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HYPERSENSITIVITY
REACTIONS
HYPERSENSITIVITY REACTIONS
Innocous materials can cause
hypersensitivity in certain
individuals
leading to unwanted inflammation
damaged cells and tissues
Non-proper reaction of the immune system to foreign substances
Mainly harmless substances – after second or multiple exposure
AN OVERVIEW OF HYPERSENSITIVITY
REACTIONS
Type I.
Type II.
„immediate”
Type III.
Type IV.
„late”
Antibody mediated
T cell mediated
TYPES OF ANTIBODY MEDIATED
HYPERSENSITIVITY REACTIONS
FcRIα)
TYPE I HYPERSENSITIVITY
REACTION
ALLERGY
SENSITISATION PROCESS
Once sensitized (immunized), every following exposure
to the allergen elicits the allergic reactions.
MAST CELL RESPONSE TO
SURFACE FcεRI CROSSLINKING
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
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
LTD4
LTE4
LATE MEDIATORS
mediátorok
EARLY MEDIATORS
citokinek
IL-3, IL-4,
IL-5, IL-6
TNFa
Biogenic amins – histamin
Enzymes – triptase, chymase,
carboxypeptidase
ACUTE AND CHRONIC PHASE
OF THE ALLERGIC RESPONSE
THE EFFECT OF MAST CELL DEGRANULATION
VARIES WITH THE TISSUE EXPOSED TO ALLERGEN
SYSTEMIC ANAPHYLAXIS IS CAUSED BY ALLERGENS THAT REACH THE BLOOD STREAM
Pruritus
Short/Common ragweed (Ambrosia artemisiifolia)
Short/Common ragweed (Ambrosia artemisiifolia)
Green leaf back
Mugwort (Artemisia vulgaris)
White leaf back
Mugwort (Artemisia vulgaris) –
?
Wormwood (Artemisia absinthium) – Absinthe (thujone: max 35 mg/l)
MAST CELL DEGRANULATION,
ALLERGIC REACTION IN THE SKIN OF
A SENSIBILIZED INDIVIDUAL
PRICK TEST
Prick test
ImmunoCAP
Specific IgE Blood Test
Anti-IgE
Serum IgE
Allergen
Solid phase
COMPARISON OF SKIN TEST
TO SPECIFIC IgE TESTING
allergens
speed
(result)
medication
disease
cost
sensitivity
Skin Prick test
Specific IgE
many
20 min
almost all
1-2 days
no antihistamines
severe eczema:
difficult
€ 20 (total)
high
no problem
no problem
€ 20 per specific IgE
slightly lower
TYPE II HYPERSENSITIVITY
IgG type antibodies bound to
cell surface or tissue antigens
• cells expressing the antigen become sensitive to complement
mediated lysis or to opsonized phagocytosis
• frustrated phagocytosis  tissue damage
• the antibody inhibits or stimulates target cell function
no tissue damage (e.g. M. gravis – receptor-blocking antibodies)
MECHANISMS OF TYPE II HYPERSENSITIVITY REACTIONS
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
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
Absorbed antigen
Opsonized surface Binding Frustrated
(drug)
phagocytosis
Enzyme release
EXAMPLES - TYPE II HYPERSENSITIVITY
Newborn haemolytic anaemia
Transfusion reaction
Hyperacut allograft rejection
Drug-derived
• Haemolitic anaemia
• Thrombocytopenia
• Agranulocytosis
•
•
Penicillin-based antibiotics
Anti-arithmic quinidine
Goodpasture syndrome (kidney, basal membrane - collagen type IV)
Pemphigus vulgaris (mucosal bubbles)  against desmosomal antigens,
interruption of epidermal and mucosal connections, acantolysis
(desintegration into single cells)
Myasthaenia gravis (anti-acetyl-choline receptor antibodies)
Graves-Basedow-Flajani disease (anti-TSH-receptor antibodies)
DEVELOPMENT OF DRUG
SENSITIVITY I.
DEVELOPMENT OF DRUG SENSITIVITY II.
TYPE III HYPERSENSITIVITY
Antibodies binding to soluble antigens
forming small circulating immune complexes
which are deposited in various tissues
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, basophils and thrombocytes
SYMPTOMES CAUSED BY TYPE III HYPERSENSITIVITY REACTIONS
DEPEND ON THE SITE OF IMMUNECOMPLEX DEPOSITION
ARTHUS-REACTION
• Localized Type III hypersensitivity
• Local vasculitis develops as a result of immune complex deposition
• Inhaled antigens (fungi, animal feces) may induce similar reaction in
the lung
• IgG type antibody
• ‘Farmers lung’ and ‘piegeon-breeder’s lung’
MANIFESTATION OF TYPE III HYPERSENSITIVITY IN
LUPUS ERYTHEMATOSUS
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
visible 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
Glomerulus of a healthy
individual. Relatively wide
spaces between capillary
loops.
One of the feared complications
of the systemic autoimmune
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.
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.
TYPE IV HYPERSENSITIVITY
REACTION
T CELL MEDIATED PROCESS
TYPE IV (DELAYED-TYPE)
HYPERSENSITIVITY
Delayed-type hypersensitivity is mediated by T cells
DELAYED-TYPE (TYPE IV)
HYPERSENSITIVITY
DELAYED-TYPE (TYPE IV) HYPERSENSITIVITY
DELAYED-TYPE HYPERSENSITIVITY (DTH)
(e.g. tuberculin skin test)
TH1 from a previous
immunization (memory)
Tuberculin skin test
Introduction of Ag
Ag = antigen
Purified protein
derivate (PPD)
CHEMICAL MEDIATORS OF DTH
DTH as a result of a contact-sensitizing agent*
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
CELIAC DISEASE