure on adjacent tissues e.g. leprosy

47. Type 1V H/S. (granuloma.)

48. Clinical examples( type IV ): 1. Chronic infections : - T.B. - leprosy - fungal infections -parasitic infections 2. Contact dermatitis

49. Type IV H/S ( Contact Dermatitis )

50. Diagnosis (type 1v ): 1. Delayed skin test 2. Patch test 3. Lymphocyte transformation test (blood test) ( detection of activation markers by flow cytometry )

51. Patch test