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Type 4 Delayed Hypersensitivity / Cell- mediated hypersensitivity 

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Type IV hypersensitivity resulting from the interaction between a T-lymphocyte and a specific antigen to which the individual has been previously sensitized.

References:

Contact dermatitis: What is it, causes, signs, symptoms, and more | osmosis. (n.d.-a). https://www.osmosis.org/answers/contact-dermatitis

PMID: 20812765.

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Repeated antigen exposure (from infections, chemicals, or environmental allergens)

Chronic infections (e.g., Mycobacterium tuberculosis, Mycobacterium leprae)

Contact with certain chemicals or metals (e.g., nickel, latex, poison ivy, hair dyes)

Genetic predisposition to strong T-cell–mediated immune responses

Autoimmune disorders (e.g., Type 1 diabetes, multiple sclerosis)

Previous sensitization to the antigen (prior exposure primes T-cells)

Prolonged or excessive inflammation that activates T lymphocytes

Environmental or occupational exposure (e.g., healthcare workers with frequent latex contact)

Weakened or dysregulated immune system (e.g., HIV, chronic stress, immunosuppressive therapy altering balance)

References: Huether, S. E., McCance, K. L., & Brashers, V. L. (2025). Understanding pathophysiology (8th ed.). Elsevier.

Abbas, A. K., Lichtman, A. H., & Pillai, S. (2023). Cellular and molecular immunology (10th ed.). Elsevier.

McCance, K. L., & Huether, S. E. (2023). Pathophysiology: The biologic basis for disease in adults and children (9th ed.). Elsevier.

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Hypersensitivity, Overview of the 4 Types, Animation.

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Type IV hypersensitivity reactions, also known as delayed-type hypersensitivity (DTH), are mediated by T lymphocytes and macrophages rather than antibodies. These reactions typically take 24-72 hours to develop after exposure to an antigen, hence the term "delayed." This delay is due to the time required for T cells to be activated, proliferate, and migrate to the site of antigen exposure, and for macrophages to be recruited and activated.

The pathophysiology involves two main phases: sensitization and elicitation (effector phase).

Phase 1: Sensitization (Primary Exposure)

During the initial exposure to an antigen (e.g., a pathogen, a chemical sensitizer, or a transplant antigen), antigen-presenting cells (APCs), primarily dendritic cells, capture the antigen.

1. Antigen Capture and Processing: Dendritic cells in the periphery capture the antigen.

2. Migration to Lymph Nodes: The activated dendritic cells migrate to regional lymph nodes.

3. Antigen Presentation to T Cells: Within the lymph node, the dendritic cells process the antigen and present antigenic peptides on MHC class II molecules to naive CD4+ T helper (Th) cells, or on MHC class I molecules to naive CD8+ cytotoxic T lymphocytes (CTLs). Co-stimulatory molecules (e.g., B7-1/B7-2 on APCs binding to CD28 on T cells) are also crucial for full T cell activation.

Phase 2: Elicitation/Effector Phase (Subsequent Exposure)

Upon re-exposure to the same antigen, the previously sensitized T cells are rapidly activated, leading to an inflammatory response.

1. Antigen Re-exposure at Tissue Site: The antigen is re-introduced into the tissue.

2. Migration of Sensitized T Cells: Memory T cells, specifically Th1 cells, are recruited from the circulation to the site of antigen exposure. This recruitment is facilitated by adhesion molecules (e.g., selectins and integrins) on endothelial cells and chemokines produced at the inflammatory site.

3. T Cell Activation and Cytokine Release: Upon encountering the antigen presented by local APCs (like macrophages or Langerhans cells), the sensitized Th1 cells become activated. They release a variety of cytokines that mediate the inflammatory response.

Organ/Tissue Level Manifestations and Examples:

Skin (e.g., Tuberculin Reaction, Contact Dermatitis):

Tuberculin Skin Test (Mantoux test): In sensitized individuals, injection of tuberculin purified protein derivative (PPD) causes a localized erythematous, indurated lesion appearing 24-72 hours later. Histologically, there's a perivascular cuff of lymphocytes and monocytes, and edema.

Contact Dermatitis (e.g., poison ivy, nickel allergy): Re-exposure to the allergen causes a pruritic, erythematous, vesicular rash at the site of contact. Epidermal cells are damaged (spongiosis), and there's a dense infiltrate of lymphocytes and macrophages in the dermis and epidermis.

Lungs (e.g., Tuberculosis, Sarcoidosis):

Tuberculosis: Chronic infection by M. tuberculosis leads to extensive granuloma formation in the lungs. These granulomas can undergo caseous necrosis, leading to cavitation and severe lung damage.

Sarcoidosis: A multi-systemic granulomatous disease often affecting the lungs. Non-caseating granulomas are formed by activated macrophages and lymphocytes.

Pancreas (e.g., Type 1 Diabetes Mellitus):

In Type 1 Diabetes, autoreactive CD8+ CTLs (and possibly Th1 cells) specifically target and destroy the insulin-producing beta cells in the pancreatic islets of Langerhans, leading to insulin deficiency.

Gastrointestinal Tract (e.g., Crohn's Disease):

Crohn's disease is characterized by chronic inflammation and granuloma formation anywhere in the GI tract. While multifactorial, it involves dysregulated Th1 and Th17 responses against commensal bacteria.

Transplant Rejection (Chronic Rejection):

While acute rejection can involve both cellular and humoral immunity, chronic rejection often has a significant cell-mediated component, leading to fibrosis and gradual organ dysfunction.

References:

1. Abbas, A. K., Lichtman, A. H., & Pillai, S. (2022). Cellular and Molecular Immunology (10th ed.). Elsevier. (This is a foundational textbook for immunology, covering all hypersensitivity types in detail).

2. Kumar, V., Abbas, A. K., & Aster, J. C. (2021). Robbins Basic Pathology (11th ed.). Elsevier. (Excellent for understanding the tissue-level changes and organ manifestations of Type IV hypersensitivity).

3. Janeway, C. A., Jr., Travers, P., Walport, M., & Shlomchik, M. J. (2001). Immunobiology: The Immune System in Health and Disease (5th ed.). Garland Science. (While an older edition, the principles of hypersensitivity are well-explained).

4. Chaplin, D. D. (2010). Overview of the Immune Response. Journal of Allergy and Clinical Immunology, 125(2 Suppl 2), S3-S23.

5. Gell, P. G. H., & Coombs, R. R. A. (1963). Clinical Aspects of Immunology. Blackwell Scientific Publications. (The original classification of hypersensitivity reactions).

6. Huether, S. E., McCance, K. L., & Brashers, V. L. (2025). Understanding pathophysiology (8th ed.). Elsevier.

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Development of Allergic Contact Dermatitis

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Whether this condition conforms to the traditional definition of the hypersensitivity type it is representing, and why or why not

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Whether this condition conforms to the traditional definition of the hypersensitivity type it is representing, and why or why not

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The condition from the case study conforms with the traditional definition of Type IV hypersensitivity that it is representing which are erythematous pruritic vesicles on hands, legs and feet.

Rationale

Allergic Type IV reactions elicited by environmental antigens (poison ivy) that is, hapten (small molecule that cannot trigger an immune response own) and become immunogenic after binding to larger (carrier) proteins which is on the skin in this case - contact dermatitis.

For our case study as illustrated in the image, the first contact with allergen sensitizes (produces reactive T cells) the patient but does not produce a rash. however, secondary contact activates type IV cell mediated reaction that causes the erythematous pruritus on hands, legs and feet.

References:

Rogers, J. (2025). McCance & Huether's Pathophysiology (9th ed.). Elsevier - Evolve. https://pageburstls.elsevier.com/books/9780323789905

Image credit:

Rogers, J. (2025). McCance & Huether's Pathophysiology (9th ed.). Elsevier - Evolve. https://pageburstls.elsevier.com/books/9780323789905

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Delayed onset (usually 24–72 hours after exposure to the antigen)

Localized redness and inflammation at the site of antigen exposure

Induration (hardening) and swelling due to T-cell and macrophage infiltration

Itching or burning sensation at the affected area

Erythema (skin redness) and warmth

Papules or vesicles (small bumps or fluid-filled blisters), especially in contact dermatitis

Tissue damage or necrosis in severe or chronic reactions

Granuloma formation in persistent infections (e.g., tuberculosis, leprosy)

Ulceration in advanced or prolonged inflammation

Systemic symptoms (in some cases): fever, malaise, or lymph node enlargement if widespread inflammation occurs

References

1. Huether, S. E., McCance, K. L., & Brashers, V. L. (2025). Understanding pathophysiology (8th ed.). Elsevier.

2. McCance, K. L., & Huether, S. E. (2023). Pathophysiology: The biologic basis for disease in adults and children (9th ed.). Elsevier.

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Corticosteroids (Primary Treatment)

Topical: Mild Contact Dermatitis

Systemic: Severe reactions, transplant rejection, granulomatous disease

MOA: Suppress T-cell activation and inflammatory mediators

Calcineurin Inhibitors

Topical: Tracolimus and Pimecrolimus for contact dermatitis

Systemic: Transplant rejection prevention

MOA: Suppress T-cell function

Immunosuppressants

Azathiprine and Mycophenolate: Transplant rejection, severe autoimmune conditions

Methotrexate: Crohn's Disease and Sarcoidosis

MOA: Block T-cell proliferation

Antihistamines

Symptom relief of pruritus in contact dermatitis

Avoidance or Elimination

Remove or avoid triggering allergen

Gloves can be worn to prevent nighttime itching

References:

Contact dermatitis: What is it, causes, signs, symptoms, and more | osmosis. (n.d.-a). https://www.osmosis.org/answers/contact-dermatitis

Le, T., Bhushan, V., Qiu, C., Chalise, A., & Kaparaliotis, P. (2025). First aid for the USMLE Step 1 2025 (35th ed.). McGraw-Hill Education / Medical.

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Mechanism of Type IV - Cell Mediated Hypersensitivity

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Cellular pathophysiology, including principal effector cells and antibodies as applicable

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Cellular pathophysiology, including principal effector cells and antibodies as applicable

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Type IV hypersensitivity are cell mediated hypersensitivity reactions mediated by T lymphocytes. Type IV mechanisms occur through presentation of antigens on major histocompatibility molecules (a process of compatibility of tissue and organ between a donor and recipient) to T cells. Th cells then produce Th1 and Th17 cytokines which then recruit and produce lymphokines (interferon-γ) to activate macrophages and stimulate T cells to differentiate into T cytotoxic cells (Tc cells) which induces apoptosis and directly kills target cells.

The macrophages attach to targets and release soluble factors like lysosomal enzymes and toxic reactive oxygen species responsible for tissue damage or destruction. However, the response is delayed (about 24-72 hrs.) because of the time needed for sensitized T cells to travel to site of antigen re-exposure and time needed to produce cytokines that will activate other cells including macrophages.

If T cells or macrophages cannot kill or remove the target cells, they surround and contain the antigens through formation of multiple granulomas that can lead to tissue damage or organ dysfunction.

References:

Rogers, J. (2025). McCance & Huether's Pathophysiology (9th ed.). Elsevier - Evolve. https://pageburstls.elsevier.com/books/9780323789905

Image credit:

Rogers, J. (2025). McCance & Huether's Pathophysiology (9th ed.). Elsevier - Evolve. https://pageburstls.elsevier.com/books/9780323789905