Antibody-dependent cellular cytotoxicity
An antibody can combine with a cell-associated antigen such as a tumor or viral antigen, but if the antibody is not a subclass that activates complement, it may not induce cytotoxicity. However, because the Fc tail of the antibody is exposed, various leukocytes recognize the Fc domain and are directed to the cell through the antibody. Binding to the antibody then activates various leukocyte cytotoxic mechanisms, including degranulation and cytokine production.
Because human leukocytes express various types of Fc receptors—IgG subclasses have 3 different Fcg receptors, IgE has 2 different Fce receptors, and so on—leukocyte subsets differ in their capacity to recognize and bind different antibody isotypes. Classically, antibody-dependent cellular cytotoxicity (ADCC) was observed to be mediated by a subset of large granular (non-T, non-B) lymphocytes, called killer cells, that induce cell death in a manner similar to CTLs. The killer cell itself is nonspecific but gains antigen specificity through interaction with specific antibody. Macrophages, NK cells, certain T lymphocytes, and neutrophils can also participate in ADCC using other Fc receptor types. An IgE-dependent form of ADCC may also exist for eosinophils.
ADCC is presumed to be important in tumor surveillance, antimicrobial host protection, graft rejection, and certain autoimmune diseases, such as cutaneous systemic lupus erythematosus. However, this effector mechanism probably does not play an important role in uveitis, although it might contribute to antiparasitic immunity.
Acute IgE-mediated mast-cell degranulation
Mast cells bind IgE antibodies to their surface through a high-affinity Fc receptor specific for IgE molecules, positioning the antigen-recognition site of the bound IgE externally (Fig 2–9). Combining 2 adjacent IgE antibody molecules with a specific allergen causes degranulation of the mast cell and release of preformed and de novo synthesized mediators within minutes. This acute inflammatory reaction is called immediate hypersensitivity (previously termed Coombs and Gell type I, or anaphylaxis).
Preformed mediators include histamine, serotonin, proteoglycans (heparin), neutral proteases (ie, tryptase, chymase), chemotactic factors (eosinophil, neutrophil, or monocyte), and possibly basic fibroblast growth factor. Among the newly generated mediators are the arachidonic acid metabolites prostaglandin D2, leukotrienes, and thromboxane as well as Th2-type cytokines (IL-4, IL-5, IL-6, IL-9, IL-10, IL-13), TNF-α, IL-1, and CCL2.
The resulting effects include vasodilation, increased capillary permeability, contraction of bronchial and gastrointestinal smooth muscle, and increased mucous secretion in mucosal sites. Mast cell-derived cytokines play a role in the late phase of allergic response by activating endothelial cells to recruit eosinophils and other inflammatory cells at the site of hypersensitivity reactions, thus sustaining inflammation. When severe, the immediate hypersensitivity response can produce a systemic reaction, with manifestations ranging from generalized skin lesions, such as erythema, urticaria, or angioedema, to severely altered vascular permeability with plasma leakage into tissues and airway obstruction or hypotensive shock.
Figure 2-9 Schematic representation of IgE-mediated mast cell degranulation.
Delves PJ, Martin SJ, Burton DR, Roitt IM. Roitt’s Essential Immunology. 13th ed. Hoboken, NJ: Wiley-Blackwell; 2017.
Muranski P, Restifo NP. Essentials of Th17 cell commitment and plasticity. Blood. 2013;121(13):2402–2414.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.