Download 8-Hypersensitivity and Autoimmunity

Hypersensitivity and Autoimmunity
Aims & Objectives:
• Understand the terms hypersensitivity, allergy,
autoimmunity and autoimmune disease
• Understand the classification and mechanisms of
immunologically mediated tissue damage
(hypersensitivity reactions), and know examples of
diseases reflecting each of these
• Understand what we mean by organ specific and
non-organ specific autoimmune diseases, and know
examples of both
Definitions:
Hypersensitivity: exaggerated or inappropriate immune
reaction resulting in tissue damage
Allergy: hypersensitivity reaction to an extrinsic (often
innocuous) antigen
Autoimmunity: immune response with specificity for self
antigen(s)
Autoimmune disease: disease in which an autoimmune
response plays a pathogenetic role
Hypersensitivity reactions –
the mechanisms of allergy and autoimmunity
(Gell and Coombs classification)
Types of hypersensitivity
reactions
Type I:
Type II:
Type III:
Type IV:
anaphylactic or immediate
cytotoxic
Immune complex
cell mediated or delayed
5
Type I (immediate) hypersensitivity reactions
Mechanism of type I hypersensitivity
Extrinsic allergen
pollens house dust mite
animal dander foods (eg peanut)
wasp / bee venom
IgE
Th2 response
IL-4 / IL-13
mast cells
Priming
sensitization
elicitation
Mediators of type I hypersensitivity
vasodilatation
increased vascular permeability
tissue oedema
smooth muscle contraction
chemoattraction
Most allergic reactions occur at mucosal sites (site of interaction with allergen)
Sensitization against allergens and
type-I hypersensitivity
B cell
TH2
Histamine, tryptase,
kininegenase, ECFA
Leukotriene-B4, C4, D4,
Newly
prostaglandin D, PAF
synthesized mediators
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Allergic rhinitis (Hay fever)
Anaphylaxis – systemic type I hypersensitivity:
a medical emergency
Clinical features of anaphylaxis:
Generalized urticaria
Angioedema esp. around eyes, lips, tongue and larynx
Gastrointestinal symptoms (nausea, cramps, vomiting, diarrheoa)
Bronchospasm
Hypotension
i.m. injection of adrenaline (1:1000)
Loss of consciousness
Death
plus i.v. antihistamine, i.v.hydrocortisone and oxygen
Skin (prick) test for allergy
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Type II (antibody mediated) hypersensitivity
Antibody to tissue bound or cellular antigen:
Type II hypersensitivity
role of complement and phagocytes
14
Type II hypersensitivity induced by
exogenous agents
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Mechanism and prevention of Rhesus disease
Rhesus disease of the newborn –
a type II hypersensitivity disease
Stimulatory and blocking antibodies
in type II hypersensitivity
Stimulatory Abs
TSH receptor in
Grave’s disease
Blocking Abs
ACh R in
myasthenia gravis
intrinsic factor in
pernicious anaemia
insulin receptor in
diabetes
Myasthenia gravis
the mechanism
Grave’s disease
Type III (immune complex) mediated
hypersensitivity
Soluble antigen
Immune complexes deposit
in small vessels (esp joints,
kidneys, skin)
Complement activation
Neutrophil attraction and
activation
Platelet aggregation and
microthrombus formation
Type III hypersensitivity
mechanism
22
Arthus reaction
Arthus reaction
Type-III
Weal & flare reaction
Type-I
23
Serum sickness
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Early and late joint changes in
rheumatoid arthritis
Typical “butterfly” malar rash in SLE
Type IV (delayed) hypersensitivity
Type IV hypersensitivity
 Delayed reaction
 36 to 48 hours
 Characterized by induration
and erythema
 Also known as cell
mediated hypersensitivity
 Tuberculin test is the most
common example
28
Tuberculin test
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Contact hypersensitivity (to nickel)
Contact dermatitis reaction to
leather
31
Granuloma in a leprosy patient
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Type IV hypersensitivity and coeliac disease
Type IV hypersensitivity
the three forms
34
“Patch” testing for contact hypersensitivity
Summary or hypersensitivity reactions
Autoimmunity and autoimmune disease
Peripheral tolerance
Autoantibodies and disease
• presence of antibodies to self antigens indicates an autoimmune
process or reaction
• but does not necessarily equate with presence of disease
(eg low titre ANA in elderly or after infection)
• some (but not all) autoantibodies cause disease (pathogenetic)
• some autoantibodies provide useful diagnostic markers of disease
(often in association with other clinical features)
• some autoantibodies can be used to monitor disease activity
(often pathogenetic antibodies)
• some autoantibodies have a higher predictive value than others
(eg IgA endomysial Ab vs IgA gliadin Ab vs reticulin Ab in coeliac disease)
• autoantibodies to many autoantigens are found (in low titres) in the
elderly in the absence of disease (eg ANA)
Comparison of organ specific and non-organ
specific autoimmune diseases
Organ specific
Non-organ specific
Antigen
localized to given organ
or tissue
widespread distribution
throughout the body
Lesions
confined to target organ
or tissue
multiple organs / tissues affected;
immune complexes deposit in
joints, skin and kidneys
Overlap
with other organ specific
antibodies and diseases
overlap with other non-organ
specific antibodies and diseases
Examples
autoimmune thyroid disease
(Grave’s; Hashimoto’s)
myasthenia gravis
pernicious anaemia
diabetes mellitus
SLE
rheumatoid arthritis
systemic sclerosis
systemic vascultitis
Autoantibodies and autoimmunity
(Some) autoantibodies of clinical significance in organ specific and
non-organ specific autoimmune disease:
Antigen
thyroid peroxidase
TSH receptor
islet cell
acetyl choline R
t transglutaminase /
endomysial
basement membrane
mitochondrial (M2)
ANCA (MPO / PR3)
“rheumatoid factor”
dsDNA
Distribution
thyroid gland
thyroid gland
pancreas
neuromuscular junction
GI tract
Disease
Hashimoto’s thyroiditis
Grave’s disease
type I diabetes
myasthenia gravis
coeliac disease
kidney / lung
all cells
neutrophils
immunoglobulin Fc
all cells
Goodpastures syndrome
1o biliary cirrhosis
systemic vasculitis
rheumatoid arthritis
SLE
Causes of autoimmunity –
breakdown of self tolerance
Molecular mimicry:
cross reactivity between pathogen and self antigen
Defective immunoregulation:
aberrant Ag presentation by dendritic cells
(failure of) regulatory T cells
cytokines: excess immune stimulation
lack of suppression
Exposure of “hidden” self antigens:
eg sympathetic opthalmia
T cell bypass / hapten: eg drug induced autoimmune cytopenias
Genetic susceptibility:
HLA and non-HLA genes
In most cases, trigger not known
Summary
• autoimmune reactions and diseases are relatively common, and
represent a breakdown of immunological tolerance
• autoimmunity can be organ-specific or non-organ specific, depending
on the distribution of the autoantigen
• allergic represents an exaggerated immune response to extrinsic antigen.
Allergic diseases are common, and are becoming more common
(especially in children)
• allergic and autoimmune diseases are mediated by mechanisms of
hypersensitivity
• hypersensitivity reactions represent exaggerated or inappropriate
immune reactions, resulting in tissue damage
Summary
• Four major types of hypersensitivity reaction have been
defined, depending on the underlying immunological
mechanism
Type I
IgE
Type II
IgG
Type III
Ag-Ab complexes
Type IV
delayed / T cell mediated
• Anaphylaxis (systemic type I hypersensitivity reaction)
represents a medical emergency, is potentially lifethreatening, and is effectively treated with i.m. adrenaline
• In many autoimmune diseases, there is overlap between
different types of hypersensitivity reaction