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Type 1: Allergy

Type I hypersensitivity (most commonly allergies) stem from overproduction of IgE. Thus, it requires an initial encounter so that isotype switching can occur -- in secondary responses, the IgE crosslinks the antigen (and F(c)εRI and causes mast-cell and basophil degranulation.

Atopic allergies and asthmatics are becoming more common in economically developed nations. This is due to changes in exposure to childhood infectious disease (atopy is negatively associated with measles, hepatitis A or tuberculosis infections), environmental pollution (diesel exhaust enhances TH2 responses, leading to higher IgE production), allergen levels (crazy cat ladies) and dietary changes.

IL-4 is pivotal in regulating the IgE response: IgG1 and IgE account ∼2% of all antibodies secreted by splenic B cells incubated with LPS; IgG1 accounts for ∼50% and IgE accounts for ∼20% of all antibodies secreted by B cells incubated with LPS and IL-4. IL-4 knockout mice cannot mount an IgE response to parasites. IL-4 stimulates isotype switching by activating the promoters for Iε, and Iγ1 (the I regions for ε and γ1 isotype genes). TH1 cells enhance response to IL-3, IL-4 and IL-10. TH2 cells reduce response to IFN-γ.

What Determines IgE Response?

Ag DoseRepeated low antigen doses usually elicit an IgE response, while higher antigen doses elicit switch to IgG.
Ag PresentationAdjuvants alter the immune response without changing the antigen; certain adjuvants can bias toward IgE response.
GenotypeThe individual's genotype (outside of MHC) can predispose to allergies. For example, mutations in the IL-4 gene promoter lead to constitutive IL-4 expression and excessive IgE levels.

Primary Mediators of Type I Hypersensitivity

Histamine and serotoninHistamine and serotonin increase vascular permeability and induce smooth-muscle contraction.
ECF-AEosinophil chemotactic factor attracts eosinophils.
NCF-ANeutrophil chemotactic factor attracts neutrophils.
ProteasesBronchial mucus secretion, degradation of blood vessel basement membrane and generation of complement cleavage products (such as C3a and C5a).

Secondary Mediators of Type I Hypersensitivity

PAFPlatelet-activating factor (PAF) induces platelet aggregation and degranulation, as well as contraction of pulmonary smooth muscles.
LeukotrienesLeukotrienes are slow reactive substances of anaphylaxis (SRS-A) that increase vascular permeability and induce contraction of pulmonary smooth muscles.
ProstaglandinProstaglandins induce vasodilation, contraction of pulmonary smooth muscles, platelet aggregation and itching.
BradykininBradykinin increases vascular permeability and induces smooth-muscle contraction.
IL-1 & IFN-αThese two cytokines induce systemic anaphylaxis and increased expression of CAMs on blood vessel endothelial cells.
IL-4 & IL-13IL-4 & -13 stimulate IgE production.
Their effects are described here.

Types of Allergic Reactions

AnaphylaxisDisseminated mast-cell activation causes widespread vasodilation, causing a catastrophic loss of blood pressure, constriction of airways and epiglottal swelling that frequently causes suffocation.
Wheal & Flare RxnLocal mast-cell activation in skin causes local vasodilation and extravasation of fluid.
Allergic RhinitisAllergic rhinitis (aka hay fever) is caused by mucosal MCs beneath nasal epithelium activating to cause sneezing and a runny nose.
Allergic AsthmaActivation of submucosal MCs in lower airways.
UrticariaAka hives, urticaria is activation of skin mast-cells usually by ingested allergens carried via blood.

Drug Treatments for Allergies

AntihistaminesBlock H1 and H2 receptors on target cells.
CortisoneReduces histamine levels by blocking histadine to histamine conversion, and stimulates mast-cell cAMP production.
Cromolyn SodiumBlock Ca2+ influx into mast-cells.
EpinpephrineAka adrenaline: prevents degranulation by stimulating cAMP production via binding β-adrenergic receptors on mast-cells; relaxes smooth muscle; reduces vascular permeability; improves cardiac output to avoid cardiac collapse.
TheophylineBlocks phosphodiesterase, prolonging high mast-cell cAMP levels and prevent degranulation.

Type 4: Delayed-Type Hypersensitivity

Delayed-type hypersensitivity (DTH) is a TH1-mediated localized inflammatory reaction that effectively clears intracellular pathogens (such as viruses) and contact allergens (such as poison oak and poison ivy).

DTH is characterized by large influxes of inflammatory cells (like mφs), tissue damage and delayed onset. DTH reactions functional antibodies and a functional complement system; it cannot occur without B1 cells nor C5. There are two phases related to delayed-type hypersensitivity:

SensitizationThe sensitization phase occurs 1-2 weeks following primary antigen contact; TH1 cells proliferate in response to presented antigens (APCs include Langerhans cells, mφs and thymus vascular endothelial cells). Occasionally CD8 (cytotoxic thymocytes) will also proliferate in response to this antigen presentation.
EffectorThe effector phase peaks 48-72 hours after subsequent antigen exposures, and involves tremendous cytokine secretion that amplifies inflammatory cells. These inflammatory cells are almost entirely not antigen-specific, and show increased phagocytosis and APC activity.

Contact allergens (such as poison oak) are usually small molecules which complex with skin proteins; these complexes are internalized by Langerhans cells (APCs found in skin) and then presented to TH cells. Also, when DTH is continuously activated, normal tissue is damaged due to a continuous assault of lytic enzymes. This can occur in the lungs of Mycobacterium tuberculosis patients, as well as lesions in Mycobacterium leprae patients.