Type III hypersensitivity

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Type III hypersensitivity
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Type III hypersensitivity, in the Gell and Coombs classification of allergic reactions, occurs when there is accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes. There are three steps that lead to this response. [1] The first step is immune complex formation, which involves the binding of antigens to antibodies to form mobile immune complexes. The second step is immune complex deposition, during which the complexes leave the plasma and are deposited into tissues. Finally, the third step is the inflammatory reaction, during which the classical pathway is activated and macrophages and neutrophils are recruited to the affected tissues. Such reactions may progress to immune complex diseases.

Contents

Types

Some clinical examples:

DiseaseTarget antigenMain effects
Systemic lupus erythematosus Nuclear antigens
Rheumatoid Arthritis Antibody complexes: specifically IgM to IgG
Post-streptococcal glomerulonephritis Streptococcal cell wall antigens
  • Nephritis
Polyarteritis nodosa Hepatitis B virus surface antigen
Reactive arthritis Several bacterial antigens
  • Acute arthritis
Serum sickness Various
  • Arthritis
  • Vasculitis
  • Nephritis
Arthus reaction Various
  • Cutaneous vasculitis
Farmer's Lung Inhaled antigens (often mould or hay dust)
  • Alveolar inflammation
Henoch–Schönlein purpura (IgA vasculitis)Unknown, likely respiratory pathogen
Unless else specified in boxes, then ref is: [2]

Other examples are:

Pathogenesis

Gel and Coombs defined type III hypersensitivity reactions as those involving soluble immune complexes (in contrast to type II hypersensitivities which involve membrane-bound antigens that can be targeted by cytotoxic antibodies). In the presence of a multivalent antigen (one which can bind multiple antibodies simultaneously), the antibodies may crosslink to form lattices of antibody and antigen known as immune complexes. The size of an immune complex is an important determinant of its properties: larger immune complexes tend to be phagocytosed more easily than smaller ones, which have a tendency to get trapped in the vasculature wherein they may provoke inflammation. Larger immune complexes also bind more avidly to Fc receptors, however. Immune complex size depends on both the quantity of antigen and antibody, with smaller complexes occurring at both a great excess of antigen and a relatively small amount. [1] Another determinant of immune complex properties is its charge, and in particular the charge of the antigen. Positively charged antigens have an affinity for negatively charged surfaces such as the basement membrane of glomeruli in the kidney or skin; however this may also be because the antigens are trafficking to those sites before the immune complex is formed. IgG or IgM within the immune complexes may furthermore recruit the classical pathway of the complement cascade and bind C1q which can result in immune complexes containing C3. C3 can then be bound by CD35 on the surface of erythrocytes which delivers these immune complexes to phagocytes such as Kupffer cells and red pulp macrophages. This is particularly expedient for large immune complexes. Nonetheless, while complement may promote attachment of immune complexes to phagocytes, the process is mediated by the Fc receptors, [4] [5] and so the role of complement in this process is best viewed as an expediter of phagocytosis. This is particularly noteworthy because systemic lupus erythematosus, a canonical type III hypersensitivity-driven autoimmune disease, has been associated with deficiency of certain components of the complement cascade, which promote persistence of the immune complexes. [6]

The mechanism by which immune complexes are pathogenic is complex and much of what we know is derived from experimental models of the Arthus reaction and serum sickness. These models support that Fc receptors play a dominant role in the response which can be augmented by the complement system via the anaphylatoxin C5a. [7] Ligation of Fc receptors on the surfaces of immune effector cells can give rise to a number of responses, [8] such as degranulation (e.g., of mast cells, causing histamine liberation and subsequent urticaria), phagocytosis, release of pro-inflammatory cytokines and chemokines, platelet activation [9] resulting in the formation of clots, etc.

Signs and symptoms

Immune complex glomerulonephritis, as seen in Henoch-Schonlein purpura; this is an example of IgA involvement in a nephropathy Henoch-Schonlein nephritis IgA immunostaining.jpg
Immune complex glomerulonephritis, as seen in Henoch-Schönlein purpura; this is an example of IgA involvement in a nephropathy

The reaction can take hours, days, or even weeks to develop, depending on whether or not there is immunological memory of the precipitating antigen. Typically, clinical features emerge a week following initial antigen challenge, when the deposited immune complexes can precipitate an inflammatory response. Because of the nature of the antibody aggregation, tissues that are associated with blood filtration at considerable osmotic and hydrostatic gradient (e.g. sites of urinary and synovial fluid formation, kidney glomeruli and joint tissues respectively) bear the brunt of the damage. Hence, vasculitis, glomerulonephritis and arthritis are commonly associated conditions as a result of type III hypersensitivity responses. [10]

As observed under methods of histopathology, acute necrotizing vasculitis within the affected tissues is observed concomitant to neutrophilic infiltration, along with notable eosinophilic deposition (fibrinoid necrosis). Often, immunofluorescence microscopy can be used to visualize the immune complexes. [10] Skin response to hypersensitivity of this type is referred to as an Arthus reaction and is characterized by local erythema and some induration. Platelet aggregation, especially in microvasculature, can cause localized clot formation, leading to blotchy hemorrhages. This typifies the response to injection of foreign antigen sufficient to lead to the condition of serum sickness. [11]

The relevance of the Gell and Coombs classification of allergic reactions is questioned in the modern-day understanding of allergy, and it has limited utility in clinical practice. [5]

See also

Related Research Articles

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out damaged cells and tissues, and initiate tissue repair.

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<span class="mw-page-title-main">Hypersensitivity</span> Medical condition

Hypersensitivity is an abnormal physiological condition in which there is an undesirable and adverse immune response to antigen. It is an abnormality in the immune system that causes immune diseases including allergies and autoimmunity. It is caused by many types of particles and substances from the external environment or from within the body that are recognized by the immune cells as antigens. The immune reactions are usually referred to as an over-reaction of the immune system and they are often damaging and uncomfortable.

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body.

<span class="mw-page-title-main">Type I hypersensitivity</span> Type of allergic reaction

Type I hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an allergic reaction provoked by re-exposure to a specific type of antigen referred to as an allergen. Type I is distinct from type II, type III and type IV hypersensitivities. The relevance of the Gell and Coombs classification of allergic reactions has been questioned in the modern-day understanding of allergy, and it has limited utility in clinical practice.

<span class="mw-page-title-main">Glomerulonephritis</span> Term for several kidney diseases

Glomerulonephritis (GN) is a term used to refer to several kidney diseases. Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.

<span class="mw-page-title-main">Anti-neutrophil cytoplasmic antibody</span> Group of autoantibodies

Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of autoantibodies, mainly of the IgG type, against antigens in the cytoplasm of neutrophils and monocytes. They are detected as a blood test in a number of autoimmune disorders, but are particularly associated with systemic vasculitis, so called ANCA-associated vasculitides (AAV).

The direct and indirect Coombs tests, also known as antiglobulin test (AGT), are blood tests used in immunohematology. The direct Coombs test detects antibodies that are stuck to the surface of the red blood cells. Since these antibodies sometimes destroy red blood cells they can cause anemia; this test can help clarify the condition. The indirect Coombs test detects antibodies that are floating freely in the blood. These antibodies could act against certain red blood cells; the test can be carried out to diagnose reactions to a blood transfusion.

<span class="mw-page-title-main">Cryoglobulinemia</span> Medical condition

Cryoglobulinemia is a medical condition in which the blood contains large amounts of pathological cold sensitive antibodies called cryoglobulins – proteins that become insoluble at reduced temperatures. This should be contrasted with cold agglutinins, which cause agglutination of red blood cells.

<span class="mw-page-title-main">Antibody opsonization</span> Immune system process

Antibody opsonization is a process by which a pathogen is marked for phagocytosis.

<span class="mw-page-title-main">Innate immune system</span> One of the two main immunity strategies

The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

Autoimmune hemolytic anemia (AIHA) occurs when antibodies directed against the person's own red blood cells (RBCs) cause them to burst (lyse), leading to an insufficient number of oxygen-carrying red blood cells in the circulation. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases. The intracellular components of the RBCs are released into the circulating blood and into tissues, leading to some of the characteristic symptoms of this condition. The antibodies are usually directed against high-incidence antigens, therefore they also commonly act on allogenic RBCs. AIHA is a relatively rare condition, with an incidence of 5–10 cases per 1 million persons per year in the warm-antibody type and 0.45 to 1.9 cases per 1 million persons per year in the cold antibody type. Autoimmune hemolysis might be a precursor of later onset systemic lupus erythematosus.

<span class="mw-page-title-main">Farmer's lung</span> Hypersensitivity pneumonitis

Farmer's lung is a hypersensitivity pneumonitis induced by the inhalation of biologic dusts coming from hay dust or mold spores or any other agricultural products. It results in a type III hypersensitivity inflammatory response and can progress to become a chronic condition which is considered potentially dangerous.

<span class="mw-page-title-main">Immune complex</span> Molecule formed binding antigens to antibodies

An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen of its own with a specific epitope. After an antigen-antibody reaction, the immune complexes can be subject to any of a number of responses, including complement deposition, opsonization, phagocytosis, or processing by proteases. Red blood cells carrying CR1-receptors on their surface may bind C3b-coated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return to the general circulation.

In immunology, the Arthus reaction is a type of local type III hypersensitivity reaction. Type III hypersensitivity reactions are immune complex-mediated, and involve the deposition of antigen/antibody complexes mainly in the vascular walls, serosa, and glomeruli. This reaction is usually encountered in experimental settings following the injection of antigens.

Serum sickness in humans is a reaction to proteins in antiserum derived from a non-human animal source, occurring 5–10 days after exposure. Symptoms often include a rash, joint pain, fever, and lymphadenopathy. It is a type of hypersensitivity, specifically immune complex hypersensitivity. The term serum sickness–like reaction (SSLR) is occasionally used to refer to similar illnesses that arise from the introduction of certain non-protein substances, such as penicillin.

Type II hypersensitivity, in the Gell and Coombs classification of allergic reactions, is an antibody mediated process in which IgG and IgM antibodies are directed against antigens on cells or extracellular material. This subsequently leads to cell lysis, tissue damage or loss of function through mechanisms such as

  1. complement activation via the classical complement pathway
  2. Antibody-dependent cellular cytotoxicity or
  3. anti-receptor activity.

The following outline is provided as an overview of and topical guide to immunology:

Type IV hypersensitivity, in the Gell and Coombs classification of allergic reactions, often called delayed-type hypersensitivity, is a type of hypersensitivity reaction that can take a day or more to develop. Unlike the other types, it is not humoral but rather is a type of cell-mediated response. This response involves the interaction of T cells, monocytes, and macrophages.

References

  1. 1 2 Usman, Norina; Annamaraju, Pavan (2021), "Type III Hypersensitivity Reaction", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   32644548 , retrieved 2021-11-26
  2. ↑ Table 5-3 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN   1-4160-2973-7. 8th edition.
  3. ↑ Ibrahim AM, Siddique MS. "Subacute Bacterial Endocarditis Prophylaxis". National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 22 July 2021.
  4. 1 2 "Type III Hypersensitivity Reaction". The Lecturio Medical Concept Library. Retrieved 22 July 2021.
  5. 1 2 Descotes, Jacques; Choquet-Kastylevsky, Geneviève (February 2001). "Gell and Coombs's classification: is it still valid?". Toxicology. 158 (1–2): 43–49. doi:10.1016/S0300-483X(00)00400-5. PMID   11164991.
  6. ↑ Kaul, Arvind; Gordon, Caroline; Crow, Mary K.; Touma, Zahi; Urowitz, Murray B.; van Vollenhoven, Ronald; Ruiz-Irastorza, Guillermo; Hughes, Graham (2016-06-16). "Systemic lupus erythematosus". Nature Reviews Disease Primers. 2 (1): 1–21. doi:10.1038/nrdp.2016.39. ISSN   2056-676X.
  7. ↑ Ravetch, Jeffrey V. (2002-12-15). "A full complement of receptors in immune complex diseases". The Journal of Clinical Investigation. 110 (12): 1759–1761. doi:10.1172/JCI17349. ISSN   0021-9738. PMC   151658 . PMID   12488423.
  8. ↑ Bournazos, Stylianos; Wang, Taia T.; Dahan, Rony; Maamary, Jad; Ravetch, Jeffrey V. (2017-04-26). "Signaling by Antibodies: Recent Progress". Annual Review of Immunology. 35 (1): 285–311. doi:10.1146/annurev-immunol-051116-052433. ISSN   0732-0582. PMC   5613280 .
  9. ↑ Greinacher, Andreas (2015-07-16). Solomon, Caren G. (ed.). "Heparin-Induced Thrombocytopenia". New England Journal of Medicine. 373 (3): 252–261. doi:10.1056/NEJMcp1411910. ISSN   0028-4793.
  10. 1 2 Kumar, Vinay (2010). "6". Robbins and Cotran Pathologic Mechanisms of Disease (8th ed.). Philadelphia: Elsevier. pp. 204–205.
  11. ↑ Parham, Peter (2009). "12". The Immune System (3rd ed.). New York, NY: Garland Science. p. 389.
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