Immunopathological reactions, allergy MUDr. Adam Klocperk Department of Immunology 2nd Faculty of Medicine, Charles University in Prague

Immunopathological? Regular (defensive) reactions Antibodies, cells, cytokines, peptides… Dysregulated Pathological effect Reaction against a target Harmless outside OR my own inside OR microbe  „hypersensitivity“ disorders

Classification Coombs & Gell (1963) Based on mechanism of reaction Immediate, allergy IgE on mast cells Antibody-mediated cytotoxic effect of antibodies Immune-complex mediated deposition of immune complexes T-cell mediated direct T-cell cytotoxicity or coordination with other cells (5. Receptor mediated autoimmunity)

Type 1 – IgE mediated reaction Intended as defence against parasites Sneezing, mucus production, swelling… Reaction against harmless outside

Vocabulary – anti-confusion Hypersensitivity = dysregulated reaction to antigens (includes other Coombs & Gell types) Atopy = predisposition to Th2 & IgE reaction Allergy = clinical manifestation of atopy Allergen = substance causing it

IgE reaction is a two-step process Sensitization Immediate reaction Abbas et al, Cellular & Molecular Immunology, 9th Edition, p. 438

Sensitization First exposure to allergen Capture by APCs (DCs, Mfs) Mucosa, skin Capture by APCs (DCs, Mfs) Transfer to lymph nodes Via lymphatic veins Presentation to T-cells, B-cells MHC-II context, co-stimulatory molecules Tfh & Th2 reaction IL-4, 5, 13 production Support of B-cell switch to IgE Production of IgE antibodies by B-cells Binding of IgE to Fcε receptors on mast cells & basophils

Immediate reaction Re-exposure to allergen Cross-linking of Fcε receptors Intracellular signaling Release of mediators histamine leukotriens prostaglandins Early-phase clinical symptoms Late-phase response

Early-phase clinical symptoms Edema, swelling, shock Itching Nerve ending stimulation Dyspnea, cough Diarrhea, cramps Repeated  fibrosis ECP = eosinophilic cationic protein membrane attacking clinical importance (e.g. asthma) Abbas et al, Cellular & Molecular Immunology, 9th Edition, p. 446

Late-phase response 2-12 hrs later chemotaxis of other cells (PMN, PLT, LY, EOS) can continue, in chronic stimulation !! DO NOT CONFUSE !! it is not delayed-type hypersensitivity, Type 4

Allergens anything can be an allergen EAACI Molecular Allergology User‘s Guide, 2016, p. 62 Allergens anything can be an allergen foods, plants, venoms, drugs, metals, latex… molecular names – Der p 1, Bet v 1 etc Dermatophagoides = dust mites Betula = birch panallergens = shared between things e.g. profilin = birch (Bet v 2), peanuts (Ara h 5), apple (Mal d 1) etc knowing specific molecular ag is important cross-reactivity (birch – apple) prognosis (e.g. Gal d 1 = ovomucoid = persistent egg allergy, cooked not tolerated, Ara h 8 = peanut = not anaphylaxis)

Allergens - panallergens extract Genus specific Allergen Crossreactive panallergen

Risk factors, predisposition Genetic Family history Environmental Stress Hormones Nutrition Smoking, pollution Respiratory infections asthma Hygiene hypothesis infections  Th1 skew 1 sibling 30 % 1 parent 40 % 2 parents 50-60 % 2 parents same form 70 %

Hygiene hypothesis Zweiman B, Schwartz L, Inflammatory Mechanisms in Allergic Diseases, 2002

Clinical forms of allergy atopic dermatitis / eczema food allergy allergic rhinitis/conjuctivitis allergic asthma anaphylaxis „atopic march“ = progression from one for of atopic disease to another, usually eczema  rhinitis  asthma

Atopic dermatitis chronic intermittent pruritic disease skin defect & allergic sensitization frequent in infants 10-20% children, 2% adults improves with age different topical distribution

Atopic dermatitis 50 % resolve before 7 years of age 90 % resolve before adulthood !! Differential diagnosis !! Primary immunodeficiency (SCID, Omenn, Netherton‘s...) T-cell lymphoma Psoriasis Scabies Contact dermatitis

Allergic rhinitis 10-30% of population in the developed world Itching Sneezing Nasal serous secretion Nasal obstruction edema of nasal mucosa EARLIER: Seasonal × Perennial

Bronchial asthma chronic inflammation of lower airways bronchial hyperreactivity exacerbated by irritation stress, cold, excercise, infection exposure to allergen spasm of smooth muscle  dyspnea, cough, wheezing

Anaphylaxis – anaphylactic shock bronchospasm & other symptoms vasodilation decreased blood pressure, tachycardia insufficient perfusion of organs multiple-organ failure common causes foods (peanuts, fish, vegetables) insect venom (wasp, bee, hornet)

Diagnosis ! Precise & targeted medical history Blood count + differential, ECP Total IgE Specific IgE Skin prick test Atopy patch test FENO (forced exhalation nitric oxide), lung function tests Basophil activation test

History Familial predisposition Work exposure Social Personal wood dust, feathers, latex, wool, animals... Social type of accomodation, bed, cohabitants, city, … Personal circumstances around birth, tolerance of non-milk foods, of vaccines, infectious morbidity, adenectomies…

Blood count + differential Increased eosinophils Dif.dg.: parasites, malignities, PIDs, vasculitis, autoimmunities (SLE, Sjögren‘s...) and others ECP = eosinophilic cationic protein antimicrobial protein correlates with eosinophilic inflammation elevated in allergy, asthma...

IgE Total IgE × Specific IgE allergen extracts (birch, peanuts, wheat, soy, egg…) allergen extract mixtures (grasses, trees, birds…) molecular components (Bet v 1, Der p 1…)

Total IgE does not reflect clinical problems severe allergy with normal total IgE elevated in cord blood  atopic predisposition extremely elevated  poor prognosis

Skin prick tests best clinical correlation native allergens or extracts forearm, back read in 15 minutes

FENO produced in airway epithelium produced by iNOS (inducible nitric oxid synthase) increased in allergic bronchial inflammation (asthma)

Basophil activation test little blood needed measure degranulation (CD63) of basophils after anti-specific IgE stimulation no need for oral challenge tests or skin-pricks in some cases higher specificity & sensitivity

Treatment of allergic diseases avoidance of allergen antihistaminics (topical, oral) antileukotriens cromoglycans corticosteroids (topical) immunosuppression epinephrine biologic therapy specific allergen immunotherapy (SAIT)

Epinephrine increases vascular pressure increases heart rate, volume used to stave off anaphylactic shock + antihistaminics + corticosteroids i.v. + short acting beta-agonists

Antihistaminics 4 histamine receptors, G-protein coupled throughout the body, including the brain 1st generation = e.g. Dithiaden (bisuleptin) 2nd generation = lower penetration of blood-brain barrier  less sedative, e.g. Zyrtec (cetirizine) 3rd generation = different enantiomer or metabolite (e.g. Aerius (levocetirizine), Xyzal (desloratadin))

Antileukotriens inhibit production or activity of leukotriens e.g. Singulair (montelukast) used in asthma

Biologic therapy anti-IgE (Omalizumab)  asthma in poorly controlled asthma s.c. injections every 2-4 weeks anti-IL4/13 (Dupilimumab)  atopic dermatitis

Specific allergen immunotherapy repeated administration of small doses of allergen sublingual/subcutaneous administration development of tolerance isotype switch to IgA, IgG4, induction of Tregs ! also tried for autoimmunities, but without great effect  causal, not symptomatic lasts 3-5 years

In conclusion many of your patients will have it good diagnosis is important for good management talk to your allergologist/immunologist (they are nice people ) IgE is not everything (but it‘s important) many treatment options, including causal therapy some may be limited by price/availability