Immune Complexes

Paul Eggleton, University of Exeter Medical School, Exeter, UK
Moazzam Javed, University of Exeter Medical School, Exeter, UK
David Pulavar, University of Exeter Medical School, Exeter, UK
Gemma Sheldon, University of Exeter Medical School, Exeter, UK

Published online: April 2015

DOI: 10.1002/9780470015902.a0001118.pub2

Abstract

Antigen–antibody complexes are formed when the body's immune system raises antibodies against antigenic determinants of host or foreign substances that recognise and bind to the antigen molecules. Normally, insoluble immune complexes that are formed are cleared by the phagocytic cells of the immune system, but when an excess of antigen–antibody are present, the immune complexes are often deposited in tissues, where they can elicit complement activation, localised inflammation resulting in the generation of tissue lesions in a variety of autoimmune diseases, exacerbating disease pathology. Conversely, exogenous antigen–antibody complexes can trigger specific cell‐mediated immunity when taken up, processed and presented with MHC class I molecules by dendritic cells. This results in direct priming of CD8+ cytotoxic T cells, by a process termed ‘cross‐presentation’. This can be of benefit in the induction of tumour protection and immunity against viral infections. Therefore, the generation of immune complexes can initiate both autoimmunity and protection against tumours and infectious agents.

Key Concepts

  • IgG and IgM are the two major classes of antibodies involved in immune complex formation.
  • The Fab region of antibodies can bind to many antigens comprising proteins, carbohydrates, nucleic acids or lipids.
  • In the blood circulation, small antigen–antibody complexes form soluble lattices when either antibody or antigen is present in excess.
  • When antigens and specific antibody are present in equivalent concentrations, large insoluble complexes can form, initiating an inflammatory reaction.
  • Insoluble immune complexes often deposit in joints and filtration organs (e.g. kidneys), leading to recruitment and activation of complement proteins and phagocytes.
  • The Fc portion of antibodies can bind to Fc receptors (FcRs) on cells and C1q, activating immune responses.
  • Tumour antigen–antibody complexes can activate dendritic cell maturation and promote the development of long‐lasting CD8 memory T cells against tumour antigens.
  • Viral antigens presented to T cells by dendritic cells results in rapid cellular immunity, while antigen–antibody complexes sustain the T‐cell effector memory.

Keywords: antibodies; antigens; complement; cross‐presentation; immune complexes diseases

Figure 1. Types of antibody–antigen complexes formed. (a) Antibodies of the class IgM, IgA, IgG or IgE can bind to IgG and form small soluble or larger insoluble complexes that are deposited in various tissues of the body. IgM rheumatoid factors are the most frequently formed and react with modified Fc regions of IgG. (b) Post‐translational modification of host proteins during stress can potentially lead to overstimulation of the immune response resulting in proteolytic fragments of self‐antigen eliciting an autoimmune response. (c) Peptides can be generated from host anti‐sense DNA or peptides from microbes that arose from DNA sequences homologous to anti‐sense DNA. The complementary peptides initiate the production of antibodies, which in turn trigger release of autoantibodies against self‐antigens. (d) The majority of circulating antibodies recognise and bind to either soluble ‘non‐self’ or foreign antigens or attach to epitopes on the surface of microorganisms, enhancing complement fixation and lysis of microorganisms, followed by clearance by phagocytes. (e) Antigen–antibody immune complexes can deposit in filtration organs such at the kidney and bind to the glomerular basement membrane, leading to complement activation and type III hypersensitivity inflammation.
Figure 2. Failure of maintaining self‐tolerance to antigens owing to post‐translational modification. (a) During the process of apoptosis, host proteins cluster in specific sub‐cellular compartments. Ribosomal antigens and endoplasmic reticulum proteins localise in small blebs, while nuclear autoantigens cluster in apoptotic bodies. These are then recognised by various systemic proteins such as C1q, C‐reactive protein and serum amyloid P and removed in a non‐inflammatory way by the phagocytic system. (b) However, if these clearance mechanisms are defective, then the apoptotic bodies and blebs eventually release their intracellular components, which can be proteolytically cleaved by a number of enzymes or modified by oxidative stress conditions. (c) Modification of proteins by proteolytic enzymes can expose cleavage sites in proteins or generate distinct amino acid fragments that are targets for antibody in various autoimmune diseases. These modifications include proteolytic cleavage by caspases or granzyme B, transglutamination, (de)phosphorylation and also citrullination. Non‐enzymatic modifications of proteins can arise from direct exposure to reactive oxygen, chlorine, sulphur or nitrogen species. These proteins can then be engulfed by professional antigen‐presenting cells and then present modified host peptides to helper T cells, which in turn can trigger effector B cells to generate antibodies against modified self‐peptides.
Figure 3. Antigen–antibody complexes can bind to professional antigen‐presenting cells and promote and sustain long‐lasting CD8 T‐cell immunity against microbial and tumour antigens. During tumour or virally infected cell death, antibodies previously generated by B cells can form antigen–antibody complexes that are taking up by dendritic cells via Fc receptors, triggering an ITAM‐dependent signalling pathway, ultimately leading to dendritic cell maturation and processing of antigens via MHC class I molecules to naïve T cells by a process of cross‐presentation. This leads to a long and sustained cytotoxic T‐cell response against antigens, greater than that can be achieved by presentation of antigen alone.
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Further Reading

Behnen M, Leschczyk C, Moller S, et al. (2014) Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac‐1. Journal of Immunology 193: 1954–1965.

Davies KA (1996) Complement, immune complexes and systemic lupus erythematosus. British Journal of Rheumatology 35: 5–23.

Janczy JR, Ciraci C, Haasken S, et al. (2014) Immune complexes inhibit IL‐1 secretion and inflammasome activation. Journal of Immunology 193: 5190–5198.

Lawley TJ (1995) Immune complexes. In: Frank MM, Austin K, Claman HN and Unanue ER, (eds). Smaster's Immunologic Diseases, 5th edn, pp. 321–330. Boston: Little Brown.

Maddison PJ and Huey P (2004) Serological profile. In: Isenberg DA, Maddison PJ, Woo P, Glass D and Breedveld FC, (eds). Oxford Textbook of Rheumatology, 3rd edn, pp. 491–499. Oxford: Oxford University Press.

Rojko JL, Evans MG, Price SA, et al. (2014) Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical‐related immune complexes: review and case studies. Toxicologic Pathology 42: 725–764.

Platzer B, Stout M and Fiebiger E (2014) Antigen cross‐presentation of immune complexes. Frontiers in Immunology 5: 140.

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Wener MH (2014) Tests for circulating immune complexes. Methods in Molecular Biology 1134: 47–57.

Related Sub-Topics:

Diagnostics, Therapeutics and Methods | Antibodies | Antigens | Autoimmunity
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Article Title: Immune Complexes
 
How to Cite close
Eggleton, Paul, Javed, Moazzam, Pulavar, David, and Sheldon, Gemma(Apr 2015) Immune Complexes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001118.pub2]