www.dgci.sote.huLecture ED 2015
Láng, Orsolya MD, PhDDept. Genetics, Cell & Immunobiology, Semmelweis University
Hypersensitivity
Hypersensitivity - Tolerance
Hypersensitivity:
Immune reaction leads to pathology upon recognition of either harmless environmental
antigens or self-antigens
Autoimmunity:
Autoreactivity is inevitable
Dysregulation or failure of self-tolerance => autoimmune disorder
Tolerance:
immunological unresponsiveness to (self)-antigens (tolerogen) that have
the capacity to elicit an immune response
Common:adaptive immune system
Hypersensitivity (HS) – Allergy The most common immunological abnormality. Increasing number of affected people (25-40%) Potential reasons: Environmental pollution (?)
Lack of selection (?)
General mechanism
Sensitization
Repeat exposure
Tissue injury ordisease
Robert Royston Amos ("Robin") Coombs: British immunologist, co-discoverer of the Coombs test (Arthur Mourant and Rob Race) in 1945
Gell - Coombs classification of hypersensitivity in 1963
First exposure
Four classifications
Type I (Immediate) hypersensitivity Type II (cytotoxic) hypersensitivity Type III (immune complex mediated) hypersensitivity Type IV (delayed) hypersensitivity
Types of hypersensitivities (Gell - Coombs classification)
Type Mediator Mechanism Time Disorders
I IgE mediated Mast cells and basophils
Histamine
Immediate1-2 mins
AllergyAnaphylaxy
(local and systemic)
II Cell or matrix associated antigens connecting IgG
4-6 hrs Transfusion reactionErythroblastosis
fetalisMyasthaenia gravis
Basedow disease
III Soluble antigen -IgG immunecomplex
Complement
2-8 hrs Arthus reactionRA, SLE
IV T cell mediatedT-cell response to antigens
Delayed2-3 days
Mantoux testChronic allergy
Contact dermatitis
Type I. hypersensitivity (HS)Immediate HS
or Allergy , Atopy
Atopy – inherited tendency to respond immunologically to inhaled or ingested allergens with increased IgE production
Hay fever
Bronchial asthma
Food allergies
Anaphylaxis
Common types of immediate HSInhaled allergens Ingestion
or injection
HivesUrticaria
Skin contact
Main characteristics of the allergenes
Small size proteins or glycoproteins:
- Carried on desiccated particles (pollen grains or mite feces), where they are very stable
- Have enzyme activity that facilitate the transmucosal penetrance- Small, molecular wheight is 5 to 70 kDa (dustmite: der p1 15 kD), - High solubility- Small dose (ragweed: 1µg/year)- MHCII binding
What do they have in common?
?
Hevein domain
Cross-reactive allergenes
http://ainotes.wikispaces.com/Pollen+Food+Allergy+Syndrome
Type I. hypersensitivity
First exposure
APC and Th2 activation
Class switch
IgE productionIgE+ memory B-cells
cross -linkedIgEMast cellsBasophils
FcᵋRI receptor
Repeat exposure
ACTIVATION and DEGRANULATION
Nature Review, Drug Discoverys alapján
IL4, IL13
IgE production Hypersensitivity
Degranulation
Afferent phase
13
Class switch of BCR genes
INF
IL5
IL-4 IL-13
FcƐRI (high affinity)
FcƐRII (low affinity)FcƐRIIa on B cells
FcƐRIIb(CD23)
on mast cells and basophils
on B cells, T cells, Mφ-s, DC-s and basophils
Fc receptors
Kd= 10-11 M[IgE] = 10-9 M
MC are always coated with IgE bound receptors
15
Signaling induced by cross-linking of IgE
Effects of IgE cross-linking
(phospholipids)
17
Degranulation of MC
Other degranulators Immune
Anaphylatoxins: C5a, C3a Modulator
IL3 Non Immune
Bacterial products, gastrine, physical (cold), stress, chemical (gases, smoke), etc.
Intracellular signalling: Ca++
Inhibitors of degranulation Pharmacotherpy: cromoglicinum
Pro-inflammatory mediators released
by mast cells, basophils and
eosinophils
Gilfillan et al. Nature Reviews Immunology 6, 218-230 (March 2006) | doi:10.1038/nri1782
Primary mediators are in preformed granules
Physiological effect of mast cell degranulation
Histamine receptors
Histamine is the key mediator and their receptors
H1: e.g GIT, bronchoconstriction ↑; vessel permeabilty↑
H2: e.g. vasodilataion ↑; secretion of exocrine gland(e.g. gastric acid)↑; secretion
(H3: neural system)
H4: eosinophil chemotaxis
MC (Connective tissue) Mucosal MCsIntravenous ,
high doseSubcutanous,
low doseInhalation, low dose
Ingestion
Systemic anaphylaxis
urticaria Hay fever,
Bronchial asthma
Food allergy:
diarrhea, vomiting
utricaria, anaphylaxis
Role of the Mast cells (MC)
capillaries capillaries SM in brochus SM in intestin
Nature Medicine 18, 693–704 (2012) doi:10.1038/nm.2755
Immediate reaction in respiratory tract
Immediate and late phase symptoms
After 2 hrs After 1 day
PEFR = peak expiratory flow rate
Chronic inflammation and complications (tissue remodelling)
Nature Medicine 18, 693–704 (2012) doi:10.1038/nm.2755
Atopy
Atopy is the term for the genetic trait to have a predisposition for localized anaphylaxis.
Atopic individuals have higher levels of IgE and eosinophils.
Allergy – Multifactorial disorder
Allergy
GeneticsFcƐRI beta chain - 11q13
IL-3, IL-4, IL5, IL-9, IL-13 and GMCSF coding genes - 5q31MHCII allels - 6p
Environmental factorsFailure of tolerance during
childhood
Dysregulaion of the Immune system
Activation of Th1 and Th2 subpopulationIgE production
ImmunodeficiencyIncreased eosinophil count
28
DER p1 in the faeces of the house dust mite penetrates the airway epithelium
29
Bronchial asthma
normal bronchiole severe asthma
• Anaphylactic shock is the most serious
• Symptoms are directly related to the massive release of vasoactive substances leading to fall in blood pressure, shock, difficulty in breathing and even death.
• It can be due to the following:– Horse gamma globulin given to patients who are sensitized to
horse protein.– Injection of a drug that is capable of acting as a hapten into a
patient who is sensitive, ie, penicillin.– Following a wasp or bee sting in highly sensitive individuals.– Foods – peanuts, shellfish, etc.
Anaphylaxis
31
Staphylococcus exotoxins may serve either as superantigens or allergens
!
Non specific T-cell activation
– Avoidance of known allergens
– Localized reactions use OTC antihistamines and decongestants.
– Asthma uses combination – antihistamines, bronchodilators and corticosteroids.
– Systemic use epinephrine
– Hyposensitization – inject antigen to cause production of IgG which binds to antigen (allergen) before it reaches IgE coated cells.
– Monocolonal anti-IgE – inject, binds to receptors on mast cells blocking them from the IgE.
Therapy
Administration of increasing doses of antigen
desensitization
34
DESENSITIZATION – Allergen-specific immunotherapy
http://www.fpnotebook.com
http://www.voedselallergie.nl/allergic-and-non-allergic-hypersensitivity-to-food
Repeated administration of the sensitizing allergen usually by subcutaneous injection or, more recently, by sublingual application.
Both IgE- and IgG-specific antibodies increase during postdesensitization therapy.
IgG acts as blocking Ab
35
Anti-IgE therapy
Nature Reviews Immunology 8, 218-230 (March 2008)
Monoclonal antibody
In vivo test - Intradermal allergy test (Prick test)
Small amount of allergen injected into skin Look for wheal formation of 3mm or greater in diameter Simple, inexpensive, can screen for multiple allergens. Stop anti-histamines 24-72 hours before test. Danger of systemic reaction Not for children under 3
In vitro test
Protein arrayRAST RadioAllergoSorbent Test
Measure total IgE or antigen-specific IgE in serum Less sensitive than skin tests.R IST, RAST, Allergen specific and Microarray will be covered later.
Anaphylaxis vs. Anaphylactoid reaction (pseudoallergy)
Anaphylaxy/ allergy Anaphylactoid reaction/ pseudoallergy
IgE mediated allergic reaction in sentizized patient
triggering material is capable of direct mast cell or basophil degranulation to induce, and thus cause histamine release
•Foods (particularly nuts and seafood) •Drugs (particularly beta-lactam antibiotics) •Insect stings/bites (bees, wasps and fire ants) •Latex •….
•Drugs (particularly NSAIDs, aspirin, opioids) •Radiographic contrast media (CT/MR)•High histamine containing food (red wine), bacterial toxins generated from histidine (scombroid fish - fish that were inadequately refrigerated or preserved after being caught)
Ibuprofen v.COX1 inhibitor
No test!
4 type of pseudoallergy based on COX1 inhibition
http://allergycases.blogspot.hu/2010/07/allergic-and-pseudoallergic-reactions.html
Type II. hypersensitivity (HS)
Type II. hypersensitivity
Cell surface antigen (IgG v. IgM)
Antigens:Intrinsic - autoantigen, Membrane component(receptor)
Extrinsic antigenRBC – tarnsfusion, Rh incompatibilityAbsorbed drugs or metabolits
Opsonization => phagocytozisFc-receptor mediated phagocytosis/ cell lysis (macrophage, NK cell, neutrophil & eozinophil)
Complement activation=> cell lysis
ADCC (antibody dependent cellular cytotoxicity)
Abnormal physiologic response:
Ab inhibits binding of neurotransmitteranti Ach R: myasthenia gravis
Ab stimulate receptoranti-TSH R: autoimmune thyroiditis
Pathomechanisms of type II. hypersensitivity
Hemolysis
Transfusion reactionIncompatible transfusion - IgM
Polytransfused - IgGMultipara - IgG
Not only RBC, but Platelets or leukocytes
Complication:Erythroblastosis fetalis
Rh incompatibility
Haemolytical disease of the newborn
Erythroblastosis fetalis
Erythroblastosis fetalis
Passive immunizationwith anti-Rh
Haemolytic anaemia and thrombocytopeny
Drugs/ metabolits can act as a hapten – e.g. penicillin
Drug allergy (penicillin)
Myastenia Gravis
3 hrs after methyl prednisolon treatment
ptosis
Altering signal transduction
- Autoimmune thyroiditisGraves- Basedow
exophtalmus
+
Type III. HS
Soluble antigen-antibody complex - IMMUNE COMPLEX disease
Pathomechanism
Solubile Ag - Ab (IgG or IgM) => IC =>Complement activation=> inflammation and tissue injury
Mechanism of the tissue destruction similar in all tissueSeverity depends upon: size of the IC,
ratio of Ag/Ab, affinity of Ab, isotype of Ab
The consequence of the tissue damage depends on the site of deposition
1. Local immune complex diseaseArthus reaction – skin
necrotic vasculitis – vascular wall pneumonitis – farmer’s lung
2. Acute-systemic immune complex disease acute serum disease (7-10 days) 3. Chronic immune complex disease SLE Rheumatoid arthritis
Pathomechanism – Arthus reaction
Ag exposureor vaccination
Ag –Ab complexComplement
activation
Mast cell degranulationFcgammaRIII
Inflammation
4-12 hrs severe pain, swelling, induration, edema, hemorrhage, and occasionally by necrosis
Key mediators: C3a C5a
Arthus reaction(experimental):
- local response induced by intradermal injection of the Ag in sentitized patient
Vasculitis Farmer’s lung
Actinomyces:Saccharapolyspora rectivirgula
Type IV. HST cell mediated disease
Delayed HS
Ags inducing type IV. HS
Contact Ag Nickel salts, chromate
Poision ivry, oak
picricchlorine
Hair stain
IC bacteria Mycobacterium tuberculosis, leprae
Lysteria monocytogenes
Brucella abortus
Fungi Candida albicans
Pneumocystis carinii
Cryptococcus neoformans
histoplasmosis
Viruses Herpes simplex
Small pox
Measles
DTH – delayed Type HypressensitivityIt takes aprx 12 hrs as Th1 cells are involved
Type IV. HS
Syndrome Antigen Symptomes
Late type hypersensitivity ProteinsInsect proteinMycobacterial protein(tuberculin, lepromin)
Local skin swelling:ErythemaInduration (hardening)Cellular infiltrationDermatitis
Contact hypersensitivity Haptens Pentadeca-chatechol (poison
ivy) Paraphenylene diamine (hair
stain) Metallic ions: Nickel,
Chromium
Local skin reaction:ErythemaCellular infiltrationBlistersIntra-epidermal foci
Gluten sensitive enteropathyCeliac disease – flour
sensitivity
Gliadin (grain protein) Atrophy of microvilli in the small intestine
UndernutritionDamaged exocrine secretion of
pancreas
Th17Neutrophil
recruitment
Langerhans scells uptake the Ag
Ag presentation to TH1 cells
Activation of the keratinocytes
Macrophage activation
inflammation
Contact reaction
TNF-alpha, betaTissue
destruction
INFgammaMacrophage
activation
Tetsuya Honda(2013) 133, 303-315. doi:10.1038/jid.2012.284
A schematic view of the sensitization phase
Activation of the innate immune system by contact allergens (haptens, Ni2+)
Upon reexposure to haptens
Tuberculin Hypersensitivity Mantoux test (it detects infection)
• Maximum at 48-72 hours• Inflitration of lesion with mononuclear cells• Responsible for lesions associated with bacterial allergy
– cavitation, caseation, general toxemia seen in TB
• May progress to granulomatous reaction in unresolved infection
Granuloma Formation
Diagnostic test: Patch test – Epicutan testAllergen containig adhesive tape is fixed to the back,
evaluation after 48, 96 hrs and later (4.-6. days).
Steroids, antihistamins may influence the test result
Diagnosis based on the reaction
Latex allergy
Type I. HS
Latex-allergen
UrticariaAnafilaxy
Type IV. HS
Chemicals
DTHDermatitis
Not immunological
Chemicals, soapa
Irritative contact dermatitis
It is important to distinguishi: side effect Toxicity Intolerance Idiosyncrasy immun mediated reaction - hypersensitivity
Penicillin
Penicillin-RBC
IgM, IgG
Hemolytic anaemia
Type II. drug induced anaemia
Complement
Penicillin
Penicillin-protein
IgG
IgG immuncomplex
Serum sicknessglomerulonephritis
Type III. HS
Penicillin-protein
IgE
IgE-Mast cell
Penicillin
Systemic anaphylaxis
urticaria
Type I. Drug allergy
target
Penicillin
Penicillin-protein
TDTH
Macrophage activation
Contact dermatitis
Type IV. HS
targettargettarget
Penicillin allergy
Allegies in dentristry
Chlorhexidine: including allergy (Type I HS ) and allergic contact dermatitis/stomatitis (Type IV HS)
Metals- e.g. Ti : Type I and VI. HS stomatitis, facial erythema
Flouride - Type I and VI. HS skin rashes, mouth lesions
MELISA test (Memory Lymphocyte Immunostimulation Assay )
clinically useful in identifying metal hypersensitivities
1.Blood sample2.Lymphocytes are isolated and then incubated for 5days with individual metals. 3. in HS patient if T cells re-encounter that metal in the culture, they proliferate, 4. Assessment is based measurement of T cell proliferation has occurred in response to that metal.
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