Hypersensitivity and Autoimmunity
Dec 17, 2015
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 selfantigen(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)
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Types of hypersensitivity reactions
Types of hypersensitivity reactions
Type I: anaphylactic or immediate
Type II: cytotoxic
Type III: Immune complex
Type IV: cell mediated or delayed
Type I: anaphylactic or immediate
Type II: cytotoxic
Type III: Immune complex
Type IV: cell mediated or delayed
Type I (immediate) hypersensitivity reactions
Mechanism of type I hypersensitivity
Extrinsic allergenpollens house dust miteanimal dander foods (eg peanut)wasp / bee venom
Th2 response
IgE
mast cells
IL-4 / IL-13
Priming sensitization elicitation
Mediators of type I hypersensitivity
vasodilatationincreased vascular permeabilitytissue oedemasmooth muscle contractionchemoattraction
Most allergic reactions occur at mucosal sites (site of interaction with allergen)
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Sensitization against allergens and type-I hypersensitivity
Sensitization against allergens and type-I hypersensitivity
B cell
Histamine, tryptase, kininegenase, ECFA
Leukotriene-B4, C4, D4, prostaglandin D, PAF
Newly
synthesized mediators
TH2
Allergic rhinitis (Hay fever)
Anaphylaxis – systemic type I hypersensitivity:a medical emergency
Clinical features of anaphylaxis:
Generalized urticariaAngioedema esp. around eyes, lips, tongue and larynxGastrointestinal symptoms (nausea, cramps, vomiting, diarrheoa)BronchospasmHypotension Loss of consciousnessDeath
i.m. injection of adrenaline (1:1000)
plus i.v. antihistamine, i.v.hydrocortisone and oxygen
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Skin (prick) test for allergySkin (prick) test for allergy
Type II (antibody mediated) hypersensitivity
Antibody to tissue bound or cellular antigen:
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Type II hypersensitivityrole of complement and phagocytes
Type II hypersensitivityrole of complement and phagocytes
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Type II hypersensitivity induced by exogenous agents
Type II hypersensitivity induced by exogenous agents
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 AbsTSH receptor in Grave’s disease
Blocking AbsACh R inmyasthenia gravis
intrinsic factor inpernicious anaemia
insulin receptor indiabetes
Myasthenia gravisthe mechanism
Myasthenia gravisthe mechanism
Grave’s diseaseGrave’s disease
Type III (immune complex) mediated hypersensitivity
Soluble antigen
Immune complexes depositin small vessels (esp joints, kidneys, skin)
Complement activation
Neutrophil attraction and activation
Platelet aggregation and microthrombus formation
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Type III hypersensitivity mechanismType III hypersensitivity mechanism
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Arthus reactionArthus reaction
Arthus reactionType-III
Weal & flare reactionType-I
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Serum sicknessSerum sickness
Early and late joint changes in rheumatoid arthritis
Typical “butterfly” malar rash in SLE
Type IV (delayed) hypersensitivity
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Type IV hypersensitivityType 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
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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Tuberculin testTuberculin test
Contact hypersensitivity (to nickel)
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Contact dermatitis reaction to leather
Contact dermatitis reaction to leather
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Granuloma in a leprosy patientGranuloma in a leprosy patient
Type IV hypersensitivity and coeliac disease
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Type IV hypersensitivitythe three forms
Type IV hypersensitivitythe three forms
“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 widespread distribution or tissue throughout the body
Lesions confined to target organ multiple organs / tissues affected;or tissue
immune complexes deposit in joints, skin and kidneys
Overlap with other organ specific overlap with other non-organantibodies and diseases specific antibodies and diseases
Examples autoimmune thyroid disease SLE (Grave’s; Hashimoto’s) rheumatoid arthritismyasthenia gravis systemic sclerosispernicious anaemia systemic vascultitisdiabetes mellitus
Autoantibodies and autoimmunity
(Some) autoantibodies of clinical significance in organ specific and non-organ specific autoimmune disease:
Antigen Distribution Disease
thyroid peroxidase thyroid gland Hashimoto’s thyroiditis
TSH receptor thyroid gland Grave’s disease
islet cell pancreas type I diabetes
acetyl choline R neuromuscular junction myasthenia gravis
t transglutaminase / GI tract coeliac disease
endomysial
basement membrane kidney / lung Goodpastures syndrome
mitochondrial (M2) all cells 1o biliary cirrhosis
ANCA (MPO / PR3) neutrophils systemic vasculitis
“rheumatoid factor” immunoglobulin Fc rheumatoid arthritis
dsDNA all cells 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 cellscytokines: 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 IgEType II IgGType III Ag-Ab complexes Type IV delayed / T cell mediated
• Anaphylaxis (systemic type I hypersensitivity reaction) represents a medical emergency, is potentially life- threatening, and is effectively treated with i.m. adrenaline
• In many autoimmune diseases, there is overlap between different types of hypersensitivity reaction