Hypersensitivity
Type I Hypersensitivity (IgE)
Triggered by allergens, causes immediate allergic reactions.
After allergen presentation from APCs activates T cells, becoming TH2 cells. TH2 releases IL-4, causing B cells to switch classes from IgM to IgE antibodies (specific to the antigen). It also releases IL-5 which activates and produces eosinophils.
Upon re-exposure to the allergen, IgE binds Fc on mast cells and causes them to release histamine. At the late phase (8-12 hours), IL4, 5, and 10 are released, leading to prolonged inflammatory response.
Type II Hypersensitivity
Antibody mediated, where IgG or IgM are directed against host cells. Leads to destruction of healthy cells. Self-reactive B come from defective central tolerance when negative selection fails. Intrinsic antigens are what the host cell makes, while extrinsic antigens are from some medications (e.g. penicillin).
This is the culprit in ABO mismatch.
Mechanism 1A: Complement System
IgG and IgM activates complement proteins which will kill the host cell that's bound to the antigen that's complexed with the immunoglobulins.
For example, a penicillin allergy. Penicillin binds to a red blood cell and activates complement. The chemotactic factors attract neutrophils, which kill the RBC. This can result in hemolytic anemia, thrombocytopenia, or neutropenia.
Antibodies binding to intrinsic antigens on collagen in kidney glomeruli or lung alveoli can also cause Goodpasture's syndrome.
Mechanism 1B: Complement System + MAC
After activation of complement results in the membrane attack complex on host cells.
Mechanism 2: Phagocytosis
IgG antibodies coat the target cell and bind C3b. This complex marks the cell for opsonization.
In the spleen, macrophages recognize IgG antigens and phagocytose
In the liver, Kupffer cells (liver macrophages) recognize C3b antigens and phagocytose
Mechanism 3: Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
NK cells recognize IgG/C3b and bind the Fc part of the antibody, and kill the cell via perforins, granzymes, and granulysins.
Mechanism 4: Antibody-Mediated Cellular Dysfunction
Antibody binds to the cell and impairs physiologic function just by being annoying and present.
Antibodies specific to acetylcholine receptors in muscle result in myasthenia gravis.
Antibodies specific for receptors which stimulate thyroid hormone production can result in Graves' disease (hypothyroidism).
Type III Hypersensitivity
Mediated by immune complexes which bind to soluble antigens (in plasma). These float around in blood longer and are less immunogenic. The clinical symptoms appear where immune complexes are deposited and complement proteins are rapidly consumed.
IgG antibodies bind to the soluble antigens, which deposit on the basement membrane of blood vessels. This activates the complement system, specifically C3a, C4a, and C5a, an cases edema. C3 and C4 are rapidly consumed here.
In response to complements, neutrophils degranulate and cause vasculitis.
Clinical pearls
Localized symptoms
Synovial joints: Arthritis
Kidneys (urine): Glomerulonephritis
Blood vessels: Vasculitis
Systemic lupus erythematosus
IgG is specific for DNA, and binding creates an IgG/DNA autoantigen. This leads to damage in multiple organ systems.
Serum sickness
After receiving antivenom, the body makes antibodies and forms complexes upon re-exposure.
Hypersensitivity Pneumonitis (HP, Farmer's lung)
Inhaled antigens deposit in the lungs and cause an immune reaction upon re-exposure.
Type IV Hypersensitivity
A delayed (24-72 hour), T-cell mediated reaction which cause inflammation and tissue damage.
Mechanism 1: CD4+
A T cell binds the TCR and CD4 co-receptor on an APC. The CD4 T cell also expresses a CD28 receptor, which binds B7 on the APC and results in release of signaling molecules which differentiate CD4 cells into TH1 or TH17.
IL-12 → TH1 cells → IL-2 (T cell proliferation) / INF-gamma → macrophages → TNF, IL-1, IL-6
IL-6 / TGF-beta → TH17 cells → IL-17 → neutrophil recruitment
CD8 cells are also activated via MHC Class I, triggering apoptosis in the target cell.
Clinical pearls
Type I diabetes mellitus
CD8 T cells attack pancreatic islet cells.
Hashimoto thyroiditis
CD8 cells attack thyroid epithelial cells.