Transcript Hypersensitivity

Hypersensitivity
Láng, Orsolya MD, PhD
Dept. Genetics, Cell & Immunobiology, Semmelweis University
Lecture ED 2015
www.dgci.sote.hu
Hypersensitivity - Tolerance
Hypersensitivity:
Tolerance:
Immune reaction leads to pathology upon
recognition of either harmless environmental
antigens or self-antigens
immunological unresponsiveness to
(self)-antigens (tolerogen) that have
the capacity to elicit an immune
response
Autoimmunity:
Autoreactivity is inevitable
Dysregulation or failure of self-tolerance =>
autoimmune disorder
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
First exposure
Sensitization
Repeat exposure
Tissue injury or
disease
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
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
I
IgE mediated
Mast cells and basophils
Mechanism
Time
Disorders
Immediate
1-2 mins
Allergy
Anaphylaxy
(local and systemic)
Histamine
II
Cell or matrix associated
antigens connecting IgG
4-6 hrs
Transfusion reaction
Erythroblastosis
fetalis
Myasthaenia gravis
Basedow disease
III
Soluble antigen -IgG
immunecomplex
2-8 hrs
Arthus reaction
RA, SLE
Delayed
2-3 days
Mantoux test
Chronic allergy
Contact dermatitis
Complement
IV
T cell mediated
T-cell response to antigens
Type I. hypersensitivity (HS)
Immediate HS
or
Allergy , Atopy
Atopy – inherited tendency to respond immunologically to inhaled or
ingested allergens with increased IgE production
Common types of immediate HS
Skin contact
Inhaled allergens
Ingestion
Hives
Urticaria
Hay fever
Food allergies
or injection
Bronchial asthma
Anaphylaxis
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
Afferent phase
IgE production
Hypersensitivity
IL4, IL13
Degranulation
First exposure
Class switch
APC and Th2 activation
IgE production
IgE+ memory B-cells
cross -linkedIgE
Mast cells
Basophils
FcᵋRI receptor
Repeat exposure
ACTIVATION and
DEGRANULATION
Nature Review, Drug Discoverys alapján
Class switch of BCR genes
INF
IL5
IL-4
IL-13
13
Fce receptors
on mast cells and basophils
FcƐRI (high affinity)
MC are always coated with
IgE bound receptors
Kd= 10-11 M
[IgE] = 10-9 M
FcƐRII (low affinity)
(CD23)
FcƐRIIa
FcƐRIIb
on B cells
on B cells, T cells, Mφ-s,
DC-s and basophils
Signaling induced by cross-linking of IgE
15
Effects of IgE cross-linking
(phospholipids)
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
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Cells
Molecules
Effect
Preformed granules
Histamine
Increases permeabilty, SM contraction
Tryptase
Carboxypeptidase
Chymase
Acidic hydrolase
Cathepsin G
Mast cell, basophils
Pro-inflammatory
mediators released
by mast cells,
basophils and
eosinophils
Mechanism of
production
Heparin
anticoagulant
Chondroitinsulphate E
Released from the
membrane
PGD2
Vasodilatation, brochoconstriction, chemotaxis
LTB4
Bronchoconstriction, mucus secretioon, increased
vasopermeability
LTC4
LTE4
Nucleus,
de novo synthesis
Preformed granules
PAF
Leukocyte activation and chemoattraction
IL3,IL4,IL5,IL6,IL13
Mast cell proliferation, inflammation, IgE
synthesis, activation of eosinophyls
GM-CSF
Scell proliferation
TNF
imflammation
CCL2,CCL3,CCL5
Chemotaxis
MBP( major basic protein)
Toxic compound
Tissue destruction
Eosinophils
Primary mediators are
in preformed granules
ECP( Eosinophil catioinic
protein)
peroxidase
Lysosomal hydrolase
Lysophospholipase
Nucleus,
de novo synthesis
RANTES, IL8, eotaxin
Chemotaxis
IL10
B cell proliferation
Gilfillan et al. Nature Reviews Immunology 6, 218-230 (March 2006) | doi:10.1038/nri1782
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
Role of the Mast cells (MC)
MC (Connective tissue)
Intravenous ,
high dose
capillaries
Systemic anaphylaxis
Subcutanous,
low dose
capillaries
urticaria
Mucosal MCs
Inhalation,
low dose
SM in brochus
Ingestion
SM in intestin
Hay fever,
Food allergy:
Bronchial asthma
diarrhea, vomiting
utricaria, anaphylaxis
Immediate reaction in respiratory tract
Nature Medicine 18, 693–704 (2012) doi:10.1038/nm.2755
Immediate and late phase symptoms
PEFR = peak expiratory flow rate
After 2 hrs
After 1 day
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
Genetics
FcƐRI beta chain - 11q13
IL-3, IL-4, IL5, IL-9, IL-13 and GMCSF coding genes - 5q31
MHCII allels - 6p
Allergy
Dysregulaion of the
Immune system
Activation of Th1 and Th2
subpopulation
IgE production
Immunodeficiency
Increased eosinophil count
Environmental factors
Failure of tolerance during
childhood
DER p1 in the faeces of the house dust mite penetrates the
airway epithelium
28
Bronchial asthma
normal bronchiole
severe asthma
29
Anaphylaxis
• 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.
Staphylococcus exotoxins may serve either as superantigens or
allergens
Non specific T-cell activation
!
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Therapy
– 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.
Administration of increasing doses of antigen
desensitization
DESENSITIZATION – Allergen-specific
immunotherapy
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
http://www.fpnotebook.com
34
http://www.voedselallergie.nl/allergic-and-non-allergic-hypersensitivity-to-food
Anti-IgE therapy
Monoclonal antibody
Nature Reviews Immunology 8, 218-230 (March 2008)
35
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
 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.
RAST RadioAllergoSorbent Test
Protein array
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)
4 type of pseudoallergy
based on COX1 inhibition
Ibuprofen v.
COX1 inhibitor
No test!
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 antigen
RBC – tarnsfusion, Rh incompatibility
Absorbed drugs or metabolits
Pathomechanisms of type II. hypersensitivity
Opsonization => phagocytozis
Fc-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
neurotransmitter
anti Ach R: myasthenia gravis
Ab stimulate receptor
anti-TSH R: autoimmune thyroiditis
Hemolysis
Transfusion reaction
Rh incompatibility
Incompatible transfusion - IgM
Polytransfused - IgG
Multipara - IgG
Complication:
Erythroblastosis fetalis
Not only RBC, but Platelets or leukocytes
Erythroblastosis fetalis
Haemolytical disease of the newborn
Erythroblastosis fetalis
Passive immunization
with anti-Rh
Haemolytic anaemia and thrombocytopeny
Drugs/ metabolits can act as a hapten – e.g. penicillin
Drug allergy (penicillin)
Altering signal transduction
-
Myastenia Gravis
+
Autoimmune thyroiditis
Graves- Basedow
ptosis
3 hrs after methyl
prednisolon treatment
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 tissue
Severity 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 disease
Arthus 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 exposure
or vaccination
Ag –Ab complex
Complement
activation
Mast cell
degranulation
FcgammaRIII
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. HS
T cell mediated disease
Delayed HS
Ags inducing type IV. HS
DTH – delayed Type Hypressensitivity
It takes aprx 12 hrs as Th1 cells are involved
Contact Ag
Nickel salts, chromate
Poision ivry, oak
picricchlorine
Hair stain
IC bacteria
Mycobacterium tuberculosis, leprae
Microbial induced
Lysteria monocytogenes
Brucella abortus
Fungi
Candida albicans
Pneumocystis carinii
Cryptococcus neoformans
histoplasmosis
Viruses
Herpes simplex
Small pox
Measles
Type IV. HS
Syndrome
Antigen
Symptomes
Late type hypersensitivity
Proteins
Insect protein
Mycobacterial protein
(tuberculin, lepromin)
Local skin swelling:
Erythema
Induration (hardening)
Cellular infiltration
Dermatitis
Contact hypersensitivity
Haptens
Pentadeca-chatechol (poison
ivy)
Paraphenylene diamine (hair
stain)
Metallic ions: Nickel,
Chromium
Local skin reaction:
Erythema
Cellular infiltration
Blisters
Intra-epidermal foci
Gluten sensitive enteropathy Gliadin (grain protein)
Celiac disease – flour
sensitivity
Atrophy of microvilli in the small
intestine
Undernutrition
Damaged exocrine secretion of
pancreas
Th17
Neutrophil
recruitment
Contact reaction
Langerhans scells
uptake the Ag
Ag presentation to
TH1 cells
INFgamma
Macrophage
activation
Activation of the
keratinocytes
Macrophage
activation
inflammation
TNF-alpha, beta
Tissue
destruction
A schematic view of the sensitization phase
Tetsuya Honda
(2013) 133, 303-315. doi:10.1038/jid.2012.284
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 test
Allergen 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
Type IV. HS
Not immunological
Latex-allergen
Chemicals
Chemicals, soapa
Urticaria
Anafilaxy
DTH
Dermatitis
Irritative contact dermatitis
It is important to distinguishi:
 side effect
 Toxicity
 Intolerance
 Idiosyncrasy
 immun mediated reaction - hypersensitivity
Penicillin allergy
Type I. Drug allergy
Type II. drug
induced anaemia
Penicillin
Penicillin
Penicillin-protein
Penicillin-RBC
IgM, IgG
IgE
target
Systemic
anaphylaxis
urticaria
target
Hemolytic
anaemia
Type IV. HS
Penicillin
Penicillin
Penicillin-protein
Penicillin-protein
IgG
Complement
IgE-Mast cell
Type III. HS
TDTH
IgG immuncomplex
Macrophage activation
target
Serum sickness
glomerulonephritis
target
Contact dermatitis
Allegies in dentristry
Chlorhexidine: including allergy (Type I HS ) and
allergic contact dermatitis/stomatitis (Type IV HS)
Flouride - Type I and VI. HS skin rashes, mouth lesions
Metals- e.g. Ti : Type I and VI. HS
stomatitis, facial erythema
MELISA test
(Memory Lymphocyte Immunostimulation Assay )
clinically useful in identifying metal hypersensitivities
1.Blood sample
2.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.