Hypersensitivity Reactions Flashcards
What is hypersensitivity?
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)
Gell and Coombs Classification
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
Type I
- 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
Type II
- 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
Type III
- 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
Type IV
- 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
Type I Hypersensitivity
- 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
World prevalence of allergy
- 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
Hygeine hypothesis
- Parasitic infections - endemic to tropical countries
- Epidemic allergy affects the industrialised countries
- Inverse correlation between incidence of parasitic infection and of allergic disease
Type I Hypersensitivity
- 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)
Allergens
- Allergen is an immunogen that causes an allergy
- Pollen
- Animal dander
- House dust
- Mice faeces
- Some food
- Bee venom
Allergenicity
- Sensitisation route
- Genetics of recipient
- Ability to evoke a Th2 mediated response
Features of inhaled allergens that favour type 2 immunity and IgE production
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
What is atopy?
- 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
IgE receptors
- 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
IgE high affinity receptor FcERI
- 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)
Low affinity IgE receptor FcERI
- Has a single membrane spanning domain
- Two isoforms: CD23, CD23a
- Protolytic cleavage of CD23 generates soluble CD23
The role of the mast cell
- 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
Mast cell degranulation
- Initiated by: IgE cross-linkage
-> Anaphylatoxins: C3a, C5a
-> Drugs
IgE receptor cross-linkage
- 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
Type I - Sequence of Events
- 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
Consequences of Type I
- 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
House dust mite induced allergic asthma
- HDM protease allergens disrupt epithelial barrier function
- Tissue injury - DAMPs
- Cytokine upregulation
- Eosinophil recruitment
Type II Hypersensitivity
- 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
Consequences of antibody binding to cell surface antigen:
- 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)
Antibodies to ABO antigens (isohaemaglutinins - IgM)
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
Haemolytic disease of the newborn
- 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
Effects of anti-Rh antibodies
- 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
Goodpasture’s Syndrome
- Reaction to basement membrane antigen
Type III Hypersensitivity
- 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
- Antibodies formed against microbial agents (eg. chronic hepatitis B)
Type III Reactions
- Localised
-> Arthus reaction - Generalised
-> Serum sickness
The Arthus Reaction
- 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
Intrinsic allergic alveolitis
- 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
Farmer’s lung
- 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
Type IV hypersensitivity
- 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
Contact hypersensitivity
- 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
Coeliac disease
- 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
