Hypersensitivity Flashcards
Hypersensitivity
Excessive or abnormal secondary immune response to a sensitizing agent
Allergen
IgE mediated disease, require sensitization
Affects only those that are sensitized to the allergen
Not dose-dependent
Irritants
Not mediated through IgE
Dose dependent response, affects all
Type I Hypersensitivity
Mast cell and/or basophil dependent (IgE-dependent)
Initial response is immediate (within 15 mins)
Degranulates releasing preformed mediators
Histamine
Short half-life
Only produced by mast cells and basophils
At least 3 receptors (H1-3R)
Role of H1/H2R
Toxic to parasites
Increases vascular permeability
Causes smooth muscle contraction
Heparin
Released by mast cells
Similar effects as histamine
Mast Cell Enzymes
Tryptase: Two forms (Alpha - Constitutively, Beta - Activated mast cell)
Identifiable in serum for up to 4 hours after release
Only mast cells make this protein
Single best marker of mast cell activation
Leads to remodeling of connective tissue matrix
Chymase, Cathespin G, Carboxypeptidase: Remodeling of connective tissue matrives
Mast Cell Cytokines
IL-4/13: Associated with Th2 cells and lead to Ig class switching in B cells to the production of IgE IL-3/5, GM-CSF: Promote the survival and activation TNF: Activates endothelium and leads to adhesion molecule expression, some exists as preformed mediator
Mast Cell Chemokines
MIP-1a (CCL3): Chemotactic for monocytes/macrophages/neutrophils/T cells/eosinophils
RANTES (CCL5) and Eotaxin (CCL11): Chemotactic for T cells and eosinophils
Mast Cell Lipid Mediators
Leukotrienes C4, D4, E4: Eosinophil migration, smooth muscle contraction, vascular permeability, mucus hypersecretion
Platelet activating factor (PAF): Attracts eosinophils and other leukocytes; activates eosinophils, neutrophils, and platelets; increases production of lipid mediators
What reduces the threshold for histamine release?
Cytokines/chemokines Antigen exposure Histamine-releasing factor Autoantibody Psychological factors
What increases the threshold for histamine release?
Corticosteroids
Antihistamines
Cromolyn (in vitro)
What results in elevated eosinophil count?
Neoplasia Asthma Allergy Connective tissue disease Parasitic disease
What is CCR3 for?
Eosinophil receptor for Eotaxin (only known receptor) and RANTES (CCL5)
What do corticosteroids result in?
Induce rapid apoptosis of eosinophils
Inhibit the production of IL-5
Inhibition of AP-1 and NFkB via GRa
What produces IL-5?
Th2 lymphocytes and other cells
IL-5 effects in vitro on eosinophils
Prolongs survival, enhances leukotriene production, cytotoxicity for parasites
Augments B2 integrin-mediated adhesion and transendothelial migration
IL-5 effects in vivo
Infusion causes eosinophilia
Levels increased in some diseases with eosinophilia
Levels increased in fluids obtained from sites of experimental allergic late phase reactions
Function of lysophospholipase
Degrades lysophospholipids
Function of MBP
Mast cell activation, helminthotoxic
Function of ECP
Same as MBP plus neurotoxic
Function of EDN
Neurotoxin
Function of PAF
Bronchoconstriction and activates platelets
Function of LTC4
Bronchoconstriction, mucus hypersecretion, edema
Examples of Type I hypersensitivity
Allergic Rhinitis
Asthma
Anaphylaxis
Urticaria
What causes allergic rhinitis?
Due to cross-linking of IgE in nasal mucosa and ocular conjunctiva with specific antigen exposure
Systemic symptoms are rare
Mechanism of Asthma
Symptoms are due in part to IgE mediated disease in lower airways
Wheezing, shortness of breath due to increased airway constriction (prevents exhalation)
Increased mucus secretion and production (mucus plugging)
Definition of Type II hypersensitivity
Antibody (IgG or IgM) binding to cell or matrix bound antigen
Mechanism of Type II hypersensitivity
Phagocytic or NK cells bind ot the antibody via their Fc receptor
Target tissue is then destroyed
Complement may be involved (increases binding via C’ receptors on phagocytic cells)
Mechanism of drug based Type II hypersensitivity
IgG is formed against drug-cell antigen
Erythrocytes and platelets are targeted resulting in spleen damage
Only targets cell-bound drug
Examples of drug based Type II hypersensitivity
Penicillin, Quinidine, Methyldopa
Definition of Type III hypersensitivity
Antibody (IgG) against a soluble antigen
Mechanism of Type III hypersensitivity
Antigen-antibody complex activates complement
Activate FcyR expressing cells and complement
Large complexes cleared by phagocytes
Small complexes precipitate on blood vessel walls where leukocytes bind and activate against them
Where is there high risk for Type III hypersensitivity?
Highly vascularized beds with narrow vessels, where the complexes are most likely to precipitate on the endothelial walls
Specifically: Kidneys, vessels, joints, and skins
What cells are recruited with Type III hypersensitivity and what do they do?
Phagocytes (neutrophil predominant) release their lysosomal enzymes and cause tissue destruction
Arthus reaction
Type III reaction when skin being sensitized when exposed to specific antigen
Involves activation of mast cell and other leukocytes via FcyRIII and not complement
Serum sickness
Type III systemic reaction from injection of large quantities of foreign protein
Timeframe of serum sickness
Reaction happens 7-10 days post exposure (time length for IgM to IgG) which is the peak of Ag-Ab complexes
Ag drops below Ab post this point
Next exposure will have a much shorter time course
Symptoms of serum sickness
Flu-like, urticarial rash, arthritis, glomerulonephritis
Farmer’s lung
Alveolitis due to a type III reaction against hay dust or mold spores
Inflammation in and destruction of the alveolar wall
Examples of systemic antigen excess situations (Type III)
Autoimmune diseases
Infections: Viral hepatitis or subacute bacterial endocarditis
Recurrent antigen production
Definition of Type IV hypersensitivity
Cell-mediated reaction (No antibodies)
Mechanism of Type IV hypersensitivity
Antigen enters the skin (typically target) and then binds to self proteins
Bound antigen must be taken up and processed by APCs to T-cells
24-72 hour latency to reaction
Involves CD4+ Th1 cells or CD8+ T cells
Mediators important in Type iV and role
IFN-y: Induces expression of adhesion molecules, activates macrophages
TNFa and Lymphotoxin (LT): Local tissue destruction, induces expression of adhesion molecules
IL-3 and GM-CSF: Stimulate monocyte production
Chemokines: Recruit macrophages to site
Tuberculin response
Type IV hypersensitivity reaction where TB derived peptides are injected in skin
Th1 mediated response develops in 48-72 hours for previously exposed individuals
What are contact hypersensitivity reactions and what is an example?
Chemical exposure to skin where compounds bind with self proteins and generate a response with extensive macrophage mediated inflammation
Example: Poison ivy or Rhus Dermatitis (due to pentadecacatechol)
