Contributors:Ursula Florjanczyk, MScBMC, Jennifer Montague, PhD, Evan Debevec-McKenney, Corinne Tarantino
A hypersensitivity reaction is an overreaction to a foreign antigen or against its own tissue which then causes serious damage to the body’s tissues. There are four types of hypersensitivity reactions: type I is immunoglobulin E, or IgE mediated; type II is mediated by antibodies that activate cellular cytotoxicity, type III is mediated by immune-complexes, and type IV is a delayed T cell mediated hypersensitivity reaction. A “cell mediated reaction” is not dependent on antibodies, which makes it different from the other 3 types. It’s called a delayed reaction because it usually takes 48 to 72 hours to recruit enough T cells and cause the reaction.
Let’s start by discussing the physiology of T cells. T cell precursors originate in the bone marrow but they migrate to the Thymus to mature; which is why they’re called T cells. In the thymus, they differentiate into many different types of T cells; this include T helper cells, and cytotoxic T cells, or killer T cells. Let’s talk about helper T cells first.
When a pathogen enters the body, APCs like macrophages or dendritic cells, then engulf and digest the pathogen and the fragments are then presented on the APC’s surface via proteins called major histocompatibility complex class II, or MHC II. Now these fragments serve as antigens which are any thing that could trigger an immune response. So the APCs present these antigens to naive T helper cells which have never been exposed to antigens. The T helper cells will recognize the antigen with their T cell receptors or TCRs, and mature. They will then release cytokines that enhance the immune response. One of these is interleukin 2 which causes the T cell and other T cells to proliferate. Other cytokines can attract immune cells like macrophages and neutrophils to the area, and they can also cause the blood vessel walls to become leaky, allowing these additional immune cells to reach the tissue where that pathogen is located.
Now, another type of T cell is the killer T cell which specializes in eliminating cells in the body that’s become “abnormal.” This could be a cell infected by a virus or a cell that mutated and became cancerous. When a cell gets invaded by a virus, some of the virus will be broken down and the fragments will be presented on the cell’s surface via MHC II proteins. These fragments act as antigens that can be recognized by killer T cells. Killer T cells then bind to the distressed cell and release enzymes like perforin, which form pores on the cell membrane, and granzymes, which go into the cell and cause it to undergo apoptosis, or programmed cell death.
Now, Type IV hypersensitivity reactions are caused by exposure to an antigen, most commonly viruses, bacteria, fungi, some medications like antibiotics or anticonvulsants, or plant oils like those found in poison ivy. So, a type IV hypersensitivity reaction occurs when T helper cells or killer T cells overreact to exogenous or endogenous antigens and over proliferate. So if the antigen is encountered again, a larger than normal immune response occurs. T helper cells will attract other immune cells like macrophages and neutrophils to cause damage to the tissue where the antigen is found, while Killer T cells will attack the cells of the tissue directly.
Okay, so clinical manifestations of type IV hypersensitivity reactions depend on the specific disorder. For disorders associated with T helper cells, one of the most common is allergic contact dermatitis. Common triggers include poison ivy, certain metals like nickel, and cosmetics or lotion. These allergens cause local inflammation in the skin. Common symptoms include red, itchy, painful rash with blisters, or patches of dry, cracked, scaly skin.
The tuberculosis skin test or PPD test is also an example of type IV hypersensitivity, here the antigen being picked up is PPD, or purified protein derivative, that was injected into the skin. So in most cases, if the person has previously been exposed to tuberculosis, they will have a larger number of helper T cells that will recognize PPD, so they’ll have a larger reaction. This takes the form of an induration where there’s swelling and hardening of the skin near the injection site. 2 to 3 days after administering the PPD, the induration is measured to see if an adequate type IV hypersensitivity reaction has occurred.