Type IV Delayed (Cell-Mediated) Hypersensitivity
Type IV hypersensitivity reaction is called delayed type hyper-sensitivity (DTH), because the response is delayed. It starts hours or days after primary contact with the antigen and often lasts for days. The reaction is characterized by large influxes of nonspecific inflammatory cells, in particular, macrophages. It differs from the other types of hypersensitivity by being medi-ated through cell-mediated immunity. This reaction occurs due to the activation of specifically sensitized T lymphocytes rather than the antibodies.
Initially described by Robert Koch in tuberculosis as a local-ized reaction, this form of hypersensitivity was known as tuber-culin reaction. Later, on realization that the reaction can be elicited in various pathologic conditions, it was renamed as delayed type hypersensitivity.
The DTH response begins with an initial sensitization phase of 1–2 weeks after primary contact with an antigen (Fig. 19-4):
· TH1 subtypes CD4 are the cells activated during the sensi-tization phase.
· A variety of antigen-presenting cells (APCs) including Langerhans cells and macrophages have been shown to be involved in the activation of a DTH response. These cells are believed to pick up the antigen that enters through the skin and transport it to regional lymph nodes, where T cells are activated by the antigen.
· The APCs present antigens complexed in the groove of major histocompatibility complex (MHC) molecules expressed on the cell surface of the APCs.
· For most protein antigens or haptens associated with skin DTH, CD41 T cells are presented with antigens bound to
MHC class II alleles, human leukocyte antigen (HLA)-DR, HLA-DP, and HLA-DQ. Specific MHC class II alleles are recognized to produce excessive immune activation to antigens.
· On subsequent exposure, the effector phase is stimulated. The TH1 cells are responsible in secreting a variety of cyto-kines that recruit and activate macrophages and other non-specific inflammatory cells.
· The response is marked only after 2–3 days of the second exposure. Generally, the pathogen is cleared rapidly with little tissue damage. However, in some cases, especially if the antigen is not easily cleared, a prolonged DTH response can itself become destructive to the host, as the intense inflam-matory response develops into a visible granulomatous reaction.
DTH reactions are of two types: contact hypersensitivity and tuberculin-type hypersensitivity reactions.
Contact hypersensitivity is a manifestation of DTH occur-ring after sensitization with certain substances. These include drugs, such as sulfonamides and neomycin; plant products, such as poison ivy and poison oak; chemicals, such as formaldehyde and nickel; and cosmetics, soaps and other substances.
This reaction manifests when these substances acting as haptens enter the skin and combine with body proteins to become complete antigens to which a person becomes sensi-tized. On second exposure to the same antigen, the immune system responds by attack of cytotoxic T cells that cause dam-age, mostly in the skin.
The condition manifests as itching, erythema, vesicle, eczema, or necrosis of skin within 12–48 hours of the second exposure.
Tuberculin reaction is a typical example of delayed hypersen-sitivity to antigens of microorganisms, which is being used for diagnosis of the disease.
Tuberculin skin test: This test is carried out to deter-mine whether an individual has been exposed previously to Mycobacterium tuberculosis or not. In this test, a small amountof tuberculin (PPD), a protein derived from the cell wall of M. tuberculosis, is injected intradermally. Development of ared, slightly swollen, firm lesion at the site of injection after 48–72 hours indicates a positive test. A positive test indicates that the person has been infected with the bacteria but does not confirm the presence of the disease, tuberculosis. However, if a person with a tuberculin-negative skin test becomes positive, then it indicates that the patient has been recently infected. The skin test, however, can even become negative in:
· Infected persons receiving therapy with immunosuppressive drugs (such as corticosteroids and anticancer drugs) and
· In those suffering from the diseases associated with sup-pressed cell-mediated immunity (such as AIDS, sarcoidosis, lymphoma, post measles vaccination, etc.).
The response to M. tuberculosis illustrates that while on one hand mechanisms involved in DTH are required for defense against the organism; on the other hand, these are also responsible for tissue damage in the longer run. Cytokines (like TNF and IFN-g), which have been produced to activate the macrophages and thus contain the infection, also trigger other cascades that lead finally to extensive tissue damage.
Various other skin tests are used to detect DTH. These include many skin tests in bacterial, fungal, viral, and helmin-thic infections.
Lepromin test is a useful test for leprosy. A positive lepromin test indicates the presence of tuberculoid leprosy with intact
cell-mediated immunity. On the other hand, a negative lepro-min test indicates the presence of lepromatous leprosy with impaired cell-mediated immunity.
Positive skin tests in coccidioidomycosis, paracoccidioido-mycosis and other fungal infections suggest exposure to the fungi. In both viral and parasitic infections, skin tests are less specific and less useful than the serological tests for diagnosis.