Hypersensitivity: Immune Complex Mediated (Type III)


An immune response in the form of antibody production against a foreign substance is often mounted to remove any detrimental antigen from the host. In type III hypersensitivity, overproduction of immunoglobulin G (IgG) and IgM to a foreign or self‐antigen can lead to the formation and deposition of excessive amounts of insoluble intermediate‐sized immune complexes, which can be difficult to remove from various tissues by phagocytosis. This in turn may trigger classical complement activation, leading to overproduction of other inflammatory mediators, leading to the recruitment, activation and degranulation of peripheral blood granulocytes, such as basophils or an influx of marginating neutrophils to specific tissues, such as the kidneys, lungs and joints culminating in damage. Depending on the frequency of exposure and route of entry, type III hypersensitivity reactions can develop over hours, weeks or years. Examples of type III hypersensitivity reactions include drug‐induced serum sickness, farmer's lung and systemic lupus erythematosus.

Key Concepts:

  • Hypersensitivity type III reactions involve the interaction of IgG or IgM immunoglobulins with antigen to form immune complexes.

  • Intermediate‐sized immune complexes are difficult to remove by the process of phagocytosis.

  • Complement proteins bind to immune complexes as part of the normal physiological process.

  • During hypersensitivity type III reactions sustained complement–immune complex interaction leads to the production of activated complement components, responsible for the recruitment of phagocytes.

  • Cell‐mediated tissue damage occurs as part of type III hypersensitivity, involving activated basophils in the peripheral circulation and marginating neutrophils in the vascular and other tissues.

  • Fc receptors on the surface of granulocytes are important in inducing the immunecomplex‐mediated inflammation.

  • Type III hypersensitivity reactions can manifest as acute or chronic reactions and can occur systemically or in specific tissues.

  • Self and foreign antigens can provoke type III hypersensitivity reactions.

  • Nonspecific immunosuppressive treatments are commonly used to treat type III hypersensitivity reactions.

Keywords: complement; granulocytes; immune complexes; Arthus reaction; vasculitis; phagocytes; immunoglobulin; rheumatoid factor; autoimmune

Figure 1.

Activation of the Arthus reaction. (a) Intradermal injection of antigen combines within hours to antibody from the blood and forms ICs. The complexes bind to C1q, the first component of complement, which triggers activation of the whole complement cascade. A number of the complement components subsequently formed are small cationic peptides called anaphylatoxins (C3a, C4a and C5a), which lead to the recruitment and activation of mast cells, macrophages and neutrophils. (b) Release of histamine, lysosomal enzymes and free radicals can induce local tissue damage. C3b acts as an opsonin, binding to ICs which are adsorbed on to CR1‐expressing phagocytes, which are further activated causing additional inflammatory damage to nearby vessel walls. (c) ICs in complement‐deficient individuals can bind directly to endothelial cells and platelets, upregulating P‐selectin and other inflammatory mediators, which in turn trigger migration of neutrophils to sites of immune complex formation. (d) ICs bind directly to Fc receptors or, if coated with inactivatable C3biC3 aC3b (iC3b) fragments, to Mac‐1 (CR3) receptors, inducing spreading of the phagocytes, which ultimately leads to the release of inflammatory mediators.

Figure 2.

Examples of type III hypersensitivity reactions. Type III reactions can generate IgM and IgG complexes with a diverse array of antigens, including bacterial, viral and fungal molecules, manufactured products and self molecules, including IgG, which can form an immune complex with IgM to form (RF) in some autoimmune diseases. Some of these ICs circulate systemically within the body, eventually being deposited in sites of filtration , for example, kidneys, joint spaces and lungs. Other ICs can deposit locally at the site of their formation to provoke cutaneous and vascular inflammation.

Figure 3.

Potential therapeutic target sites to prevent type III hypersensitivity reactions. (a) Formation of ICs and binding to C1q activates complement. Both C1q and C3b bind to the complexes to limit the size and help to solubilise them, respectively. (b) However, release of intracellular components (e.g. calreticulin, decorin and proteochondroitin sulfate) can inhibit C1q‐mediated complement activation by competing with complexes for C1q binding. (c) The generation of later‐stage proinflammatory complement components C5a and C5b–C9 can be blocked by inhibiting cleavage of C5 with anti‐C5 monoclonal antibodies. (d) The presence of ICs leads to local upregulation of P‐selectin and increased surface expression of FcR and Mac‐1 receptors on inflammatory cells. (e) Specific monoclonal antibodies and specifically engineered peptides may inhibit the action of these inflammatory mediators, the objective being to reduce the release of chemokines by cells and impair neutrophil accumulation at sites of immune complex deposition.



Batsford SR, Mezzano S, Mihatsch M, Schiltz E and Rodriguez‐Iturbe B (2005) Is the nephritogenic antigen in post‐streptococcal glomerulonephritis pyrogenic exotoxin B (SPE B) or GAPDH? Kidney International 68: 1120–1129.

Bentz S, Hausmann M, Piberger H et al. (2010) Clinical relevance of IgG antibodies against food antigens in Crohn's disease: a double‐blind cross‐over diet intervention study. Digestion 81: 252–264.

Clynes R, Dumitru C and Ravetch JV (1998) Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279: 1052–1054.

Hopken UE, Lu B, Gerard NP and Gerard C (1997) Impaired inflammatory responses in the reverse Arthus reaction through genetic deletion of the C5a receptor. Journal of Experimental Medicine 186: 749–756.

Morgan AJ and Schwartz RA (2010) Cutaneous polyarteritis nodosa: a comprehensive review. International Journal of Dermatology 49: 750–756.

Nigrovic PA, Malbec O, Lu B. et al. (2010) C5a receptor enables participation of mast cells in immune complex arthritis independently of Fcgamma receptor modulation. Arthitis & Rheum 62: 3323–3333.

Samuelsson A, Twers TL and Ravetch JV (2001) Anti‐inflammatory activity of IViG mediated through the inhibitory Fc receptor. Science 291: 484–486.

Santos LL, Huang XR, Berndt MC and Holdsworth SR (1998) P‐selectin requirement for neutrophil accumulation and injury in the direct passive Arthus reaction. Clinical and Experimental Immunology 112: 281–286.

Scherer K, Spoerl D and Bircher AJ (2010) Adverse drug reactions to biologics. Journal of the German Society of Dermatology 8: 411–426.

Shushakova N, Skokowa J, Schulman J et al. (2002) C5a anaphylatoxins is a major regulator of activating versus inhibitory FcγRs in immune‐complex‐induced lung disease. Journal of Clinical Investigations 110: 1823–1830.

Sindrilaru A, Seeliger S, Ehrchen JM et al. (2007) Site of blood vessel damage and relevance of CD18 in a murine model of immune complex‐mediated vasculitis. Journal of Investigative Dermatology 127: 447–454.

Takai T, Ono M, Hikida M, Ohmori H and Ravetch JV (1996) Augmented humoral and anaphylactic responses in FcrRII deficient mice. Nature 379: 346–349.

Tang T, Rosenkranz A, Assmann KJM et al. (1997) A role for Mac‐1 (CD11b/CD18) in immune complex‐stimulated neutrophil function in vivo: Mac‐1 deficiency abrogates sustained Fcγ receptor‐dependent neutrophil adhesion and complement‐dependent proteinuria in acute glomerulonephritis. Journal of Experimental Medicine 186: 1853–1863.

Tarr J and Eggleton P (2005) Immune function of C1q and its modulators CD91 and CD93. Critical Reviews in Immunology 25: 305–330.

Uzunismail H, Cengiz M, Uzun H et al. (2012) The effects of provocation by foods with raised IgG antibodies and additives on the course of Crohn's disease: a pilot study. Turkish Journal of Gastroenterology 23: 19–27.

Von Pirquet C and Schick B (1905) Zur frage des aggressins. Wiener Klinische Wochenschrift 18: 531.

Welch TR and Blystone LW (2008) Immune complex glomerulonephritis following bone marrow transplantation in C3 deficient mice. PloS One 3: e3334.

Yanaba K, Komura K, Horikawa M et al. (2004) P‐selectin glycoprotein ligand‐1 is required for the development of cutaneous vasculitis induced by immune complex deposition. Journal of Leukocyte Biology 76: 374–382.

Further Reading

Abbas AK, Lichtman AH and Pillai S (2012) Cellular and Molecular Immunology, 7th edn. Philadelphia, PA: Elsevier/Saunders.

Amulic B, Cazalet C, Hayes GL, Metzler KD and Zychlinsky (2012) Neutrophil function: from mechanisms to disease. Annual Review of Immunology 30: 459–489.

Cheng MH and Anderson MS (2012) Monogenic autoimmunity. Annual Review of Immunology 30: 393–427.

Katlenberg JM and Kaplan MJ (2013) Mechanisms of premature atherosclerosis in rheumatoid arthritis and lupus. Annual Review of Medicine 64: 4.1–4.15.

Ravetch JV and Clynes RA (1998) Divergent roles for Fc and complement in vivo. Annual Review of Immunology 16: 421–432.

Virella G and Tsokos GC (2007) Immune complex diseases. In: Virella G (ed.) Medical Immunology, 6th edn, chap. 23, pp. 323–334. New York: Informa Healthcare USA, Inc.

Wener MH (2010) Immune complexes in systemic lupus erythematosus. In: Lahita RG, Tsokos G, Buyon JP and Kolke T (eds) Systemic Lupus Erythematosus, 5th edn, chap. 19, pp. 321–328. Academic Press.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Eggleton, Paul(May 2013) Hypersensitivity: Immune Complex Mediated (Type III). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001138.pub3]