24.4: Type IV Hypersensitivities

Learning Objectives

• Describe the three subtypes of type IV hypersensitivity
• Explain how T cells contribute to tissue damage in type IV hypersensitivity

Type IV Hypersensitivities

Type IV hypersensitivities are not mediated by antibodies like the other three types of hypersensitivities. Rather, type IV hypersensitivities are regulated by T cells and involve the action of effector cells. These types of hypersensitivities can be organized into three subcategories based on T-cell subtype, type of antigen, and the resulting effector mechanism (Table \(\PageIndex{5}\)).

In the first type IV subcategory, CD4 T_H1-mediated reactions are described as delayed-type hypersensitivities (DTH). The sensitization step involves the introduction of antigen into the skin and phagocytosis by local antigen presenting cells (APCs). The APCs activate helper T cells, stimulating clonal proliferation and differentiation into memory T_H1 cells. Upon subsequent exposure to the antigen, these sensitized memory T_H1 cells release cytokines that activate macrophages, and activated macrophages are responsible for much of the tissue damage. Examples of this T_H1-mediated hypersensitivity are observed in tuberculin the Mantoux skin test and contact dermatitis, such as occurs in latex allergy reactions.

In the second type IV subcategory, CD4 T_H2-mediated reactions result in chronic asthma or chronic allergic rhinitis. In these cases, the soluble antigen is first inhaled, resulting in eosinophil recruitment and activation with the release of cytokines and inflammatory mediators.

In the third type IV subcategory, CD8 cytotoxic T lymphocyte (CTL)-mediated reactions are associated with tissue transplant rejection and contact dermatitis (Figure \(\PageIndex{7}\)). For this form of cell-mediated hypersensitivity, APCs process and present the antigen with MHC I to naïve CD8 T cells. When these naïve CD8 T cells are activated, they proliferate and differentiate into CTLs. Activated T_H1 cells can also enhance the activation of the CTLs. The activated CTLs then target and induce granzyme-mediated apoptosis in cells presenting the same antigen with MHC I. These target cells could be “self” cells that have absorbed the foreign antigen (such as with contact dermatitis due to poison ivy), or they could be transplanted tissue cells displaying foreign antigen from the donor.

Figure \(\PageIndex{7}\): Exposure to hapten antigens in poison ivy can cause contact dermatitis, a type IV hypersensitivity. (a) The first exposure to poison ivy does not result in a reaction. However, sensitization stimulates helper T cells, leading to production of memory helper T cells that can become reactivated on future exposures. (b) Upon secondary exposure, the memory helper T cells become reactivated, producing inflammatory cytokines that stimulate macrophages and cytotoxic T cells to induce an inflammatory lesion at the exposed site. This lesion, which will persist until the allergen is removed, can inflict significant tissue damage if it continues long enough.

Table \(\PageIndex{5}\): Type IV Hypersensitivities

Subcategory	Antigen	Effector Mechanism	Examples
1	Soluble antigen	Activated macrophages damage tissue and promote inflammatory response	Contact dermatitis (e.g., exposure to latex) and delayed-type hypersensitivity (e.g., tuberculin reaction)
2	Soluble antigen	Eosinophil recruitment and activation release cytokines and pro-inflammatory chemicals	Chronic asthma and chronic allergic rhinitis
3	Cell-associated antigen	CTL-mediated cytotoxicity	Contact dermatitis (e.g., contact with poison ivy) and tissue-transplant rejection

Query \(\PageIndex{1}\)

Query \(\PageIndex{1}\)

Using Delayed Hypersensitivity to Test for TB

Austrian pediatrician Clemans von Pirquet (1874–1929) first described allergy mechanisms, including type III serum sickness.⁹ His interest led to the development of a test for tuberculosis (TB), using the tuberculin antigen, based on earlier work identifying the TB pathogen performed by Robert Koch. Pirquet’s method involved scarification, which results in simultaneous multiple punctures, using a device with an array of needles to break the skin numerous times in a small area. The device Pirquet used was similar to the tine testdevice with four needles seen in Figure \(\PageIndex{8}\).

The tips of all the needles in the array are coated with tuberculin, a protein extract of TB bacteria, effectively introducing the tuberculin into the skin. One to 3 days later, the area can be examined for a delayed hypersensitivity reaction, signs of which include swelling and redness.

As you can imagine, scarification was not a pleasant experience,¹⁰ and the numerous skin punctures put the patient at risk of developing bacterial infection of the skin. Mantoux modified Pirquet’s test to use a single subcutaneous injection of purified tuberculin material. A positive test, which is indicated by a delayed localized swelling at the injection site, does not necessarily mean that the patient is currently infected with active TB. Because type IV (delayed-type) hypersensitivity is mediated by reactivation of memory T cells, such cells may have been created recently (due to an active current infection) or years prior (if a patient had TB and had spontaneously cleared it, or if it had gone into latency). However, the test can be used to confirm infection in cases in which symptoms in the patient or findings on a radiograph suggest its presence.

Figure \(\PageIndex{8}\): The modern version of Pirquet’s scarification is the tine test, which uses devices like this to administer tuberculin antigen into the skin, usually on the inside of the forearm. The tine test is considered less reliable than the Mantoux test. (credit: modification of work by the Centers for Disease Control and Prevention)

Key Concepts and Summary

• Type IV hypersensitivities are not mediated by antibodies, but by helper T-cell activation of macrophages, eosinophils, and cytotoxic T cells.

Footnotes

1. B. Huber “100 Jahre Allergie: Clemens von Pirquet–sein Allergiebegriff und das ihm zugrunde liegende Krankheitsverständnis.” Wiener Klinische Wochenschrift 118 no. 19–20 (2006):573–579.
2. C.A. Stewart. “The Pirquet Test: Comparison of the Scarification and the Puncture Methods of Application.” Archives of Pediatrics & Adolescent Medicine 35 no. 3 (1928):388–391.