Hypersensitivity Type III: Mechanisms and Clinical Manifestations

Type III hypersensitivity reaction is an abnormal immune response mediated by the formation of antigen-antibody complexes or immune complexes. In general, hypersensitivity means an inappropriate or overreaction against an antigen (which is otherwise harmless); symptoms are seen in those individuals who have had at least one previous exposure to such antigen. Type III is different from other types of hypersensitivity reactions in that antigen-antibody complexes are performed in the circulation before their deposition in tissues in this type of reaction.

Type III hypersensitivity reactions can be associated with medications, autoimmune, or infectious conditions. The response may be systemic or localized, depending on the site involved.

Usually, an immune complex is formed to clear antigens by phagocytic cells and red blood cells. And such an immune complex is removed by phagocytes of the spleen and lymph nodes. But, when the excess amount of immune complexes form and persist, these cause tissue damage by complement and immune cell activation.

Mechanism

Like in type II hypersensitivity reactions, cell injury caused in the type III reaction is by complement system activation. But here, immune complexes are formed first when antibodies bind to antigens. The immune complexes can then precipitate in various tissues of joints, skin, blood vessel walls, the kidney’s glomerular basement membrane, and the brain’s choroid plexus. Such depositions trigger complement activation. It leads to the recruitment of inflammatory cells like monocytes and neutrophils that release lytic enzymes and free radicals at the site. 

The whole process is described in three main steps:

  1. Immune complex formation: Exposure to exogenous as well as endogenous antigens triggers the formation of antibodies. Foreign proteins like microorganisms or pharmaceutical products are exogenous antigens, whereas self-antigens are endogenous antigens against which autoantibodies are generated (causing autoimmunity). The antigen can enter the body from ingestion, inhalation, or subcutaneous route. The antigens bind to antibodies and form circulating immune complexes. Such complexes migrate out of plasma later and deposit in host tissues.
  2. Immune complex deposition: The pathogenicity of immune complexes partly depends on the antigen-antibody ratio. When antibodies are produced in excess amounts, the complexes are insoluble, so they do not circulate and are phagocytosed by macrophages in the lymph nodes and spleen. Whereas in the case of antigen excess, the aggregates are smaller. Thus, they can freely filter out of circulation in organs where the blood is transformed into fluids such as urine and synovial fluid. Therefore, immune complexes affect glomeruli and joints in such cases. Larger immune complexes are deposited on the basement membrane of blood vessel walls or kidney glomeruli. In contrast, smaller complexes may pass through the basement membrane and be deposited in the sub epithelium.
Site of deposition of immune complexesInfection
Blood vesselsVasculitis
Kidney (glomerulus)Glomerulonephritis
JointsArthritis
  1. Inflammation and Tissue Damage: The final step of type III hypersensitivity reaction is activating the classical complement pathway. The complement split products, C3a and C5a, are released, which are anaphylactic, causing localized mast-cell degranulation and consequent increase in local vascular permeability. The immune complexes and the complement produce an influx of polymorphonuclear leukocytes into the site. Phagocytosis is hindered because the complex is deposited on the basement membrane surface. The C3b component acts as an opsonin, coating immune complexes, where neutrophils come and bind with it. As a result, proteolytic enzymes, pro-inflammatory cytokines, and reactive oxygen species are released, damaging the tissues. Similarly, further activation of the membrane attack complex can also contribute to tissue destruction. In addition, it can induce aggregation of platelets, and the resulting release of clotting factors can lead to the formation of microthrombi. The inflammatory reactions lead to tissue damage, and various systemic and localized infections occur.

Clinical Manifestation of Type III Hypersensitivity

The magnitude of the reaction depends on the quantity of immune complexes as well as their distribution within the body. A localized response occurs when immune complexes are deposited in tissue near the antigen entry. And when the complexes are formed in the blood, a reaction develops wherever the complexes are deposited. Several autoimmune diseases develop from circulating antigens or DNA-forming immune responses.

The reactions can be categorized as localized and systemic reactions.

Localized Reactions

  • Local Arthus reaction: The antigens form immune complexes with circulating IgG antibodies, activating complement and recruiting inflammatory cells, like neutrophils and mast cells. These cells release cytokines, enzymes, and other molecules that produce local inflammation at the injection site, with pain, swelling, and redness. It mainly has localized vasculitis and tissue necrosis. It can be produced by reinjecting antigens too soon after initial exposure. Sometimes, a sensitive individual may have a rapid, localized type I reaction at the site after an insect bite. Often, some 4-8 hours later, a typical Arthus reaction also develops at the site, with erythema and edema.
  • Hypersensitivity pneumonitis (farmer’s lung): Pulmonary Arthus-type reaction can also be induced by bacterial spores, fungi (mold), hay dust, or dried fecal proteins. It causes pneumonitis or alveolitis.
  • Rheumatoid arthritis: Rheumatoid arthritis is another disease resulting from an autoimmune disorder due to the immune complex known as rheumatoid factor (rf). Immune complexes get deposited in joints and damage tissues in this disease.
  • Others: The localized reaction can also occur during ingested celiac disease and injected tetanus vaccines.

Systemic Reactions

  • Serum sickness: It can be induced by older types of vaccines derived from antibodies from other species (foreign serum) or transfusions. For example, anti-venom reactions occur when anti-snake venom treatment is administered to a previously sensitized individual. Newer anti-venom treatments avoid this reaction. It can also happen by administrating therapeutic monoclonal antibodies. It was seen in world war II when soldiers were given horse serum for diphtheria.

Antibodies specific to the foreign serum proteins form circulating immune complexes. Within days or weeks after exposure, fever, weakness, generalized vasculitis (rashes), lymphadenopathy, arthritis, and sometimes glomerulonephritis can be observed.

  • Systemic Lupus Erythematosus: This is a genetic disorder caused by autoantibodies. Complexes of DNA and anti-DNA antibodies accumulate in synovial membranes, causing arthritic symptoms, or accumulate on the basement membrane of the kidney, causing progressive kidney damage. It can also affect the digestive tract, heart, and skin. Sometimes, it shows Raynaud Phenomenon during cold, characterized by numbness and cyanosis (lacking oxygen), especially in fingers.
  • Drug reactions: Allergies to penicillin and sulfonamides can also cause type III hypersensitivity reactions.
  • Infectious diseases: Type III hypersensitivity reactions can cause several contagious diseases. Post-streptococcal glomerulonephritis (PSGN) occurs when circulating complexes of antibodies and streptococcal antigens are deposited in the kidney and damage glomeruli. 

Similarly, type III hypersensitivity reaction is also seen in other infectious diseases like meningitis, hepatitis, mononucleosis, malaria, and trypanosomiasis.

Diagnosis of Type III Hypersensitivity

Detection of a specific antigen causing type III hypersensitivity is difficult. The diagnosis is primarily based on the association of antigen exposure to clinical manifestations, such as fever, arthritis, and rash. The diagnosis includes clinical history or findings and laboratory tests, like:

Blood

A blood sample is tested for CBC (complete blood count), ESR (erythrocyte sedimentation rate), CRP, complement levels, serum IgG and IgM, etc. CBC is tested especially in serum sickness and SLE (systemic lupus erythematosus). In PSGN, the level of antibodies against streptolysin O, streptokinase, or deoxyribonuclease B is tested, whether it is higher.

Urine

Urinalysis with microscopy is carried out. Proteinuria and hematuria are observed in SLE, serum sickness, and PSGN.

Imaging

X-rays and CT scans are performed, especially for pneumonia and joint involvement.

Allergic skin test

Biopsy

Renal biopsy, a skin biopsy, or a bronchoscopy

Culture

Blood, skin, throat culture.

Type I and II hypersensitivity reactions are antibody-mediated similar to type III hypersensitivity. Thus, their clinical features can overlap. In such cases, differential diagnosis is necessary.

Treatment and Management

  1. Avoidance of exposure
  • Removal of the offending agent is essential.
  • If an occupational hazard is a cause, appropriate precautions should be taken at the worksite, or one should change the nature of the work.
  • Reviewing the drug allergy list and related side effects should be carried out for the sensitive patient.
  • To avoid problems caused by older vaccines, antitoxins, or animal serum, current therapeutic antibodies are humanized or genetically engineered not to be recognized as foreign.
  1. Use of drugs and other treatments
  • Disease treatment is based on the individual patient’s condition.
  • Antihistamines and nonsteroidal anti-inflammatory drugs can provide symptomatic relief.
  • The patient must be hospitalized in cases of hemodynamic instability, life-threatening symptoms, or unclear diagnosis.
  • In some cases, dialysis or organ transplantation is to be carried out.

References

Srijana Khanal

Hello, I am Srijana Khanal. Former faculty teacher in Microbiology Department at National College, NIST. Involved in the field of teaching for almost 10 years. I am very passionate about writing (academic as well as creative). My areas of interest are basic science, immunology, genetics, and research methodology.

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