Type IV Hypersensitivities: Videos & Practice Problems

Type four hypersensitivities are delayed T cell-mediated immune responses, distinct from antibody-driven types. They involve sensitization upon first antigen exposure, with peak reactions occurring 24-72 hours later. Common examples include contact dermatitis from haptens like poison ivy oils and the tuberculin skin test using purified protein derivative (PPD) from Mycobacterium tuberculosis. These hypersensitivities can cause autoimmune diseases such as type one diabetes. The tuberculin test detects immune memory, not active infection, highlighting the role of adaptive immunity and T lymphocytes in delayed hypersensitivity reactions and inflammation.

Type IV Hypersensitivity

Type four hypersensitivity, also known as delayed cell-mediated hypersensitivity, is a unique immune response primarily mediated by T cells rather than B cells or antibodies. This distinction sets it apart from other hypersensitivity types, as the reaction involves a delayed T cell-driven process that typically peaks between 24 to 72 hours after re-exposure to an antigen. Unlike other hypersensitivities, which may also be delayed, type four hypersensitivity is characterized by the involvement of T cells, making the immune response inherently slower due to the time required for T cell activation and proliferation.

This hypersensitivity requires prior sensitization, where naive T cells encounter the antigen for the first time and differentiate into memory T cells over approximately 7 to 10 days. The hypersensitivity reaction itself only occurs upon subsequent exposures, when these memory T cells rapidly respond to the antigen. This mechanism explains why symptoms such as contact dermatitis—commonly triggered by poison ivy or latex—and autoimmune conditions like type 1 diabetes manifest after repeated antigen exposure.

Type four hypersensitivity can be triggered by foreign antigens or, in cases of failed self-tolerance, by self-antigens, leading to autoimmune diseases. For example, type 1 diabetes results from a T cell-mediated attack on pancreatic cells, illustrating how this hypersensitivity contributes to autoimmunity. Despite extensive research, the precise factors determining why certain antigens provoke type four hypersensitivity rather than other types remain under investigation, highlighting ongoing gaps in immunological understanding.

In summary, type four hypersensitivity involves a delayed, T cell-mediated immune overreaction that follows initial sensitization and leads to various clinical conditions. The process is defined by the activation and proliferation of memory T cells, which upon re-exposure to the antigen, orchestrate an immune response peaking within one to three days. This knowledge is crucial for understanding immune responses in contact dermatitis, tuberculin hypersensitivity, and autoimmune diseases, emphasizing the role of T cells in delayed hypersensitivity reactions.

Type IV Hypersensitivities Example 1

Hypersensitivity reactions are classified into four main types, often remembered by the acronym ACID. This mnemonic helps to associate each type with its underlying mechanism and clinical characteristics.

The letter A stands for allergic reactions, which correspond to Type I hypersensitivity. These reactions are rapid or immediate responses triggered by allergens. They involve the release of pro-inflammatory mediators such as histamine from mast cells and basophils, leading to symptoms like anaphylaxis, hay fever, or asthma. This immediate response is a hallmark of Type I hypersensitivity.

C represents cytotoxic, which relates to Type II hypersensitivity. In this type, antibodies bind to antigens present on the surface of cells, marking them for destruction. This antibody-mediated cytotoxicity can lead to conditions such as hemolytic anemia or transfusion reactions, where the immune system targets and destroys the body's own cells.

The letter I stands for immune complex-mediated, describing Type III hypersensitivity. This involves the formation of antigen-antibody complexes that are not efficiently cleared by phagocytes. These immune complexes deposit in tissues, triggering inflammation and tissue damage, as seen in diseases like systemic lupus erythematosus or rheumatoid arthritis.

Finally, D denotes delayed T cell-mediated hypersensitivity, which is characteristic of Type IV hypersensitivity. Unlike the other types, this reaction is mediated by T cells rather than antibodies and typically manifests several days after exposure to the antigen. Examples include contact dermatitis and the tuberculin skin test reaction.

Understanding these four types of hypersensitivity and their mechanisms is crucial for diagnosing and managing allergic and autoimmune conditions effectively.

How do type IV hypersensitivity reactions differ from type I hypersensitivity reactions?

• A. The length of time between second antigen exposure and the body’s hypersensitivity reaction.
• B. Type I reactions can be triggered by any antigen while type IV reactions are triggered by foreign cells only.
• C. Type I reactions occur after an individual has been sensitized to an allergen while type IV reactions happen during first exposure/sensitization.
• D. Type I reactions are triggered by immune complexes and type IV reactions are triggered by foreign cells.

Answer: (A)

1) Contact Dermatitis

Contact dermatitis is a type of skin inflammation caused by a type four hypersensitivity reaction, also known as allergic contact dermatitis. This condition manifests as a red, itchy, and irritated skin rash. The term "dermatitis" combines "derm," meaning skin, and "itis," meaning inflammation, highlighting that this is an inflammatory response of the skin. Allergic contact dermatitis typically results from direct contact with small molecules called haptens. Haptens are not immunogenic on their own; they must first bind to larger host proteins to trigger an immune response.

Common haptens include substances found in latex products, leather, and the oils of poison ivy. While not everyone develops a type four hypersensitivity to these substances, many individuals do. Type four hypersensitivities are less common than type one hypersensitivities but more frequent than type two and three hypersensitivities.

The immune response in allergic contact dermatitis is mediated by T cells rather than antibodies, distinguishing it as a cell-mediated hypersensitivity. Upon first exposure to a hapten, such as the oils from poison ivy, the immune system undergoes sensitization. During this phase, haptens bind to skin proteins and activate naive T cells, which proliferate and differentiate into memory T cells. Importantly, the initial contact does not cause the rash; instead, it primes the immune system.

Subsequent exposures to the same hapten lead to a rapid and robust immune response. Memory T cells recognize the hapten-protein complexes and release cytokines, causing the characteristic red, itchy rash of contact dermatitis. This reaction is delayed, typically peaking one to three days after exposure, which can make it difficult to identify the cause of the rash if the exposure was forgotten.

To diagnose allergic contact dermatitis, especially when the cause is unclear, a patch test can be employed. This test involves applying small amounts of suspected allergens to the skin to observe if a hypersensitivity reaction occurs, helping to pinpoint the offending substance.

Understanding the mechanisms of type four hypersensitivity and the role of haptens in allergic contact dermatitis is crucial for recognizing, diagnosing, and managing this common skin condition effectively.

Which of the following statements about haptens is correct?

• A. Haptens are large, immunogenic proteins.
• B. Haptens can only be produced artificially, they are not found in the natural environment.
• C. Haptens are the cause of hemolytic transfusion reactions.
• D. Haptens are small molecules that become immunogenic when they bind to a larger host protein.

Answer: (D)

Which of the following statements describes why contact dermatitis is a type IV hypersensitivity reaction?

• A. Haptens bind with proteins & become immunogenic leading to a delayed, T cell-mediated immune response.
• B. Antibodies migrate to the site of contact & mediate an immune response.
• C. Contact dermatitis causes a skin rash, which is unique to type IV hypersensitivities. 
• D. Contact dermatitis is caused by foreign antigens; other hypersensitivities are usually caused by self-antigens.

Answer: (A)

2) Tuberculin Skin Test

The tuberculin skin test, also known as the purified protein derivative (PPD) test, is a diagnostic tool used to detect a type IV hypersensitivity reaction, which is a delayed T cell-mediated immune response. This test involves injecting tuberculin, a protein extracted from Mycobacterium tuberculosis, just beneath the skin. The primary purpose of the test is to assess whether the immune system has previously encountered tuberculosis (TB) antigens, indicating immune memory rather than confirming active tuberculosis infection.

It is important to understand that a positive tuberculin skin test does not definitively diagnose active tuberculosis. Instead, it signals that the individual’s immune system has been sensitized to TB-related proteins, which could result from a past infection, current infection, or even prior vaccination with the Bacillus Calmette-Guérin (BCG) vaccine. Therefore, the test serves as a screening method to identify individuals who may require further evaluation for tuberculosis, much like a metal detector flags potential threats for additional inspection.

The test procedure involves injecting the PPD intradermally and then waiting 48 to 72 hours to observe the skin’s reaction. A negative result shows no significant skin change, indicating no hypersensitivity. A positive result is characterized by an induration—an area of raised, red, and inflamed skin—at the injection site. This induration reflects the delayed hypersensitivity response mediated by T cells recognizing the tuberculin antigen.

Understanding the tuberculin skin test requires recognizing its role in immunology as a type IV hypersensitivity assay, which relies on cellular immunity rather than antibodies. This delayed reaction is a hallmark of T cell activation and cytokine release, leading to localized inflammation. The test’s interpretation must consider patient history, including prior TB exposure and vaccination status, to guide appropriate clinical follow-up.

Red, raised, and hardened skin patches in association with tuberculin injections are called indurations. Which cells are responsible for triggering the immune response to the tuberculin which results in indurations?

• A. Sensitized B cells.
• B. Sensitized T cells.
• C. Sensitized plasma cells.
• D. Anti-tuberculin antibodies.

Answer: (B)

Which of the following statements about the tuberculin skin test is true?

• A. Patients who have not been exposed to Mycobacterium tuberculosis antigens will have a positive test result.
• B. Patients with a positive result may not know for a few days because it is a delayed hypersensitivity reaction.
• C. Patients who have not contracted TB but have been sensitized to TB antigens will have a negative test result.
• D. Patients who have recently had a TB infection will have a positive result, but patients vaccinated against TB will have a negative result.

Answer: (B)

Here’s what students ask on this topic:

What is the mechanism behind Type IV hypersensitivity and how does it differ from other hypersensitivity types?

Type IV hypersensitivity is a delayed immune response mediated by T cells rather than antibodies, which distinguishes it from Types I, II, and III hypersensitivities that involve B cells and antibodies. Upon first exposure to an antigen, naive T cells become sensitized and differentiate into memory T cells over 7 to 10 days. Upon subsequent exposure, these memory T cells recognize the antigen and release cytokines, leading to inflammation and tissue damage. The reaction typically peaks 24 to 72 hours after re-exposure, hence the term "delayed hypersensitivity." This T cell-mediated process is slower compared to antibody-mediated responses, which can occur within minutes to hours. Examples include contact dermatitis and tuberculin skin test reactions. Understanding this mechanism is crucial for recognizing how cellular immunity contributes to hypersensitivity and autoimmune diseases like type 1 diabetes.

How does contact dermatitis develop as a Type IV hypersensitivity reaction?

Contact dermatitis is a classic example of a Type IV hypersensitivity reaction caused by direct skin contact with small molecules called haptens, such as poison ivy oils or latex. Haptens are not immunogenic alone but become so when they bind to larger host proteins. During the first exposure, the immune system is sensitized as naive T cells recognize the hapten-protein complex and differentiate into memory T cells. No rash appears at this stage. Upon subsequent exposures, these memory T cells rapidly respond by releasing cytokines that cause inflammation, redness, and itching, typically peaking 1 to 3 days later. This delayed response explains why the rash appears after some time rather than immediately. Patch testing can help identify the specific allergen causing the dermatitis by observing the skin's reaction to suspected haptens.

What is the purpose of the tuberculin skin test and how does it relate to Type IV hypersensitivity?

The tuberculin skin test (also called the PPD test) is used to detect whether a person’s immune system has been previously exposed to Mycobacterium tuberculosis proteins. It involves injecting purified protein derivative (PPD) under the skin and observing the reaction 48 to 72 hours later. This test relies on a Type IV hypersensitivity reaction, where memory T cells recognize the tuberculin antigen and trigger localized inflammation, resulting in a raised, red, and swollen area called an induration. Importantly, a positive test indicates immune memory but does not confirm active tuberculosis infection. It cannot distinguish between past infection, current infection, or vaccination. Therefore, it serves as a screening tool to identify individuals who need further evaluation for tuberculosis.

Why are Type IV hypersensitivity reactions considered delayed, and what is the typical time frame for their peak response?

Type IV hypersensitivity reactions are considered delayed because they are mediated by T cells, which require time to recognize antigens, proliferate, and release cytokines that cause inflammation. Unlike antibody-mediated hypersensitivities that can occur within minutes, Type IV reactions typically take 24 to 72 hours to reach their peak. This delay is due to the cellular processes involved, including antigen presentation, T cell activation, and recruitment of other immune cells to the site of antigen exposure. The delayed nature is a hallmark of this hypersensitivity type and is important for diagnosing conditions like contact dermatitis and interpreting tests such as the tuberculin skin test.

How can Type IV hypersensitivity contribute to autoimmune diseases like type 1 diabetes?

Type IV hypersensitivity can contribute to autoimmune diseases when T cells mistakenly recognize self-antigens as foreign and mount an immune response against the body’s own tissues. In type 1 diabetes, autoreactive T cells attack insulin-producing beta cells in the pancreas, leading to their destruction and resulting in impaired insulin production. This T cell-mediated autoimmune attack is a form of delayed hypersensitivity because it involves sensitization and memory T cell responses. Failure in self-tolerance mechanisms allows these harmful T cells to persist and cause chronic inflammation and tissue damage, illustrating how Type IV hypersensitivity can underlie autoimmune pathology.