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)

Type I:
Type II:
Type III:
Type IV: anaphylactic or immediate cytotoxic
Immune complex cell mediated or delayed
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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)

B cell
TH2
Histamine, tryptase, kininegenase, ECFA
Leukotriene-B4, C4, D4, prostaglandin D, PAF
Newly synthesized mediators
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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
Loss of consciousness
Death i.m. injection of adrenaline (1:1000) plus i.v. antihistamine, i.v.hydrocortisone and oxygen

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Type II (antibody mediated) hypersensitivity
Antibody to tissue bound or cellular antigen:

role of complement and phagocytes
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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

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

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Arthus reaction
Type-III
Weal & flare reaction
Type-I
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Early and late joint changes in rheumatoid arthritis

Typical “butterfly” malar rash in SLE

Type IV (delayed) 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
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Contact hypersensitivity (to nickel)

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Type IV hypersensitivity and coeliac disease

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“Patch” testing for contact hypersensitivity

Summary or hypersensitivity reactions

Autoimmunity and autoimmune disease

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
Antigen
Lesions
Organ specific localized to given organ or tissue confined to target organ or tissue
Non-organ specific widespread distribution throughout the body multiple organs / tissues affected; immune complexes deposit in joints, skin and kidneys overlap with other non-organ specific antibodies and diseases
Overlap with other organ specific antibodies and diseases
Examples autoimmune thyroid disease SLE
(Grave’s; Hashimoto’s) rheumatoid arthritis myasthenia gravis systemic sclerosis pernicious anaemia diabetes mellitus 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
Distribution thyroid gland
Disease
Hashimoto’s thyroiditis
Grave’s disease thyroid gland pancreas type I diabetes neuromuscular junction myasthenia gravis coeliac disease t transglutaminase / GI tract endomysial basement membrane kidney / lung mitochondrial (M2) all cells
ANCA (MPO / PR3) neutrophils
“rheumatoid factor” immunoglobulin Fc dsDNA all cells
Goodpastures syndrome
1 o 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
Type II
IgE
IgG
Type III
Type IV
Ag-Ab complexes 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