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