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HYPERSENSITIVITY REACTIONS
HYPERSENSITIVITY REACTIONS
Innocous materials can cause
hypersensitivity in certain
individuals
unwanted inflammation
damaged cells and tissues
Non-proper reaction of the immune system to foreign substances
Mainly harmless substances – after second or multiple times
TYPES OF HYPERSENSITIVITY REACTIONS
Type I
Type II
Type III
Type IV
„immediate”
„delayed”
Antibody mediated
T cell
mediated
specific IgE
cell surface antigen
specifically reacting
with antibody
aspecifically
deposited soluble
immuncomplex
MHC restricted T
cell activation
mediators
produced by mast
cells
FcR mediated
inflammation,
inhibition of cell
functions
FcR mediated
complement
activation,
inflammation
cytokines,
cytotoxicity
„classic allergy”
newborn haemolytic
anaemia, penicillin
sensitivity, M. gravis
Serum sickness, SLE
Contact dermatitis
mostly appear together with autoimmune diseases
TYPES OF HYPERSENSITIVITY REACTIONS
HYPERSENSITIVITY REACTIONS
TYPE I
ALLERGY
TYPE II
TYPE III
Soluble antigen
Cell surface or matrix
antigen
Soluble antigen
IgE
Mast cell
Hay fever
Asthma
Systemic anaphylaxis
IgG – immune complex
FcγR+ cells
NK, macrophage
Certain drug allergies
(penicillin)
IgG – immune complex
FcγR+ cells
Complement
Serum sickness
Arthus reaction
TYPE I HYPERSENSITIVITY
REACTION
ALLERGY
ALLERGENES USUALLY ENTER THE BODY VIA
MUCOSAL SURFACES AND THEY ARE PRESENT AT A
LOW DOSE
DC
B cell
Th2
Th2
antigen
presentation
T cell priming
and polarization
allergy
response
 soluble proteins on te surface of small particles (pollen, dust mite „drops”)
 small Mol. Weight, soluble
 trans mucosal entry, enzymatic activity
 low dose (ragweed: 1µg/year)
Mechanism of the initiation of Th2 response
IL-4
DC
CD4+
T h2T
CD40L
IL-4
A
L
L
E
R
G
É
N
Allergen
Th2
C
D
4
0
nyá lka Mucosa
há rtya
IL-10
CD40L
B
C
D
4
0
M
H
CII
B
IgE
Mast cell degranulation,
wheel and flare reaction
Ragweed
Saline
Histamine
IgE
a
g b
I
I
TT
AA
MM
PLA2
foszfa tidil-kolin
LYSO-PC
arachidonsav
Fc eRI
I
T
A
M
MAPkináz
I
T
A
M
Lyn
MAST CELL RESPONSE TO
SURFACE FcRεI CROSSLINKING
II
TT
AA
MM
Syk
endoplazmás
retikulum
2
Ca +
5-lipoxigenáz
PIP2
PI-PLCg
DAG
IP3
foszfolipid
ciklooxigenáz
Ca 2+
PGD2
citokin gének
transzkripciója
LTC4
NFAT AP-1 NF-k B
PAF
szekretoros
granulum
2+
PKC Ca
Ca 2+
proteinek
(miozinkönnyűlánc)
foszforilációja
Ca 2+
szekréció
PGD2
LTC4
EARLY MEDIATORS
LTD4
LTE4
LATE MEDIATORS
mediátorok
citokinek
IL-3, IL-4,
IL-5, IL-6
TNFa
Biognic amins – histamin
Enzymes – triptase, chymase,
carboxypeptidase
The effect of mast cell degranulation varies with
the tissue exposed to allergen
Systemic anaphylaxis is caused by allergens
that reach the blood stream
GENETIC/ENVIRONMENTAL PREDISPOSITION TO
ALLERGY
Genetic factors
chromosome 11q
FcERβ chain gene
chromosome 11q
IL-3-5 IL-9, IL13 GMCSF
HLAII DRB1*150
Improper
immunregulation
Th1/Th2 inbalance
regulation of IgE synthesis
immunodeficiency
high eosinophil counts
allergy
Environmental
factors
lack of tolerance
Types of IgE-derived allergic response
SYNDROME
ALLERGENS
ROUTE OF ENTRY
RESPONSE
systemic
anaphylaxis
drugs
anti-serum
peanuts
intravenous
peroral
edema, increased vascular
permeability
tracheal occlusion
circulatory collapse, death
acute
utricaria
bug bite
allergy test
subcutan
local increase in blood flow
and vascular
permeability
allergic
rhynitis
pollen
dust mite drops
inhaled
irritation and edema of
nasal mucosa
airway inflammation
asthma
animal fur
pollen
dust mite drops
inhaled
bronchial constriction,
increased mucus production
food allergy
nut, peanuts,
fish, shellfish
milk, eggs
peroral
vomiting, diarrhea
pruritis (itching)
urticaria (hives)
anaphylaxia (rare)
Short/Common ragweed (Ambrosia artemisiifolia)
Short/Common ragweed (Ambrosia artemisiifolia)
levélfonák zöld
Mugwort (Artemisia vulgaris)
levélfonák fehéresen molyhos
Mugwort (Artemisia vulgaris)
Mugwort (Artemisia vulgaris) –
?
Wormwood (Arthemisia absinthium) – Absinthe (thujone: max 35 mg/l)
HYPERSENSITIVITY
REACTIONS INDUCED BY
IMMUNE COMPLEXES
TYPES II and III
Type II hypersensitivity
IgG tpye antibodies bound to the cell surface or to tissue
antigens
• cells expressing the antigen become sensitive to complement
mediated lysis or to opsonized phagocytosis
• frustrated phagocytosiss  tissue demage
• the antibody inhibits or stimulates target cell function
– no tissue damage (e.g. M. gravis – receptor blocker
antibodies)
MECHANISMS OF TYPE II
HYPERSENSITIVITY REACTIONS
Hemolytic anemia of
newborns
Erythroblastosis fetalis
NK
Mf
Killing of target
cell by effectormacrophage or
NK-cell
IgG
ADCC
IgG
C'
complement
activation
Killing of target
cell by complementmediated lysis
Receptor-specific
autoantibody
interferes with
signal transduction
Drug induced
Hemolytic anemia
Trombocytopenia
Agranulocytosis
Penicillin-based antibiotics
Anti-arythmic quinidin
Goodpasture syndrome
(type IV collagen)
Pemphigus vulgaris
(desmosomal antigens)
Damage of epidermal and
mucosal junctions,
acantholysis
MECHANISM OF THE DEVELOPMENT OF DRUG
SENSITIVITY
Th
B
Healthy cell
Drug-modified cell
surface protein
IgG type antibodies
FRUSTRATED PHAGOCYTOSIS MEDIATED BY IgG TYPE
ANTIBODIES
Binding
Opsonization Internalization
C3b
C3b
C3b
C3b
Enzyme
release
C3b
C3R
FcR
The tissue, which
can not be
phagocytosed, is
damaged
C3b
Internal or
absorbed antigen Opsonized surface Binding Frustrated Enzyme release
phagocytosis
(drug)
Examples - Type II hypersensitivity
Newborn haemolytic anaemia
Transfusion reaction
Hyperacut allograft rejection
Drug-derived
• Haemolitic anaemia
• Thrombocytopenia
• Agranulocitosis
•
•
Penicillin-based antibiotics
Anti-arithmic quinidin
Goodpasture syndrome (kidney, membrane basalis, collagen type IV)
Myasthaenia gravis (anti-acetyl-choline receptor antibodies)
Basedow-disease (anti-TSH-receptor antibodies)
Pemphigus vulgaris (mucosal bubbles)  atoantibody against desmosomal
antigen desmoglein-3, interruption of epidermal and mucosal connections,
acantolysis (disintegration into single cells)
Transplantation - hyperacut allograft
rejection
• HLA-A, B, C, DR, DQ, DP,
minor histocompatibility
antigens
• foreign MHC-antigens
recognized by T cells
Direct: self T cells - donor APCs
(CD8+ T cells)
Indirect: self APC presents donor
MHC-molecule fragments
(CD4+ T cells)
cytokine release
• Hyperacut rejection
Causes: immunization against
alloantigens, preformed antiHLA-antibodies, blood group
incompatibility
antibodies bound to endothel
activation of complement system
thrombosis of venules
vascularis necrosis
Therapy resistent
MHC I:
MHC II:
HLA typing
HLA-A, HLA-B, HLA-C
HLA-DP, HLA-DQ, HLA-DR
- used for transplantations
(generally the -B and -DR is the most important and the -C does not matter)
- diagnostical value
(connections between the HLA alleles and the diseases)
Serotyping
(microcitotoxicity tests)
Based on the serological reaction between the examined cells and the typing serum.
Complement mediated lysis with the help of MHC I and/or MHC II antigen recognizing
antibody containing serum.
There are no reaction in the case of serotype identity
(dead cells can be visualized by specific dye)
Typing sera containing antibodies to Class I and II proteins were collected from
multiparous women, or individuals who had received multiple blood transfusions.
(immunized against multiple alleles). The specificity identification have been done on
international workshops.
The procedures have been done on microtiter plates (with 10µl working aliquots –
Terasaki plates) because of the available quantity of the typing sera were always
limited. Sera have been replaced by monoclonal antibodies later.
Serotyping (2.)
HLA-D (MHC II) antigenes had been examined on nylon column separated B cells
The polymorphism of the MHC II antigens could be examined by mixed lymphocyte
reactions (MLR).
(A normal person can have 1-10% alloreactive lymphocytes.)
Microtiter plates
serotyping have some limits
– crossreactions (HLA-B27 – HLA-B7)
– there is no sera against HLA-C because of the low immunogenicity
– some subtype cannot be discriminated
Genomic DNA based examinations
- PCR-SSP is using the PCR amplification reaction directly to detect HLA
polymorphisms. Primers can be constructed specifically to complement HLA
polymorphisms; if the primers bind the complementary polymorphism and
amplify the gene segment, then the PCR product can be detected by standard
techniques. An array of PCR primers complementary to the range of HLA
polymorphisms has been constructed.
HLA-A
0201
0202
0203
…
-PCR-SSOP (sequence specific oligonucleotid probe)
The examined HLA genes are amplified by PCR with non allele specific primer pairs.
The amplificates are immobilized on nitrocellulose membranes or microtiter plates and
are hybridized by HLA allele specific labeled oligonucleotides.
The label can be enzimatic, fluorescent or radioactive
-SBT (sequence based typing)
allotypes can be evaluated by sequencing MHC region
of the genomic DNA
(minor mutations can be examined)
Diseases
(autoimmune)
HLA
frequency
concerned
control
SLE
DR3
B8
55
50
20
20
Hydralazine(?) induced lupus
erythematosus
DR4
73
32
DR3
B8
DR3
DR2
B7
B8
56
43
55
60
37
44
25
20
21
30
24
20
DR4
53
19
DR3
DR3
B8
DR3
B8
DR3
B8
DR3
DR7
B8
DR2
DR3
DR3
B8
B35
B27
DR4
72
49
40
70
46
70
50
79
60
68
88
81
82
75
70
79
95
24
22
21
20
23
20
22
22
15
22
29
20
20
22
15
9
20
Basedow-disease
Active chronic hepatitis
Sclerosis multiplex
Myasthenia gravis
Autoimmune IgA
glomerulonephritis
Type I diabetes
Addison-disease (idiotopic,
autoimmune)
Sjörgen-syndrome
Coeliaca
Goodpasture-syndrome
IgA loss
Dermatitis herpetiformis
De Qervain-thyreoiditis
Reiter-syndrome
Felty-syndrome
ref: Klinikai immunológia (II. klinikum) (OHVI 1990 szerk.: Szegedi, Gergely, Sipka, Szemere)
Stenszky Valéria: Autoimmun betegségek genetikai vonatkozásai
Diseases
Narcolepsia
Bechterew-disease
Adrenogenitális syndrome
salt lost
late
virilizing
Psoriasis vulgaris
Idiophatic haemochromatosis
Bechet-disease
Gold induced thrombocytopenia
Gold induced leucopenia
HLA
frequency
concerned
control
DR2
B27
100
89
22
9
Bw47
B14
B5
Cw6
B13
B17
DR7
A3
B51
DR3
DR3
36
57
48
56
24
27
48
76
50
50
47
1
4
10
15
8
8
23
28
11
13
13
HLA allotypes and diseases
HLA-A
A*01010101A*0214
A*01010102N
A*0215N
A*010102 A*0216
A*010103 A*021701
A*010104 A*021702
A*0102
A*0218
A*0103
A*0219
A*0104N A*022001
A*0106
A*022002
A*0107
A*0221
A*0108
A*0222
A*0109
A*0224
A*0110
A*0225
A*0111N A*0226
A*0112
A*0227
A*0113
A*0228
A*0114
A*0229
A*0115N A*0230
A*0116N A*0231
A*0117
A*0232N
A*0118N A*0233
A*0119
A*0234
A*0120
A*023501
A*02010101A*023502
A*02010102L
A*0236
A*020102 A*0237
A*020103 A*0238
A*020104 A*0239
A*020105 A*0240
A*020106 A*0241
A*020107 A*0242
A*020108 A*0243N
A*020109 A*0244
A*020110 A*0245
A*020111 A*0246
A*020112 A*0247
A*0202
A*0248
A*020301 A*0249
A*020302 A*0250
A*0204
A*0251
A*0205
A*0252
A*020601 A*0253N
A*020602 A*0254
A*020603 A*0255
A*0207
A*0256
A*0208
A*0257
A*0209
A*0258
A*0210
A*0259
A*0211
A*0260
A*0212
A*0261
A*0263
A*0309
A*0264
A*0310
A*0265
A*0311N
A*0266
A*0312
A*0267
A*0313
A*0268
A*0314
A*0269
A*0315
A*0270
A*0316
A*0271
A*0317
A*0272
A*0318
A*0273
A*0319
A*027401 A*0320
A*027402 A*0321N
A*0275
A*0322
A*0276
A*0323
A*0277
A*0324
A*0278
A*0325
A*0279
A*110101
A*0280
A*110102
A*0281
A*110103
A*0282N A*110104
A*0283N A*110105
A*0284
A*110201
A*0285
A*110202
A*0286
A*1103
A*0287
A*1104
A*0288N A*1105
A*0289
A*1106
A*0290
A*1107
A*0291
A*1108
A*0292
A*1109
A*0293
A*1110
A*0294N A*1111
A*0295
A*1112
A*0296
A*1113
A*0297
A*1114
A*0299
A*1115
A*03010101A*1116
A*03010102N
A*1117
A*03010103A*1118
A*030102 A*1119
A*030103 A*1120
A*030104 A*1121N
A*030105 A*1122
A*0302
A*1123
A*0303N A*1124
A*0304
A*1125
A*0305
A*1126
A*0306
A*1127
A*0307
A*1128
A*2301
A*2428
A*2302
A*2429
A*2303
A*2430
A*2304
A*2431
A*2305
A*2432
A*2306
A*2433
A*2307N A*2434
A*2308N A*2435
A*2309
A*2436N
A*2310
A*2437
A*2311N A*2438
A*2312
A*2439
A*2313
A*2440N
A*2314
A*2441
A*24020101A*2442
A*24020102L
A*2443
A*240202 A*2444
A*240203 A*2445N
A*240204 A*2446
A*240205 A*2447
A*240206 A*2448N
A*240207 A*2449
A*240208 A*2450
A*240209 A*2451
A*240210 A*2452
A*240211 A*2453
A*240212 A*2454
A*240301 A*2455
A*240302 A*2456
A*2404
A*2457
A*2405
A*2458
A*2406
A*2459
A*2407
A*2460N
A*2408
A*2461
A*2409N A*2462
A*2410
A*2463
A*2411N A*2464
A*2413
A*2465
A*2414
A*2466
A*2415
A*250101
A*2417
A*250102
A*2418
A*2502
A*2419
A*2503
A*2420
A*2504
A*2421
A*2505
A*2422
A*2506
A*2423
A*260101
A*2424
A*260102
A*2425
A*260103
A*2426
A*260104
A*2603
A*300102
A*2604
A*300201
A*2605
A*300202
A*2606
A*300203
A*260701 A*3003
A*260702 A*3004
A*2608
A*3006
A*2609
A*3007
A*2610
A*3008
A*2611N A*3009
A*2612
A*3010
A*2613
A*3011
A*2614
A*3012
A*2615
A*3013
A*2616
A*3014L
A*2617
A*3015
A*2618
A*3016
A*2619
A*3017
A*2620
A*3018
A*2621
A*310102
A*2622
A*3102
A*2623
A*3103
A*2624
A*3104
A*2625N A*3105
A*2626
A*3106
A*2627
A*3107
A*2628
A*3108
A*2629
A*3109
A*2630
A*3110
A*2631
A*3111
A*2632
A*3112
A*2633
A*3113
A*29010101A*3114N
A*29010102N
A*3201
A*290201 A*3202
A*290202 A*3203
A*290203 A*3204
A*2903
A*3205
A*2904
A*3206
A*2905
A*3207
A*2906
A*3208
A*2907
A*3209
A*2908N A*3210
A*2909
A*3211Q
A*2910
A*3212
A*2911
A*3213
A*2912
A*3301
A*2913
A*330301
A*2914
A*330302
A*2915
A*3304
A*3306
A*6824
A*3307
A*6825
A*3308
A*6826
A*3401
A*6827
A*3402
A*6828
A*3403
A*6829
A*3404
A*6830
A*3405
A*6831
A*3406
A*6832
A*3407
A*6833
A*3408
A*6834
A*3601
A*6835
A*3602
A*6901
A*3603
A*7401
A*3604
A*7402
A*4301
A*7403
A*6601
A*7404
A*6602
A*7405
A*6603
A*7406
A*6604
A*7407
A*6605
A*7408
A*6606
A*7409
A*680101 A*7410
A*680102 A*7411
A*680103 A*7412N
A*680104 A*8001
A*680105 A*9201
A*68020101A*9202
A*68020102A*9203
A*680301 A*9204
A*680302
A*6804
A*6805
A*6806
A*6807
A*6808
A*6809
A*6810
A*6811N
A*6812
A*6813
A*6814
A*6815
A*6816
A*6817
A*6818N
A*6819
A*6820
A*6821
A*6822
HLA-A alleles described
until october 2006
http://www.ebi.ac.uk/imgt/hla/allele.html
Type IV hypersensitivity reaction
Chemokines, cytokines,
cytotoxins
Delayed-type Hypersensitivity
(Type IV Hypersensitivity)
Delayed-type Hypersensitivity
(Type IV Hypersensitivity)
Delayed-type hypersensitivity (DTH)
(e.g., tuberculin skin test)
TH1 from a previous
immunization
(memory)
Tuberculin skin test
Chemical Mediators of DTH
Contact Dermatitis
*a contact-sensitizing agent is usually a small molecule that penetrates the
skin then binds to self-proteins, making them “look” foreign
Poison ivy
Anacardiaceae (family), Toxicodendron (genus)
Toxicodendron radicans or Rhus toxicodendron
Delayed-type hypersensitivity is mediated by T cells
(Type IV hypersensitivity)
Delayed-type Hypersensitivity
A positive tuberculin skin
test is a DTH reaction
TYPE III HYPERSENSITIVITY
Antibodies binding to soluble antigens
Small circulating immune complexes
Depends on:
Size of immune complexes
Antigen-antibody ratio
Affinity of antibody
Isotype of antibody
THE PROCESS OF TISSUE DAMAGE CAUSED BY IMMUNE
COMPLEXES
Antigen
C'
Immune complex
Antibody
Complementa ctivation
(C3a , C5a )
PMN
Chemotaxis
C'
Endothelium Ba sophil
Ba sa l membra ne
gra nulocyte
Vessel wa ll
Thrombocytes
Deposition
Blood vessel
wall
permeability
Frustrated
phagocytosis
Vasoactive
a mines
Immune complexes activate the complement system,
neutrophils, bazophil granulocytes and thrombocytes
MANIFESTATION OF TYPE III HYPERSENSITIVITY IN SLE
Facial, malar "butterfly" rash with
characteristic shape across the
cheeks. Discoid lupus erythematosus
(DLE) involves mainly the skin, it is
relatively benign compared to
systemic lupus erythematosus (SLE).
In either case, sunlight exposure
accentuates this erythematous rash. A
small number (5 to 10%) of DLE
patients go on to develop SLE (usually
the DLE patients with a positive ANA).
Here is a more severe
inflammatory skin infiltrate in the
upper dermis of a patient with
SLE in which the basal layer is
undergoing vacuolization and
dissolution, and there is purpura
with RBC's in the upper dermis
(which are the reason for the
rash).
DEPOSITION OF IMMUNE COMPLEXES IN THE SKIN OF
SLE PATIENTS
When immunofluorescence
staining with an antibody to
complement or immunoglobulin
is performed, a brightly
fluorescent signal staining the
dermal epidermal junction is
visable indicating immune
complex deposition.
Immunofluorescence staining pattern
with antibody to IgG staining immune
complexes at the dermal-epidermal
junction. If such a pattern is seen only in
skin involved by a rash, then the
diagnosis is probably DLE, but if this
pattern appears even in skin uninvolved
by a rash, then the diagnosis is SLE.
RENAL FAILURE IN IMMUNECOMPLEX DISEASES
One of the feared complications
of the rheumatic diseases is
renal failure. This is most likely
to occur in SLE. Here is a
glomerulus in which the
capillary loops are markedly
pink and thickened such that
capillary lumens are hard to
see. This is lupus nephritis.
Here is a glomerulus with
thickened pink capillary
loops, the so-called "wire
loops", in a patient with
lupus nephritis. The
surrounding renal tubules
are unremarkable.
ANA
Anti -nuclear
antibody
This is the so-called "nucleolar pattern"
of staining in which the bright
fluorescence is seen within the nucleoli
of the Hep2 cells. This pattern is more
suggestive of progressive systemic
sclerosis.
This is the so-called "rim"
pattern that is more
characteristic of SLE.
This is the so-called "speckled" pattern
of staining which is more characteristic
of the presence of autoantibodies to
extractable nuclear antigens, particularly
ribonucleoprotein. This pattern is not
very specific, but may be seen with an
entity called "mixed connective tissue
disease" which is a mix between SLE,
scleroderma, and polymyositis, but
without serious renal or pulmonary
disease. The autoimmune diseases are
very hard to classify, even for the
experts.