Immune Complex Disease

Abstract

Immune complexes derive from complex interactions between antibody, antigens, complement and various receptors as a part of adaptive immunity. Antigens bound to antibodies in immune complexes are normally cleared by various cellular mechanisms physiologically capable of eliminating even small quantities of ‘foreign’ antigens from circulation. Immune complexes can form when humans are exposed to foreign substances like proteins (infections, vaccines, drugs, etc.) or nonprotein materials (haptens) which need a protein carrier to activate the cascade. Autoimmune disorders develop when immune complexes deposit pathologically in different organs, initiating inflammatory cascades which lead to organ damage/disease. Immune complex disease can manifest in a myriad of ways when dysregulation in one or more of these components occur. Even some recombinant protein therapeutic agents used to treat autoimmunity may paradoxically form immune complexes, neutralizing therapeutic efficacy and/or manifesting as immune complex disease.

Key Concepts

  • Immunological defence mechanisms evolved from primitive, unspecialized ‘innate’ mechanisms of lower animals to more sophisticated, highly specialized ‘adaptive’ mechanisms as seen in higher animals and man.

  • Adaptive immunity uniquely involves specialized cells called lymphocytes capable of producing antibodies against a wide range of microbial and nonmicrobial antigens.

  • Antibodies are capable of complexing with soluble and/or immobilized antigens, forming a tightly bound structure called an immune complex.

  • Soluble antigens bound to antibodies in immune complexes are normally cleared by various cellular mechanisms physiologically capable of eliminating even small quantities of ‘foreign’ antigens from circulation.

  • If sufficiently large quantities of soluble antigens and their antibodies develop, large latticed immune complexes may form for a variety of different reasons.

  • Latticed immune complexes are pathologically capable of depositing systemically in any of a variety of tissue sites, creating downstream cellular damage with many different clinical presentations, all of which fall into the category of ‘immune complex disease’ (the prototype originally being referred to as ‘serum sickness’).

  • Several experimental animal models of immune complex disease have emerged yielding useful information on the cellular and soluble elements involved in its pathogenesis.

  • Immune complex disease in humans is seen primarily in the setting of infection and/or in response to various therapeutic agents of protein or nonprotein nature.

  • Adaptive immunity has also evolved to readily discriminate between self‐ and foreign antigens. Loss of ability to recognize self‐antigens results in ‘Autoimmunity’ in which both cellular and soluble immune responses against self‐antigens pathologically occur.

  • Many different autoimmune disorders in humans feature immune complex disease manifestations and generally derive from unknown self‐antigens complexed to self‐antibodies. Even some recombinant protein therapeutic agents used to treat autoimmunity may induce formation of immune complexes, neutralizing therapeutic efficacy and/or manifesting as immune complex disease.

Keywords: autoimmunity; complement; immune complexes

Figure 1.

Immune complex‐mediated glomerulonephritis. The light micrograph on top shows neutrophilic inflammation into the glomerulus. Immunofluorescence (middle) and electron micrographs (bottom) show coarse (granular) deposits of latticed antigen–antibody complexes (SLE) along the basement membrane of the glomerulus. Reproduced with permission from Abbas et al.. (Immunofluorescence micrographs are courtesy of Dr. Jean Olson, Department of Pathology, University of California, San Francisco and the electron micrograph is courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's hospital, Boston.)

Figure 2.

Urticarial rash as a consequence of a serum sickness reaction © 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

Figure 3.

The classical pathway of complement activation. Antigen–antibody complexes that activate the classical pathway may be soluble, fixed on the surface of cells (as shown) or deposited on extracellular matrices. The classical pathway is initiated by the binding of C1 to antigen‐complexed antibody molecules, which leads to the production of C3 and C5 convertases attached to the surfaces where the antibody was deposited. The C5 convertase cleaves C5 to begin the late steps of complement activation, reproduced with permission from Abbas et al.www.studentconsult.com.

Figure 4.

Serum sickness manifested as ‘nonblanching purpura’, a frequent indication of underlying immune complex deposition in the walls of small blood vessels. © 1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.

Figure 5.

Natural history of acute serum sickness in rabbits following a single injection of radiolabelled bovine serum albumin (BSA) as antigen. The disease occurs when large quantities of soluble immune complexes are present in the circulation. From Rich RR (1992) Immune complex diseases. In: Wyngaarden JB, Smith LH Jr and Bennett JC (eds), Cecil's Textbook of Medicine, 19th edn, pp. 1467–1470. Philadelphia: WB Saunders.

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References

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Further Reading

Gauthier VJ and Abrass CK (1992) Circulating immune complexes in renal injury. Seminars in Nephrology 12: 379.

Hebert LA (1991) The clearance of immune complexes from the circulation of man and other primates. American Journal of Kidney Diseases 17: 352–361.

Kimberly RP (1997) Characteristics of immune complexes and principles of immune complex diseases. In: Koopman WJ (ed.) Arthritis and Allied Conditions: A Textbook of Rheumatology, pp. 529–543. Baltimore: Williams & Wilkins.

deShazo RD (1996) Immune complex disease. In: Cecil's Textbook of Medicine, pp. 1421–1424. Philadelphia: WB Saunders.

Virella G (1993) Immune complex disease. Immunology Series 58: 379–396.

Wener M (2008) Serum sickness and serum sickness‐like reactions. In: UpToDateOnline 16.3. Section Edition. Waltham, MA: Adkinson N.

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Hardy, Kenneth J, Singh, Amrit P, and de Shazo, Richard D(Sep 2009) Immune Complex Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002164.pub2]