Antibody-dependent cell-mediated cytotoxicity

Antibody-dependent cellular cytotoxicity.

The antibody-dependent cell-mediated cytotoxicity (ADCC) is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies.^[1] In humans, ADCC is usually mediated by IgG. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.^[2]

Classical antibody-dependent cell-mediated cytotoxicity is mediated by natural killer (NK) cells; but macrophages, neutrophils and eosinophils can also mediate it.^[1] For example, eosinophils can kill certain parasitic worms known as helminths through ADCC mediated by IgE.

ADCC is part of the adaptive immune response due to its dependence on a prior antibody response.

By NK cells

The typical ADCC involves activation of NK cells by antibodies. A NK cell expresses Fc receptors, mostly CD16. These receptors recognize, and bind to, the Fc portion of an antibody, such as IgG, which has bound to the surface of a pathogen-infected target cell. The most common Fc receptor on the surface of an NK cell is called CD16 or FcγRIII. Once the Fc receptor binds to the Fc region of IgG, the Natural Killer cell releases cytokines such as IFN-γ

During replication of a virus some of the viral proteins are expressed on the cell surface membrane of the infected cell. Antibodies can then bind to these viral proteins. Next, the NK cells which have Fc Receptors will bind to that antibody, inducing the NK cell to release proteins such as perforin and proteases known as granzymes, which causes the lysis of the infected cell to hinder the spread of the virus.

Furthermore, NK cells are involved in killing tumor cells and other cells that may lack MHC I on their surface, indicating a non-self cell. This is because, generally, all nucleated cells (which excludes RBCs) of the body contain MHC I.

By eosinophils

Large parasites like helminths are too big to be engulfed and killed by phagocytosis. They also have an external structure or integument that is resistant to attack by substances released by neutrophils and macrophages. After IgE coat these parasites, the Fc receptor (FceRI) of an eosinophil will then recognize IgE. Subsequently, interaction between FceRI and the Fc portion of helminth-bound IgE signals the eosinophil to degranulate.

In vitro

Several laboratory methods exist for determining the efficacy of antibodies or effector cells in eliciting ADCC. Among these methods include chromium-51 [Cr⁵¹] release assay, europium [Eu] release assay, and sulfur-35 [S³⁵] release assay. Usually, a labelled target cell line expressing a certain surface-exposed antigen is incubated with antibody specific for that antigen. After washing, effector cells expressing Fc receptor CD16 are co-incubated with the antibody-labelled target cells. Target cell lysis is subsequently measured by release of intracellular label by a scintillation counter or spectrophotometry.

A common challenge faced by ADCC assays is high background signaling due to cellular "leakiness". While both Cr⁵¹ and Eu-based assays face this challenge, S³⁵-containing methionine and cysteine pre-incubated with target cells leads to incorporation of radio-labelled molecules into newly translated peptides.

The coupled bioluminescent method aCella TOX is now in widespread use for ADCC and other cytotoxicity assessments. Since this technique measures the release of enzymes naturally present in the target cells, no labeling step is required and no radioactive agents are used.

Monoclonal antibody action against tumors

Experiments in mice indicate that ADCC is an important mechanism of action of therapeutic monoclonal antibodies, including trastuzumab and rituximab, against tumors.^[3] In the clinic the FcgRIII 158V/F polymorphism interfere with the ability to generate ADCC responses in vitro during trastuzumab treatment.

References

1 2 Hashimoto, G.; Wright, P. F.; Karzon, D. T. (1983-11-01). "Antibody-dependent cell-mediated cytotoxicity against influenza virus-infected cells". The Journal of Infectious Diseases. 148 (5): 785–794. doi:10.1093/infdis/148.5.785. ISSN 0022-1899. PMID 6605395.
↑ Pollara, Justin; Hart, Lydia; Brewer, Faraha; Pickeral, Joy; Packard, Beverly Z.; Hoxie, James A.; Komoriya, Akira; Ochsenbauer, Christina; Kappes, John C. (2011-08-01). "High-throughput quantitative analysis of HIV-1 and SIV-specific ADCC-mediating antibody responses". Cytometry Part A. 79 (8): 603–612. doi:10.1002/cyto.a.21084. ISSN 1552-4930. PMC 3692008. PMID 21735545.
↑ Clynes, RA; Towers, TL; Presta, LG; Ravetch, JV (2000). "Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets". Nat Med. 6 (4): 443–6. doi:10.1038/74704. PMID 10742152.

External links

University of Leicester, Virus Immunopathology Notes
Antibody-Dependent Cell Cytotoxicity at the US National Library of Medicine Medical Subject Headings (MeSH)

Hypersensitivity and autoimmune diseases (279.5–6)

Type I/allergy/atopy
(IgE)

Foreign	Atopic eczema Allergic urticaria Allergic rhinitis (Hay fever) Allergic asthma Anaphylaxis Food allergy common allergies include: Milk Egg Peanut Tree nut Seafood Soy Wheat Penicillin allergy

Autoimmune	Eosinophilic esophagitis

Type II/ADCC

- IgM
- IgG

Foreign

Hemolytic disease of the newborn

Autoimmune

Cytotoxic	Autoimmune hemolytic anemia Immune thrombocytopenic purpura Bullous pemphigoid Pemphigus vulgaris Rheumatic fever Goodpasture's syndrome Guillain–Barré syndrome

"Type V"/receptor	Graves' disease Myasthenia gravis Pernicious anemia

Type III
(Immune complex)

Foreign	Henoch–Schönlein purpura Hypersensitivity vasculitis Reactive arthritis Farmer's lung Post-streptococcal glomerulonephritis Serum sickness Arthus reaction

Autoimmune	Systemic lupus erythematosus Subacute bacterial endocarditis Rheumatoid arthritis

Type IV/cell-mediated
(T cells)

Foreign	Allergic contact dermatitis Mantoux test

Autoimmune	Diabetes mellitus type 1 Hashimoto's thyroiditis Multiple sclerosis Coeliac disease Giant-cell arteritis Postorgasmic illness syndrome Reactive arthritis

GVHD	Transfusion-associated graft versus host disease

Unknown/
multiple

Foreign	Hypersensitivity pneumonitis Allergic bronchopulmonary aspergillosis Transplant rejection Latex allergy (I+IV)

Autoimmune	Sjögren's syndrome Autoimmune hepatitis Autoimmune polyendocrine syndrome APS1 APS2 Autoimmune adrenalitis Systemic autoimmune disease

Immune disorders: Lymphoid and complement immunodeficiency (D80–D85, 279.0–4)

Primary

Antibody/humoral (B)

Hypogammaglobulinemia	X-linked agammaglobulinemia Transient hypogammaglobulinemia of infancy

Dysgammaglobulinemia	IgA deficiency IgG deficiency IgM deficiency Hyper IgM syndrome (1 2 3 4 5) Wiskott-Aldrich syndrome Hyper-IgE syndrome

Other	Common variable immunodeficiency ICF syndrome

T cell deficiency (T)

thymic hypoplasia: hypoparathyroid (Di George's syndrome)
euparathyroid (Nezelof syndrome
Ataxia telangiectasia)

peripheral: Purine nucleoside phosphorylase deficiency

Hyper IgM syndrome (1)

Severe combined (B+T)

x-linked: X-SCID
autosomal: Adenosine deaminase deficiency
Omenn syndrome
ZAP70 deficiency
Bare lymphocyte syndrome

Acquired

AIDS

Leukopenia:
Lymphocytopenia

Idiopathic CD4+ lymphocytopenia

Complement deficiency

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