Type IV (Cell Mediated) Hypersensitivity- Mechanism and Examples

Hypersensitivity is a term used to describe an abnormal or excessive immune response to a foreign substance or antigen. Hypersensitivity reactions can be classified into four types based on the mechanism and the time course of the reaction.

Type IV hypersensitivity, also known as delayed type hypersensitivity or cell mediated hypersensitivity, is a type of immune reaction that involves the activation of T cells and macrophages. Unlike the other types of hypersensitivity, which are mediated by antibodies, type IV hypersensitivity does not involve antibodies or complement. Instead, it is triggered by antigens that are either presented by antigen-presenting cells (APCs) or bound to body proteins.

Type IV hypersensitivity is characterized by a delayed onset of symptoms, usually 24 to 72 hours after exposure to the antigen. The symptoms are caused by the release of inflammatory cytokines and the recruitment of other immune cells to the site of antigen exposure. The inflammation can result in tissue damage and chronic diseases.

Type IV hypersensitivity can be caused by various types of antigens, such as intracellular pathogens (e.g., Mycobacterium tuberculosis, Listeria monocytogenes), contact allergens (e.g., nickel, poison ivy), or self-antigens (e.g., in autoimmune diseases). Some examples of type IV hypersensitivity reactions are the tuberculin reaction, granuloma formation, allergic contact dermatitis, and type-1 diabetes.

In this article, we will discuss the mechanism and variants of type IV hypersensitivity and provide some examples of this type of immune response. We will also explain how type IV hypersensitivity can be diagnosed and treated.

Type IV hypersensitivity reaction is also known as delayed type hypersensitivity (DTH) because it takes about 48 to 72 hours to develop after the exposure to the antigen. Unlike other types of hypersensitivity reactions that involve antibodies, type IV hypersensitivity reaction is mediated by T cells and macrophages.

The mechanism of type IV hypersensitivity reaction can be divided into two phases: the sensitization phase and the effector phase.

Sensitization phase

The sensitization phase occurs when a person is exposed to an antigen for the first time. The antigen can be either an intracellular pathogen (such as Mycobacterium tuberculosis, Listeria monocytogenes, Histoplasma capsulatum, Herpes simplex virus, etc.) or a contact allergen (such as nickel, formaldehyde, poison ivy, etc.). The antigen is processed and presented by antigen-presenting cells (APCs), such as dendritic cells, macrophages, or B cells, to naive CD4+ T cells in the lymph nodes. The CD4+ T cells differentiate into Th1 cells under the influence of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma) produced by the APCs and natural killer (NK) cells. The Th1 cells proliferate and produce more IFN-gamma and other cytokines, such as interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-alpha). These cytokines activate and recruit more macrophages and cytotoxic CD8+ T cells to the site of antigen exposure. The sensitized Th1 cells also express chemokine receptors that allow them to migrate to the tissues where the antigen is present. The sensitization phase takes about 10 to 14 days to complete.

Effector phase

The effector phase occurs when the person is re-exposed to the same antigen. The antigen is recognized by the memory Th1 cells that have migrated to the tissues. The Th1 cells secrete more IFN-gamma and other cytokines that activate and attract more macrophages and CD8+ T cells to the site of inflammation. The activated macrophages become more efficient in killing the intracellular pathogens or phagocytosing the antigen-allergen complexes. They also secrete inflammatory mediators, such as reactive oxygen species (ROS), nitric oxide (NO), proteases, and lysozyme, that cause tissue damage and necrosis. The activated CD8+ T cells directly kill the target cells that express the antigen on their surface by releasing perforin and granzymes that induce apoptosis. The effector phase peaks at about 48 to 72 hours after the re-exposure to the antigen and then gradually subsides.

The type IV hypersensitivity reaction is beneficial in eliminating intracellular pathogens that are resistant to antibody-mediated clearance. However, it can also cause tissue damage and chronic inflammation in some cases, such as tuberculosis, leprosy, sarcoidosis, granulomatosis with polyangiitis, allergic contact dermatitis, type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, etc.

Type IV hypersensitivity reactions can be classified into four subtypes based on the type of antigen, the effector cells and the cytokines involved. These subtypes are:

• Type IVa: This subtype is mediated by Th1 cells that produce interferon gamma (IFN-γ) and activate macrophages. The macrophages then release inflammatory mediators and cause tissue damage. This subtype is responsible for tuberculin-type hypersensitivity, granuloma formation and some autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.
• Type IVb: This subtype is mediated by Th2 cells that produce interleukin-4 (IL-4) and interleukin-13 (IL-13) and activate eosinophils and mast cells. The eosinophils and mast cells then release cytotoxic granules and cause tissue damage. This subtype is responsible for some allergic reactions such as chronic asthma and atopic dermatitis.
• Type IVc: This subtype is mediated by cytotoxic T cells (CTLs) that recognize antigens on the surface of target cells and induce apoptosis. This subtype is responsible for some organ-specific autoimmune diseases such as type 1 diabetes, autoimmune thyroiditis and celiac disease.
• Type IVd: This subtype is mediated by neutrophils that are recruited by cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-8 (IL-8) and cause tissue damage by releasing reactive oxygen species and proteases. This subtype is responsible for some inflammatory diseases such as psoriasis, contact dermatitis and pustular acne.

• Contact hypersensitivity is a form of type IV hypersensitivity that occurs when the skin comes into contact with certain substances that act as haptens.
• Haptens are small molecules that can bind to body proteins and trigger an immune response.
• Some examples of haptens are nickel, formaldehyde, poison ivy, cosmetics, soaps, and latex .
• Contact hypersensitivity involves two phases: sensitization and effector .
• In the sensitization phase, the first exposure to the hapten leads to the activation and expansion of specific T cells that recognize the hapten-protein complex .
• In the effector phase, the subsequent exposure to the same hapten causes the T cells to release cytokines that recruit and activate macrophages and other inflammatory cells .
• The result is a delayed-type hypersensitivity reaction that manifests as redness, swelling, itching, vesicles, eczema, or necrosis of the skin within 12-48 hours after contact .
• Contact hypersensitivity is usually confined to the site of contact, but it can spread to other areas or become generalized in some cases .
• Contact hypersensitivity can be diagnosed by patch testing, which involves applying small amounts of suspected haptens on the skin and observing for any reaction after 48 hours .
• Contact hypersensitivity can be treated by avoiding the offending hapten, applying topical corticosteroids or calcineurin inhibitors, or taking oral antihistamines or immunosuppressants in severe cases .

Tuberculin-type hypersensitivity is a type of delayed hypersensitivity reaction that occurs due to sensitization of soluble antigens of microorganisms during many infectious diseases. It is exemplified by the tuberculin reaction, which is used as the basis of a diagnostic skin test for an immune response to tuberculosis.

The tuberculin reaction is also known as the Mantoux test. It involves injecting a small amount of purified protein derivative (PPD), which contains antigens derived from Mycobacterium tuberculosis, into the skin of a person previously exposed to the bacterium. Within 24 to 72 hours, the site of injection becomes indurated (hardened) and erythematous (reddened) due to the accumulation of mononuclear cells, mainly CD4+ T cells, in the subcutaneous tissue. The diameter of the induration is measured and interpreted according to the risk factors and exposure history of the person.

The tuberculin reaction is an example of a recall response, meaning that it reflects the memory of the immune system to a previously encountered antigen. The reaction is mediated by T helper 1 (Th1) cells, which produce cytokines such as interferon-gamma and tumor necrosis factor-alpha that activate macrophages and other inflammatory cells. These cells are responsible for containing the infection and killing the intracellular bacteria, but they also cause tissue damage and inflammation in the process.

The tuberculin reaction is not specific for tuberculosis, as it can also be positive in people who have been vaccinated with bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, or who have been infected with other mycobacteria or nontuberculous bacteria. Therefore, the test results should be interpreted with caution and in conjunction with other clinical and laboratory findings.

Type IV hypersensitivity reactions are mediated by T cells and can cause various diseases and disorders depending on the type of antigen and the site of inflammation. Some examples of type IV hypersensitivity reactions are:

• The tuberculin reaction (Mantoux test): This is a ‘recall’ response to purified mycobacterial antigens and is used as the basis of a diagnostic skin test for an immune response to tuberculosis. A small amount of tuberculin is injected into the skin of a person previously exposed to Mycobacterium tuberculosis, and the site is examined after 48-72 hours. If the person has been sensitized to the antigen, a red and swollen induration will form at the injection site, indicating the presence of activated T cells and macrophages.
• Granuloma formation: The inability to kill intracellular pathogens in macrophages often results in a chronic stimulation of the pathogen specific T cells. The cytokines produced by these T cells are responsible for ‘walling off’ the macrophages containing the persistent antigens and thus the production of granulomas. Granulomas are nodular lesions composed of epithelioid cells, multinucleated giant cells, lymphocytes, and fibroblasts. Granulomas can be seen in tuberculosis, leprosy, sarcoidosis, Crohn`s disease, and other chronic infections.
• Allergic contact dermatitis: Environmental chemicals, metals or topical medications that act as haptens can induce cell-mediated hypersensitivity particularly in the skin. Haptens are small molecules that bind to body proteins and elicit an immune response. On subsequent exposure to the same hapten, the sensitized person develops erythema, itching, vesication, eczema, or necrosis of skin within 12-48 hours. Examples of haptens that can cause allergic contact dermatitis are nickel, formaldehyde, poison ivy, latex, and penicillin.
• Type-1 diabetes: The killing of the pancreatic islet cells by cytotoxic T cells resulting in insulin deficiency. Type-1 diabetes is an autoimmune disease in which the immune system attacks the insulin-producing beta cells of the pancreas. The exact cause of this attack is unknown, but it may involve genetic susceptibility and environmental triggers. Some possible autoantigens that can activate T cells against beta cells are insulin, glutamate decarboxylase, and zinc transporter 8.

The tuberculin reaction, also known as the Mantoux test, is a diagnostic tool for detecting latent tuberculosis infection. It is based on the principle of type IV hypersensitivity, in which a delayed inflammatory response occurs in individuals who have been previously exposed to Mycobacterium tuberculosis.

The test involves injecting a purified protein derivative (PPD) of tuberculin, which contains antigens from the mycobacterium, into the forearm of the person being tested. The PPD acts as a recall antigen, stimulating the memory T cells that were sensitized during the initial infection. These T cells produce cytokines that recruit and activate macrophages and other inflammatory cells to the site of injection, resulting in a visible induration (hardening) and erythema (redness) of the skin.

The size of the induration is measured after 48 to 72 hours and is interpreted according to the risk factors and exposure history of the person being tested. A positive reaction indicates that the person has been infected with M. tuberculosis at some point in their life, but does not necessarily mean that they have active tuberculosis disease. A negative reaction means that either the person has never been infected or their immune response is too weak to mount a detectable reaction.

The tuberculin reaction is not a perfect test, as it can have false-positive and false-negative results. False-positive results can occur in people who have been vaccinated with bacillus Calmette-Guérin (BCG), a live attenuated strain of M. bovis that confers partial protection against tuberculosis, or in people who have been exposed to other environmental mycobacteria that share antigens with M. tuberculosis. False-negative results can occur in people who have impaired cell-mediated immunity due to HIV infection, malnutrition, immunosuppressive drugs, or other conditions that affect T cell function.

The tuberculin reaction is one of the most widely used tests for tuberculosis screening and diagnosis, especially in low-resource settings where more sophisticated tests are not available or affordable. However, it has some limitations and drawbacks, such as requiring two visits to a health facility, being subject to inter-observer variability, and causing discomfort and possible adverse reactions in some individuals. Therefore, newer tests based on detecting interferon gamma release by T cells or molecular identification of M. tuberculosis DNA or RNA are being developed and evaluated as alternatives or complements to the tuberculin reaction.

A granuloma is a collection of immune cells that forms around a foreign material or a persistent antigen that cannot be eliminated by the immune system. Granulomas are often seen in chronic infections caused by intracellular pathogens such as Mycobacterium tuberculosis, Listeria monocytogens, Histoplasma capsulatum, etc. Granulomas are also associated with some autoimmune diseases such as sarcoidosis and Crohn`s disease.

The formation of granulomas is a type of delayed hypersensitivity reaction mediated by Th1 cells and macrophages. When macrophages encounter an intracellular pathogen, they ingest and degrade it in their phagolysosomes. However, some pathogens can resist or escape the killing mechanisms of the macrophages and persist inside them. These pathogens also stimulate the production of cytokines such as IL-12 and TNF-alpha by the macrophages, which activate and recruit more Th1 cells to the site of infection.

The Th1 cells recognize the antigens presented by the macrophages and secrete more cytokines such as IFN-gamma and TNF-beta. These cytokines enhance the phagocytic and microbicidal activity of the macrophages and also induce them to express more MHC class II molecules and co-stimulatory molecules. This leads to a positive feedback loop that amplifies the immune response and results in the formation of a granuloma.

A granuloma consists of a central core of infected macrophages surrounded by a layer of activated epithelioid cells (modified macrophages with increased cytoplasm) and multinucleated giant cells (fused macrophages). The outer layer of the granuloma is composed of lymphocytes, fibroblasts, and collagen fibers. The granuloma serves to isolate and contain the pathogen from spreading to other tissues. However, it also causes tissue damage and inflammation in the affected organ.

Granulomas can be classified into two types based on their morphology: caseating and non-caseating. Caseating granulomas have a necrotic center that resembles cheese (caseum) due to cell death and tissue breakdown. Non-caseating granulomas have no necrosis and are more organized and compact. Caseating granulomas are typically seen in tuberculosis, while non-caseating granulomas are more common in sarcoidosis.

Granuloma formation is an example of how the immune system tries to protect the host from persistent infections, but at the same time causes chronic inflammation and tissue damage. Granulomas can impair the function of vital organs such as the lungs, liver, spleen, etc. Granulomas can also calcify over time and become visible on X-rays or CT scans. Granulomas can sometimes resolve spontaneously or with treatment, but they can also persist for years or even decades.

Allergic contact dermatitis (ACD) is a type of skin inflammation that occurs when the skin comes into contact with a substance that triggers an allergic reaction. Unlike irritant contact dermatitis, which is caused by direct damage to the skin by a substance, ACD involves an immune system response that makes the skin itchy and irritated.

ACD can be caused by various substances, such as:

• Metals, such as nickel, gold, or cobalt
• Cosmetics, such as perfumes, hair dyes, or nail polish
• Plants, such as poison ivy, poison oak, or mango
• Medications, such as antibiotics, topical steroids, or antihistamines
• Rubber products, such as latex gloves or rubber bands

The symptoms of ACD usually appear 12 to 72 hours after exposure to the allergen and may last for two to four weeks. The symptoms include:

• Redness and swelling of the skin
• Itching and burning sensation
• Blisters and oozing of fluid
• Dryness and scaling of the skin
• Hives or welts

The diagnosis of ACD is based on the history of exposure, the pattern and distribution of the rash, and sometimes a patch test . A patch test involves applying small amounts of potential allergens to the skin and observing for any reactions after 48 to 72 hours .

The treatment of ACD involves avoiding the allergen, applying moisturizers and corticosteroid creams to the affected skin, taking oral antihistamines to relieve itching, and in severe cases, taking oral corticosteroids or immunosuppressants to reduce inflammation .

The prevention of ACD involves identifying and avoiding the allergen, wearing protective clothing and gloves when handling potential irritants, and using hypoallergenic products for personal care .

ACD is a common and sometimes chronic condition that can affect the quality of life of affected individuals. However, with proper diagnosis and management, it can be controlled and prevented.

Type-1 diabetes is a chronic autoimmune disease in which the immune system attacks and destroys the insulin-producing beta cells of the pancreas. Insulin is a hormone that regulates the blood glucose level and is essential for energy metabolism. Without insulin, the body cannot use glucose as fuel and instead breaks down fats and proteins, leading to ketoacidosis and other complications.

The exact cause of type-1 diabetes is unknown, but it is believed to involve a combination of genetic and environmental factors. Some of the possible triggers for the autoimmune attack are viral infections, dietary antigens, stress, or exposure to certain chemicals.

Type-1 diabetes is an example of type IV (cell mediated) hypersensitivity, in which the antigen-specific T cells are responsible for the tissue damage. The antigens that trigger the T cell response are likely derived from the beta cells themselves or from exogenous sources that cross-react with them.

The T cell-mediated destruction of the beta cells occurs in two phases: the initiation phase and the progression phase. In the initiation phase, the antigen-presenting cells (APCs) such as dendritic cells or macrophages capture and process the antigens and present them to naive CD4+ T cells in the lymph nodes. The activated CD4+ T cells then differentiate into Th1 cells that produce cytokines such as interferon gamma (IFN-gamma) and interleukin-2 (IL-2) that promote the activation and proliferation of cytotoxic CD8+ T cells. The cytotoxic CD8+ T cells are the main effector cells that recognize and kill the beta cells by releasing perforin and granzymes.

In the progression phase, the T cell-mediated attack on the beta cells continues and leads to a gradual loss of insulin secretion and function. The beta cell mass decreases over time until it reaches a critical threshold below which hyperglycemia and clinical symptoms appear. The onset of type-1 diabetes can vary from weeks to years depending on the rate of beta cell destruction and the residual insulin production.

The diagnosis of type-1 diabetes is based on the presence of hyperglycemia, ketoacidosis, and autoantibodies against beta cell antigens such as glutamic acid decarboxylase (GAD), insulin, or islet antigen-2 (IA-2). The treatment of type-1 diabetes involves lifelong insulin replacement therapy, blood glucose monitoring, and management of complications such as cardiovascular disease, nephropathy, neuropathy, and retinopathy.

Type-1 diabetes is a serious and incurable disease that affects millions of people worldwide. However, there are several promising strategies for preventing or reversing type-1 diabetes, such as immunotherapy, gene therapy, stem cell therapy, or islet transplantation. These approaches aim to modulate the immune system, restore or replace the beta cells, or protect them from further damage.

Type IV hypersensitivity reactions are usually self-limiting and resolve within a few days or weeks after the removal of the antigen. However, some cases may require medical intervention to reduce the inflammation and tissue damage caused by the immune response. The treatment options for Type IV hypersensitivity may include:

• Topical corticosteroids: These are anti-inflammatory drugs that can be applied to the skin to reduce itching, swelling, and redness caused by contact dermatitis or other skin reactions. They work by suppressing the activity of T cells and macrophages in the affected area. Examples of topical corticosteroids are hydrocortisone, betamethasone, and clobetasol.
• Oral corticosteroids: These are systemic drugs that can be taken by mouth to treat severe or widespread Type IV hypersensitivity reactions, such as granuloma formation or type-1 diabetes. They work by reducing the production of cytokines and inhibiting the migration of inflammatory cells to the site of antigen exposure. Examples of oral corticosteroids are prednisone, methylprednisolone, and dexamethasone.
• Trigger avoidance: This is the most effective way to prevent or reduce Type IV hypersensitivity reactions. It involves identifying and avoiding the antigen that causes the immune response, such as certain foods, drugs, metals, plants, or microorganisms. For example, people with latex allergy should avoid contact with latex products, such as gloves, balloons, or condoms. People with tuberculosis should avoid exposure to tuberculin or other mycobacterial antigens.

Type IV hypersensitivity reactions can be serious and potentially life-threatening if they affect vital organs or cause severe inflammation. Therefore, it is important to seek medical attention if you experience any signs or symptoms of Type IV hypersensitivity, such as fever, joint pain, swollen lymph nodes, difficulty breathing, or skin rash. Your doctor can diagnose the type and cause of your hypersensitivity reaction and prescribe the appropriate treatment for you.

We are Compiling this Section. Thanks for your understanding.