Type III Hypersensitivity: Mechanism & Examples to Type IV Hypersensitivity: Examples & Tests

Content August 26, 2025

Type III Hypersensitivity: Immune Complex-Mediated

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In Type III hypersensitivity, immune complex—antigen-antibody (mostly IgG) complexes activate complement, which attracts neutrophils. These neutrophils then release lysosomal enzymes, leading to tissue damage. This type of hypersensitivity can be associated with vasculitis and systemic manifestations.

To visualize a Type III reaction, imagine an immune complex as three things stuck together: antigen, antibody, and complement.

Examples of Type III Hypersensitivity:

Systemic Lupus Erythematosus (SLE)
Rheumatoid arthritis
Reactive arthritis
Polyarteritis nodosa
Poststreptococcal glomerulonephritis
IgA vasculitis

Serum Sickness: A Prototypic Immune Complex Disease

Serum sickness is considered the prototypic immune complex disease. It occurs when antibodies to foreign proteins are produced. Approximately 1 to 2 weeks later, antibody-antigen complexes form and deposit in tissues → complement activation → inflammation and subsequent tissue damage, often indicated by decreased serum C3 and C4 levels.

Clinically, patients typically experience symptoms such as fever, urticaria, joint pain (arthralgia), proteinuria, and swollen lymph nodes (lymphadenopathy) about 1 to 2 weeks after exposure to the antigen. Serum sickness-like reactions can be associated with certain drugs that act as haptens, like penicillin or monoclonal antibodies, and also with infections such as hepatitis B.

Arthus Reaction: A Localized Type III Hypersensitivity

The Arthus reaction is a specific type of local, subacute immune complex-mediated hypersensitivity reaction. It occurs when an antigen is injected intradermally into an individual who has already been presensitized, meaning they have circulating IgG antibodies against that antigen. This leads to the formation of immune complexes directly in the skin, resulting in an enhanced local reaction, for example, after a booster vaccination.

The Arthus reaction is characterized by localized edema, fibrinoid necrosis, and activation of the complement system at the injection site.

Type IV Hypersensitivity: Mechanisms

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Type IV hypersensitivity, also known as delayed-type hypersensitivity, is distinct from the other types because it does not involve antibodies. Instead, it is primarily mediated by T cells and macrophages.

There are two main mechanisms involved:

Direct cell cytotoxicity: In this mechanism, CD8+ cytotoxic T cells directly recognize and kill targeted cells.
Inflammatory reaction: As shown in the illustration, an antigen is presented to a sensitized Th1 cell. These effector CD4+ T cells then recognize the antigen and release various inflammation-inducing cytokines. These cytokines, in turn, activate macrophages, leading to an inflammatory response, often resulting in delayed-type hypersensitivity.

Type IV Hypersensitivity: Clinical Manifestations and Diagnosis

Unlike other types, Type IV hypersensitivity reactions do not involve antibodies. Key examples include:

Contact dermatitis: Such as reactions to poison ivy or nickel allergy.
Graft-versus-host disease: A serious complication of transplantation.

Diagnostic tests for Type IV hypersensitivity include:

The PPD test for tuberculosis infection.
Patch tests for contact dermatitis.
Candida skin tests, used to assess T cell immune function.

To help remember the characteristics of Type IV hypersensitivity, think of the “4 T’s”: T cells, Transplant rejections, TB skin tests, and Touching (referring to contact dermatitis). Also, remember it’s the Fourth type and its reaction is typically delayed.

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