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Immunology and Immunological Disorders > Hypersensitivity Reactions > Flashcards

Hypersensitivity Reactions Flashcards

1
Q

What is hypersensitivity?

A

A hypersensitivity reaction is an exaggerated or inappropriate immune response that is to an antigen/immunogen, causing tissue damage
- Evidence that both adaptive and innate responses are involved
-> Involvement of pattern recognition receptors (PRRs)

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2
Q

Gell and Coombs Classification

A

Type - Mediator - Examples
Type I (Immediate) - IgE antibody - Hay fever and allergic asthma
Type II (Cytotoxic) - IgG and IgM antibodies - Transfusion reactions
Type III (Complex Mediated) - IgG and IgM antibodies - Farmer’s lung
Type IV (Delayed) - T-lymphocytes and macrophages - Contact dermatitis

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3
Q

Type I

A
  • IgE mediated hypersensitivity
  • Ag induces cross-linking of IgE bound to mast cells and basophils with release of vasoactive mediators
  • Typical manifestation include systemic anaphylaxis and localised anaphylaxis such as hay fever, asthma, hives, food allergies and eczema
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4
Q

Type II

A
  • IgG and IgM mediated cytotoxic hypersensitivity
  • Ab directed against cell surface antigens mediates cell destruction via complement activation or ADCC
  • Typical manifestation include blood transfusion reactions, erythroblastosis fetalis, and autoimmune haemolytic anaemia
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5
Q

Type III

A
  • IgG and IgM mediated hypersensitivity - immune complex
  • Ag-ab complexes deposited into various tissues induce complement activation and ensuing inflammatory response mediated by massive infiltration of neutrophils
  • Typical manifestations include localised Arthus reaction and generalised reactions such as serum sickness, necrotizing vasculitis, glomerulunephritis, rheumatoid arthritis, and systemic lupus erythmetatosus
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6
Q

Type IV

A
  • Cell-mediated hypersensitivity
  • Sensitized Th1 cells release cytokines that activate macrophages or Tc cells that mediate direct cellular damage. Th2 cells and CTLs mediate similar responses
  • Typical manifestations include contact dermatitis, tubercular lesions and graft rejection
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7
Q

Type I Hypersensitivity

A
  • An immediate reaction after contact with an immunogen
  • Also known as ‘immediate hypersensitivity’
  • The imunogen is referred to as an allergen
  • A humoral response involving the prodcution of IgE antibody by plasma cells
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8
Q

World prevalence of allergy

A
  • IgE production is a normal response to parasitic infections
  • Most multicellular parasites do not multiply in the body
  • Too big to phagocytose
  • Trigger a Th2 response
  • > B-cells produce parasite-specific IgE
  • > Triggers an inflammatory response
  • > Ejects parasites from human host
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9
Q

Hygeine hypothesis

A
  • Parasitic infections - endemic to tropical countries
  • Epidemic allergy affects the industrialised countries
  • Inverse correlation between incidence of parasitic infection and of allergic disease
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10
Q

Type I Hypersensitivity

A
  • IgE binds to Fc receptors on the surface of mast cells and basophils
  • Reactions due to specific triggering of IgE-sensitised mast cells by the allergen
  • Leads to release of:
  • > Pharmacological mediators of inflammation (asthma, hayfever)
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11
Q

Allergens

A
  • Allergen is an immunogen that causes an allergy
  • Pollen
  • Animal dander
  • House dust
  • Mice faeces
  • Some food
  • Bee venom
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12
Q

Allergenicity

A
  • Sensitisation route
  • Genetics of recipient
  • Ability to evoke a Th2 mediated response
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13
Q

Features of inhaled allergens that favour type 2 immunity and IgE production

A

Molecular type - Proteins: induce T-cell response
Function - Many allergens are proteases
Low dose - Favours activation of IL-4 producing TH2 cells
Low molecular mass - Allows allergen to diffuse from particle to mucus
High solubility - Allergen readily elutes from particle
High stability - Allergen survives in desicated particles
Has peptides presented by MHC class II - Needed for T-cell activation

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14
Q

What is atopy?

A
  • Atopy is the genetic predisposition to produce IgE
  • > Subjects with a family history of Type I hypersensitivity
  • > Abnormal serum IgE levels = 0.1 - 0.4/ml
  • > Levels X10 in atopics
  • The inherited atopy is multigenic, mapped to several loci
  • Chromosome 5: coding region for IL-3, -4, -15, -13, GM-CSF
  • Chromosome 11: beta chain of high affinity IgE
  • Chromosome 6: MHC genes
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15
Q

IgE receptors

A
  • Two types found on different cell types and differ 1000 fold in their affinity for IgE
    -> High affinity receptor FcRI (kd = 1-2 X10-9)
    -> Low affinity receptor FcRI (kd = 1X10-6)
  • Bound IgE is stable for weeks, not days
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16
Q

IgE high affinity receptor FcERI

A
  • Expressed constitutively on mast cells and basophils
  • Can bind IgE in serum despite its low concentration
  • Also expressed in low levels in eosinophils, monocytes and platelets
  • Receptor has 4 polypeptide chains: alpha, beta and 2 identical gamma chains OR alpha and two gamma chains (on monocytes and platelets)
17
Q

Low affinity IgE receptor FcERI

A
  • Has a single membrane spanning domain
  • Two isoforms: CD23, CD23a
  • Protolytic cleavage of CD23 generates soluble CD23
18
Q

The role of the mast cell

A
  • Key cell in the orchestration of the inflammatory response
  • Found in skin, connective tissue and mucosal epithelial tissue of respiratory, digestive and genitourinary tract
    -> Express high affinity IgE receptors on their surface
    -> Can rapidly sense PAMPs and DAMPS via PRRs expressed in/on cell surface
  • Many cytoplasmic granules
    -> Contained preformed mediators
    -> Membrane derived mediators
19
Q

Mast cell degranulation

A
  • Initiated by: IgE cross-linkage
    -> Anaphylatoxins: C3a, C5a
    -> Drugs
20
Q

IgE receptor cross-linkage

A
  • Activates protein tyrosine kinase (lyn)
  • Leads to phosphorylation reactions and generation of second messenger
  • Uptake of extracellular calcium and the release of intracellular calcium stores
  • Activation of phospholipase A2 enzyme, leading to the formation of arachidenic acid and the generation of membrane derived mediators
21
Q

Type I - Sequence of Events

A
  • Allergen absorbed through mucosa
  • APC presents processed allergen
  • B-cells produce specific IgE with T-cell help
  • Allergen specific IgE binds to mast cells via Fc receptors
  • Re-exposure: Allergen cross-links surface-bound IgE
  • Mast cell degranulation
    Example
    A first exposure to pollen, extraction of pollen allergens, activation of antigen-specific TFH2 cells. TFH2 cell activates B-cells to secrete IgE, IgE binds to FcE and arms mast cells
22
Q

Consequences of Type I

A
  • Anaphylactic shock - usually due to systemic release of mast cell mediators
  • Anaphylaxis is a generalised type I reaction, leading to vasodilation and constriction of bronchial smooth muscle
  • Food allergies - local or systemic anaphylaxis
  • Hay fever (allergic rhinitis) - affects about 10% of the population due to airborne allergens triggering mast cell degranulation in nasal mucosa
  • Allergic asthma - lower respiratory tract:
    -> Bronchial hyperreactivity
    -> Inflammatory infiltrate into the mucosa and submucosa
    -> Epithelial layer damage
    -> Goblet cell hyperplasia and excessive mucous secretion
    -> Oedema
    -> Bronchoconstriction
23
Q

House dust mite induced allergic asthma

A
  • HDM protease allergens disrupt epithelial barrier function
  • Tissue injury - DAMPs
  • Cytokine upregulation
  • Eosinophil recruitment
24
Q

Type II Hypersensitivity

A
  • Also known as cytotoxic hypersensitivity
  • Antibodies directed against antigens on surface of specific cells or tissues
  • Involves antibodies IgM and IgG
  • The antibodies interact with complement components and immune cells
25
Q

Consequences of antibody binding to cell surface antigen:

A
  • Complement activation leads to:
    -> Cell lysis
    -> Deposition of complement components (opsonisation)
    -> Macrophage and neutrophil activation
    • Lysosomal content release - localised damage
  • Antibody dependent cell-mediated cytotoxicity
    -> Cytotoxic cell binds to the Fc portion of the bound antibody via its FcR

Examples
- Blood transfusion
- Haemolytic disease of the newborn
- Hyperacute graft rejection
- Reactions to tissue antigens
- Goodpasture’s syndrome (reaction to basement membrane antigens)

26
Q

Antibodies to ABO antigens (isohaemaglutinins - IgM)

A

Genotype - blood group phenotype - antigens on erythrocytes - serum antibodies

AA - A - A - Anti-B
BB or BO - B - B - Anti-A
AB - AB - A and B - None
OO - O - None - Anti-A and Anti-B

27
Q

Haemolytic disease of the newborn

A
  • Erythroblastolis fetalis
  • Due to rhesus incompatibility
  • 85% of population are Rh+ and 15% are Rh-
  • Antibodies to Rh antigens are not normally present in Rh- people
  • Sensitisation occurs in women after delivery of RH+ baby
  • Rh antibodies are IgG: cross-placenta
  • Problems with second or subsequent pregnancies with Rh+ babies
28
Q

Effects of anti-Rh antibodies

A
  • Spontaneous abortion
  • Baby born with mild jaundice
  • Baby born with haemolytic disease of the newborn
    Prevention:
  • > Treat mother with anti-Rh antibodies (Rhogam) within 72 hours of birth of each Rh+ child
  • > Anti-Rh antibody bind RBC, before B-cell activation
29
Q

Goodpasture’s Syndrome

A
  • Reaction to basement membrane antigen
30
Q

Type III Hypersensitivity

A
  • Antibodies directed against soluble antigens in serum
  • Can also be directed against widely distributed antigen
  • Deposited antigen-antibody complexes lead to damage in affected organs
  • > Activate complement, initiate inflammation
  • Also known as immune complex hypersensitivity
  • Examples:
    -> In persistent infection
    • Antibodies formed against microbial agents (eg. chronic hepatitis B)
      -> In auto immunity
    • Antibodies formed against self-antigens
    • Immune complexes deposited in the kidney , joint, arteries, skin and lungs
31
Q

Type III Reactions

A
  • Localised
    -> Arthus reaction
  • Generalised
    -> Serum sickness
32
Q

The Arthus Reaction

A
  • Appears within 4 - 8 hours after infection (intradermal, subcutaneous) of an antigen into an animal which has high levels of circulating antibodies
  • Leads to complement activation (C3a, C5a), mast cell degranulation, neutrophil chemotaxis
  • Neutrophils unable to phagocytose the immune system complexes, leading to release of lytic enzymes and resultant tissue damage
33
Q

Intrinsic allergic alveolitis

A
  • An occupational disease due to inhalation of immunogenic proteins or spores:
    Examples:
  • > Farmer’s lung
    -> Mushroom workers disease
    -> Coffee worker’s disease
    -> Cheese worker’s disease
34
Q

Farmer’s lung

A
  • Starts with a mild cough in winter
  • Progressively worse over successive winters
  • Due to sensitisation to spores of thermophilic acitinmyocytes which grow in damp hay
  • Years of exposure lead to high levels of circulating IgG to spore antigens
    Immune complexes (IgG/antigen) precipitate in lung
  • Complement activated -> inflammation
  • Destruction of alvcolar tissue; fibrosis of damage
    Treatment; early diagnosis and avoidance; corticosteroids
35
Q

Type IV hypersensitivity

A
  • Called DTH: Delayed Type Hypersensitivity reaction
  • Takes > 12 hours to develop
  • Can develop within 72 hours of after weeks of exposure
  • Mediated by T-lymphocyte and macrophages
  • Example: The tuberculin test
    -> Determines previous infection by M. tuberculosis or previous exposure to BCG vaccine
  • Includes ‘contact hypersensitivity’
    -> Reaction to nickel, chemicals
36
Q

Contact hypersensitivity

A
  • Sensitisation: initial contact leads to a cell-mediated immune response; requires Langerhans cells
  • Chemicals are not immunogens but act as haptens after binding to skin proteins
  • Subsequent contact: Th1 respond to the APC by releasing cytokines
  • Cytokines attract and activate monocytes

-Developed a delayed-type hypersensitivity reaction
- After a second exposure to poison oak
- Cytokines such as IFN-, macrophage- chemotactic factor (MEF) and migration inhibition factor (MIF) released from sensitised TH1 cells mediate this reaction
- Tissue damage results from lytic enzymes released from activated macrophages

37
Q

Coeliac disease

A
  • A chronic condition of the upper small intestine
  • Allergic and autoimmune features
  • Reaction to gluten (antigen is gliadin)
    -> Also termed gluten-sensitive enteropathy
  • Increased T-lymphocytes, macrophages
  • Consequences:
    -> Villous atrophy in small bowel
    -> Malabsorption
  • Peptides produced from gluten (eg. Giadin) do not bind to MHC II molecules
  • Tissue glutaminase (an enzyme) modify gliadin now binds to APC
  • Giddin consequent activation of T-lymphocytes and cytokine release -> activate/kill epithelial cells

Immunology and Immunological Disorders (8 decks)

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