Type III Hypersensitivity – Definition, Types, Mechanism, Examples

What is Type III Hypersensitivity?

• Type III hypersensitivity, also known as immune complex hypersensitivity, is a type of allergic reaction classified by Gell and Coombs. It occurs when immune complexes, which are formed by the binding of antigens to antibodies, accumulate in the body without being adequately cleared by the innate immune cells. This accumulation leads to an inflammatory response and the attraction of leukocytes.
• The process of type III hypersensitivity involves three main steps. The first step is immune complex formation, where antigens and antibodies bind together to form mobile immune complexes. These complexes can circulate in the bloodstream. The second step is immune complex deposition, during which the complexes leave the plasma and get deposited into various tissues in the body. The third step is the inflammatory reaction, triggered by the activation of the classical pathway and the recruitment of macrophages and neutrophils to the affected tissues. This inflammatory response can lead to tissue damage and the development of immune complex diseases.
• Hypersensitivity refers to an exaggerated immune response that results in inappropriate reactions and the destruction of host tissues. According to the Gell and Coombs classification, there are four main types of hypersensitivity reactions: type I, type II, type III, and type IV. Type III hypersensitivity is classified as an immunoglobulin-mediated or immediate hypersensitivity reaction, where the destruction of cells is mediated by antigen-antibody complexes.
• When antibodies combine with their specific antigens, immune complexes are formed. Normally, these complexes are promptly removed from the body. However, in some cases, they persist due to their small size and are deposited in tissues, leading to various disorders. The most common sites of immune complex deposition are the joints, kidneys, and blood vessels, resulting in arthritis, nephritis, and vasculitis, respectively. Immune complexes can also be deposited in other organs, causing organ dysfunction.
• Wherever immune complexes are deposited, they activate the complement system and attract macrophages and neutrophils to the site. This activation and recruitment lead to inflammation, which can result in tissue injury. Type III hypersensitivity primarily involves antibodies of the IgG and IgM classes that combine with soluble antigens not bound to cell surfaces. The tissue damage is mainly caused by complement activation and the release of lytic enzymes from neutrophils.
• The onset of type III hypersensitivity can take hours, days, or even weeks, depending on the presence of immunological memory of the triggering antigen. The response can also become chronic, especially in autoimmune reactions where the antigen persists. Type III hypersensitivity, like other types of hypersensitivity, occurs when the mechanism of self-tolerance is breached, and self-reactive immune cells are activated to mount reactions against autoantigens, such as DNA from autologous cells.

Definition of Type III Hypersensitivity

Type III hypersensitivity is an allergic reaction characterized by the accumulation of immune complexes (antigen-antibody complexes) in tissues, leading to inflammation and tissue damage.

Types of Type III hypersensitivity reaction

Type III hypersensitivity reactions can be categorized into localized and generalized reactions.

1. Localized Type III Hypersensitivity Reaction: An example of a localized type III hypersensitivity reaction is the acute Arthus reaction. In this reaction, when an antigen is injected or enters the skin (intradermally or subcutaneously), it binds with antibodies to form immune complexes at the site. Within 4 to 8 hours, the immune complexes mediate the acute Arthus reaction. As the reaction progresses, it leads to localized tissue damage and vascular damage, resulting in the accumulation of fluids (edema) and red blood cells (erythema) at the site where the antigen entered. The severity of the reaction can range from mild swelling and redness to tissue necrosis.
2. Generalized Type III Hypersensitivity Reaction: Serum sickness is an example of a generalized type III hypersensitivity reaction. In this reaction, a large amount of antigen enters the bloodstream and binds to antibodies, leading to the formation of circulating immune complexes. If there is an excess of antigens compared to antibodies, the immune complexes formed are smaller and soluble, which are not easily phagocytosed by phagocytic cells. This imbalance results in a generalized type III hypersensitivity reaction.

The manifestation of serum sickness depends on the quantity of immune complexes formed and the sites of their deposition. The sites of deposition may vary, but accumulation of complexes often occurs at sites of blood filtration. A generalized type III hypersensitivity reaction can lead to different diseases depending on the site of complex deposition. For example, deposition in the kidneys can result in glomerulonephritis, in arteries can cause vasculitis, and in synovial joints can lead to arthritis.

Factors affects the deposition of immune complex and increase susceptibility to Type III hypersensitivity reaction

Several factors can contribute to the deposition of immune complexes and increase susceptibility to type III hypersensitivity reactions:

1. Persistent infection: In cases of persistent infections, such as malaria, a large number of immune complexes are formed as a result of the continuous presence of antigens. These immune complexes can accumulate and deposit in various tissues, triggering type III hypersensitivity reactions.
2. Complement deficiency: The complement system plays a crucial role in removing immune complexes from the bloodstream. However, when there is a deficiency in the complement system, immune complexes may not be effectively cleared. This can lead to the circulation of a large amount of immune complexes in the blood, increasing the likelihood of their deposition in tissues and the development of type III hypersensitivity reactions.
3. Autoimmunity: Autoimmune diseases involve the production of autoantibodies that target the body’s own tissues. In these conditions, a significant amount of immune complexes can be formed due to the interaction between autoantibodies and self-antigens. These immune complexes can deposit in tissues and contribute to the development of type III hypersensitivity reactions.
4. Genetic defects: Certain genetic defects can result in the formation of small and soluble immune complexes that are not efficiently phagocytosed by immune cells. As a result, these immune complexes can persist in the bloodstream and deposit in various tissues, leading to type III hypersensitivity reactions.

These factors disrupt the normal clearance mechanisms of immune complexes, allowing their accumulation and subsequent deposition in tissues. This deposition triggers an inflammatory response and tissue damage characteristic of type III hypersensitivity reactions.

The mechanism of both the types of Type III Hypersensitivity

The mechanism of both types of type III hypersensitivity reactions involves the formation and deposition of antigen-antibody complexes, leading to tissue damage and inflammation.

1. Localized Type III Hypersensitivity

In a localized type III hypersensitivity reaction, such as the acute Arthus reaction, antigen-antibody complexes are formed at the site of antigen entry. If these complexes are not cleared through phagocytosis, they persist in the circulation. Subsequently, these immune complexes deposit in the tissues.

Once deposited in the tissues, the immune complexes activate the classical complement cascade. This activation leads to the formation of complement fragments, such as C3a and C5a, which are potent mediators of inflammation. These fragments attract neutrophils and monocytes to the site of immune complex deposition.

Neutrophils, in an attempt to engulf the immune complexes, release various substances like prostaglandins, lysosomal enzymes, and free oxygen radicals. These substances cause damage to the surrounding tissues at the site of immune complex deposition. Additionally, the binding of the Fc region of the antibody in the immune complex to the Fc receptors on platelets can result in platelet aggregation, blood clot formation, and blockage of blood vessels. This can lead to hemorrhages at the site.

2. Generalized Type III Hypersensitivity

In a generalized type III hypersensitivity reaction, such as serum sickness, a large number of immune complexes are formed and circulate in the bloodstream. These complexes can deposit in various tissues throughout the body.

Similar to the localized reaction, the tissue-deposited immune complexes activate the classical complement cascade. The complement fragments generated during complement activation trigger an inflammatory response and attract neutrophils and monocytes to the site of deposition.

The attracted neutrophils release substances that cause tissue damage and inflammation, similar to the localized reaction. The binding of the Fc region of the immune complexes to platelet Fc receptors can also lead to platelet aggregation, blood clot formation, and blockage of blood vessels, resulting in hemorrhages at different sites in the body.

Overall, the mechanism of both types of type III hypersensitivity reactions involves the persistence and deposition of immune complexes, complement activation, recruitment of inflammatory cells, release of damaging substances, and potential blood vessel complications, leading to tissue damage and inflammation.

Pathophysiology of Type III Hypersensitivity

After 4-10 days following antigen exposure, an individual’s immune system produces antibodies. The antibody reacts with the antigen to create immunological complexes that circulate and can diffuse into the vascular walls, where they may trigger complement fixation and activation. These immune complexes, together with complement, induce an influx of polymorphonuclear leukocytes at the location, where proteolytic enzymes cause tissue injury. The procedure consists of three steps:

1. Immune complex formation

• Antibody production is triggered by antigen exposure, whether endogenous or exogenous. Exogenous antigens are foreign proteins, such as those found in pathogenic microorganisms and pharmaceuticals.
• Autoantibodies are produced in response to endogenous antigens, which are self-antigens (autoimmunity).
• In both instances, antigens bind to antibodies, generating immune complexes that migrate out of plasma and deposit in host tissues.

2. Immune complex deposition

• The ratio between antigen and antibody influences the pathogenicity of immune complexes.
• The complexes are insoluble, do not circulate, and are phagocytosed by macrophages in the lymph nodes and spleen when there is an excess of antibody.
• However, when there is an overabundance of antigen, the aggregates become smaller. In organs where the blood is changed into fluids such as urine and synovial fluid, they freely filter out of circulation. Immune complexes therefore influence glomeruli and joints.

3. Inflammatory reaction

• Inflammatory damage to tissues is triggered by the recruitment of macrophages and neutrophils following the deposition of immune complexes, which is followed by the activation of the classical pathway and the release of C3a and C5a.
• Symptoms can manifest as vasculitis (inflammation of the blood vessels), arthritis (inflammation of the joints), or glomerulonephritis (inflammation of the kidney glomeruli).

Examples of Type III (Immune Complex) Hypersensitivity

Type III hypersensitivity, also known as immune complex hypersensitivity, can manifest in various diseases and conditions. Here are some examples of type III hypersensitivity reactions:

1. Systemic Lupus Erythematosus (SLE): SLE is an autoimmune disease where the immune system produces antibodies that bind to certain nuclear antigens. These antibodies form immune complexes that deposit mainly in the kidneys, skin, and joints. The deposition of these immune complexes in the affected tissues contributes to the characteristic symptoms and organ damage seen in SLE.
2. Post-streptococcal Glomerulonephritis: In this condition, following a Streptococcal infection (such as strep throat or impetigo), the patient’s immune system generates antibodies to fight the pathogen. However, these antibodies can also cross-react with glomerular antigens in the kidneys. As a result, antigen-antibody complexes form and lodge on the glomerular membrane, leading to inflammation and damage to the kidneys.
3. Drug-Induced Serum Sickness: Certain drugs, although they may not be potent immunogens themselves, can act as haptens. They combine with host tissue proteins, forming drug-host protein complexes that induce an immune response. The immune complexes formed can circulate in the bloodstream and deposit in various tissues, triggering a type III hypersensitivity reaction similar to serum sickness.
4. Farmer’s Lung and Bird Fancier’s Disease: These are pulmonary diseases caused by the inhalation of specific antigens. Farmer’s Lung occurs when individuals inhale bacterial spores commonly found in moldy hay or straw, while Bird Fancier’s Disease is caused by inhaling avian serum or fecal proteins. In both cases, the inhaled antigens induce the formation of immune complexes in the lungs, leading to inflammation, tissue damage, and respiratory symptoms.

These examples illustrate how type III hypersensitivity reactions can occur in various organs and systems, resulting in a range of clinical manifestations and diseases.

Type III Hypersensitivity Diseases

Serum sickness

• As a result of immune complex deposition at various places throughout the body, a systemic inflammatory reaction occurs, leading to serum sickness.
• A single injection of a large volume of foreign serum causes the illness. Injection of foreign serum or certain medications, such as penicillin, might cause this reaction anywhere from a few days to two weeks later.
• Serum sickness, on the other hand, is classified as a hypersensitivity reaction since symptoms start right after the immunological complex is formed.
• Contrary to the type I hypersensitivity reaction, the priming and startling doses can both be administered with a single injection.
• The most common symptoms include a high temperature, lymphadenopathy, rash, arthritis, swollen spleen, and an increase in eosinophils. The illness resolves itself and has no lasting effects.

Hypersensitivity Pneumonitis (HP)

• Immune complexes are deposited in the alveoli, interstitium, terminal bronchioli, and lung parenchyma of people with HP, also known as extrinsic allergic alveolitis.
• Airborne antigens can set off an IgE-mediated allergic immunological response. However, a type III hypersensitivity disorder-like IgG response is mostly triggered by particular allergens.
• Any bacterium, protein (of plant or animal origin), or chemical (organic or inorganic) found in the environment, either at work or at home, can serve as an antigen.
• Antigens from thermophilic moulds (Micropolyspora faeni and Thermoactinomyces Vulgaris spores) that grow on crops have been linked to the development of farmers’ lung, a well-studied HP entity.
• Bird fancier’s sickness is another form of HP caused by an immune response to antigens found in bird droppings, feather wax, or immunoglobulins.
• Diagnosing HP requires a high level of suspicion. The patient’s environmental and occupational exposures should be determined through a detailed history.
• Symptoms such as fever, cough, and dyspnea may begin within 2-9 hours after antigen exposure and reach their climax within 24 hours.
• Repeated exposure to the offending antigen can make breathing difficult. Weight loss and respiratory problems are common in chronic exposure.
• Inspiratory crackles, cyanosis, clubbing, and other symptoms of right heart failure might be observed during a physical examination.

Systemic Lupus Erythematosus (SLE)

• Multiple body systems may be affected by SLE, an autoimmune disease. IgG and IgM autoantibodies to host tissue components are characteristic of this disease.
• Antibodies are typically created to attack specific components of the nucleus, including strands of double-stranded DNA, histones, and ribonuclear proteins.
• Some people have been shown to have autoantibodies that target different cell types.
• Hypercoagulability can result from autoantibodies directed against the phospholipid component of the prothrombin activator complex or cardiolipin.
• The following is a list of major clinical symptoms that may affect many organ systems:
  • Fever, decreased appetite, and exhaustion are all symptoms of a generalised illness.
  • Arthritis, arthralgia, and myalgia are all musculoskeletal conditions.
  • Malar (butterfly) rash with photosensitivity, mouth ulcers, alopecia, and other hair loss conditions are all skin manifestations.
  • Pericarditis, endocarditis, and myocarditis are all forms of heart inflammation.
  • Raynaud’s phenomenon, a form of vasculitis affecting primarily small blood vessels, showing clinically as petechiae, purpura, and superficial ulcers.
  • Symptoms related to the lungs include a pleural effusion, cough, and dyspnea.
  • Discomfort in the belly area, including nausea and vomiting.
  • Glomerulonephritis, nephritic syndrome, asymptomatic blood in the urine (hematuria) or protein in the urine (proteinuria), and impaired renal function are all renal diseases.
  • Diseases of the blood include anaemia, leukopenia, hemolysis, thrombosis, and miscarriage.
  • Diseases of the Central Nervous System, Such as Migraines and Seizures, and Stroke
  • SLE primarily affects the musculoskeletal, mucocutaneous, and respiratory systems.

Post Streptococcal Glomerulonephritis (PSGN)

• In patients with PSGN, nephritogenic strains of group A beta-hemolytic streptococci produce the deposition of immune complexes in the glomeruli.
• One to three weeks after a streptococcal infection of the throat, or three to six weeks after an infection of the skin, symptoms typically appear.
• Microscopic or gross hematuria, proteinuria, hypertension, edoema, and an increase in blood creatinine may be the presenting symptoms.

FAQ

References

• Usman N, Annamaraju P. Type III Hypersensitivity Reaction. [Updated 2022 May 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559122/
• https://www.statpearls.com/ArticleLibrary/viewarticle/30716
• https://www.lecturio.com/concepts/type-iii-hypersensitivity-reaction/
• https://www.drawittoknowit.com/course/pathology/glossary/pathophysiologic-disorder/hypersensitivity-type-iii
• https://labpedia.net/elementary-immunology/chapter-13-hypersensitivity-reaction-type-iii-immune-complex-disease/
• https://microbenotes.com/type-iii-immune-complex-hypersensitivity-mechanism-and-examples/
• https://veteriankey.com/immune-complexes-and-type-iii-hypersensitivity/
• https://www.ebi.ac.uk/ols/ontologies/efo/terms?iri=http://www.ebi.ac.uk/efo/EFO_1001222
• https://en.wikipedia.org/wiki/Type_III_hypersensitivity