Hypersensitivity and Autoimmunity

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Hypersensitivity and Autoimmunity
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• 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

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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
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Hypersensitivity reactions the mechanisms of
allergy and autoimmunity (Gell and Coombs
classification)
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Types of hypersensitivity reactions

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

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Type I (immediate) hypersensitivity reactions
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Mechanism of type I hypersensitivity
pollens house dust mite animal dander foods (eg
peanut) wasp / bee venom
Extrinsic allergen
IgE
Th2 response
IL-4 / IL-13
mast cells
Priming sensitization elicitation
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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)
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Sensitization against allergens and type-I
hypersensitivity
Histamine, tryptase, kininegenase, ECFA
Leukotriene-B4, C4, D4, prostaglandin D, PAF
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Allergic rhinitis (Hay fever)
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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 (11000)
plus i.v. antihistamine, i.v.hydrocortisone and
oxygen
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Skin (prick) test for allergy
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Type II (antibody mediated) hypersensitivity
Antibody to tissue bound or cellular antigen
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Type II hypersensitivityrole of complement and
phagocytes
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Type II hypersensitivity induced by exogenous
agents
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Mechanism and prevention of Rhesus disease
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Rhesus disease of the newborn a type II
hypersensitivity disease
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Stimulatory and blocking antibodies in type II
hypersensitivity
Stimulatory Abs TSH receptor in Graves
disease Blocking Abs ACh R in myasthenia
gravis intrinsic factor in pernicious
anaemia insulin receptor in diabetes
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Myasthenia gravisthe mechanism
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Graves disease
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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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Type III hypersensitivity mechanism
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Arthus reaction
Arthus reaction Type-III
Weal flare reaction Type-I
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Serum sickness
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Early and late joint changes in rheumatoid
arthritis
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Typical butterfly malar rash in SLE
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Type IV (delayed) hypersensitivity
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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

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Tuberculin test
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Contact hypersensitivity (to nickel)
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Contact dermatitis reaction to leather
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Granuloma in a leprosy patient
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Type IV hypersensitivity and coeliac disease
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Type IV hypersensitivitythe three forms
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Patch testing for contact hypersensitivity
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Summary or hypersensitivity reactions
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Autoimmunity and autoimmune disease
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Peripheral tolerance
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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)

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Autoantibodies and autoimmunity
(Some) autoantibodies of clinical significance in
organ specific and non-organ specific autoimmune
disease Antigen Distribution Disease thyroi
d peroxidase thyroid gland Hashimotos
thyroiditis TSH receptor thyroid gland Graves
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 rheumato
id factor immunoglobulin Fc rheumatoid
arthritis dsDNA all cells SLE
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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
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• 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

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• 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
  life-
• threatening, and is effectively treated with
  i.m. adrenaline
• In many autoimmune diseases, there is overlap
  between
• different types of hypersensitivity reaction