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Chapter: Medical Immunology: Hypersensitivity Reactions

Delayed (Type IV) Hypersensitivity Reactions

In contrast to the other types of hypersensitivity reactions discussed above, type IV or de-layed hypersensitivity is a manifestation of cell-mediated immunity.


In contrast to the other types of hypersensitivity reactions discussed above, type IV or de-layed hypersensitivity is a manifestation of cell-mediated immunity. In other words, this type of hypersensitivity reaction is due to the activation of specifically sensitized T lym-phocytes rather than to an antigen-antibody reaction.

A. The Tuberculin Test as a Prototype Type IV Reaction

Intradermal injection of tuberculin or purified protein derivative (PPD) into an individual that has been previously sensitized (by exposure to Mycobacterium tuberculosis or by BCG vaccination) is followed, 24 hours after the injection, by a skin reaction at the site of injec-tion characterized by redness and induration. Histologically, the reaction is characterized by perivenular mononuclear cell infiltration, often described as “perivascular cuffing.” Macrophages can be seen infiltrating the dermis. If the reaction is intense, a central necrotic area may develop. The cellular nature of the perivascular infiltrate, which contrasts with the predominantly edematous reaction in a cutaneous type I hypersensitivity reaction, is responsible for the induration.

B. Experimental Studies

Experiments carried out with guinea pigs investigating the elements involved in transfer of delayed hypersensitivity were critical in defining the involvement of lymphocytes in delayed hypersensitivity. When guinea pigs are immunized with egg albumin and ad-juvant, not only do they become allergic, as discussed earlier, but they also develop cell-mediated hypersensitivity to the antigen. This duality can be demonstrated by pas-sively transferring serum and lymphocytes from sensitized animals to nonsensitized re-cipients of the same strain and challenging the passively immunized animals with egg al-bumin. The animals that received serum will develop an anaphylactic response immediately after challenge, while those that received lymphocytes will only show sig-nals of a considerably less severe reaction after at least 24 hours have elapsed from the time of challenge.

Most of our knowledge about the pathogenesis of delayed hypersensitivity reactions derives from experimental studies involving contact hypersensitivity. Experimental sensi-tization through the skin is relatively easy to induce by percutaneous application of low molecular weight substances such as picric acid or dinitrochlorobenzene (DNCB). The ini-tial application leads to sensitization, a second application will elicit a delayed hypersensi-tivity reaction in the area where the antigen is applied.

1. Induction


The compounds used to induce contact hypersensitivity are not immunogenic by them-selves. It is believed that these compounds couple spontaneously to an endogenous carrier protein, and as a result of this coupling the small molecule will act as a hapten, while the endogenous protein will play the role of a carrier. A common denominator of the sensitiz-ing compounds is the expression of reactive groups, such as Cl, F, Br, and SO3H, which en-able them to bind covalently to the carrier protein.

Spontaneous sensitization to drugs, chemicals, or metals is believed to involve dif-fusion of the haptenic substance into the dermis mostly through the sweat glands (hy-drophobic substances appear to penetrate the skin more easily than hydrophilic sub-stances) and once in the dermis, the haptenic groups will react spontaneously with “carrier” proteins. By a pathway that has not been defined, the Langerhans cells of the epidermis take up the hapten carrier conjugates, and a sensitizing peptide is presented in association with MHC-II molecules. Since the carrier protein is autologous, it would be expected that the sensitizing peptide contained the covalently associated sensitizing compound.

A unique feature of delayed hypersensitivity is that T lymphocytes are mostly involved in the antihapten response, while in most experimentally induced hapten-carrier responses the hapten is recognized by B lymphocytes. This may be explained, at least in part, by the fact that Langerhans cells migrate to regional lymph nodes, where they become dendritic cells and predominantly populate the paracortical areas, where they are in optimal conditions to present antigens to CD4+ T lymphocytes .

2. Effector Mechanisms


The initial sensitization results in the acquisition of immunological memory. Later, when the sensitized individual is challenged with the same chemical, sensitized T cells will be stimulated into functionally active cells, releasing a variety of cytokines, which include IL-8, RANTES, and macrophage chemotactic proteins that attract and activate mono-cytes/macrophages, lymphocytes, basophils, eosinophils, and neutrophils. Other cytokines released by activated lymphocytes, particularly TNF and IL-1 upregulate the ex-pression of cell adhesion molecules (CAMs) in endothelial cells, facilitating the adhesion of leukocytes to the endothelium, a key step in the extravascular migration of inflamma-tory cells. As a result of the release of chemokines and of the upregulation of CAMs, a cellular infiltrate predominantly constituted by mononuclear cells, but also including granulocytes, forms in the area where the sensitizing compound has been reintroduced 24–48 hours after exposure. The tissue damage that takes place in this type of reaction is likely to be due to the effects of active oxygen radicals and enzymes (particularly pro-teases, collagenase, and cathepsins) released by the infiltrating leukocytes, activated by the chemokines and other cytokines.

In severe cases, a contact hypersensitivity reaction may exhibit an exudative, ede-matous, highly inflammatory character. The release of proteases from monocytes and macrophages may trigger the complement-dependent inflammatory pathways by directly splitting C3 and C5; C5a will add its chemotactic effects to those of chemokines released by activated mononuclear cells and will also cause increased vascular permeability, a con-stant feature of complement-dependent inflammatory processes. It is not surprising, there-fore, that a reaction which at the onset is cell mediated and associated to a mononuclear cell infiltrate, may, in time, evolve into a more classical inflammatory process with predominance of neutrophils and a more edematous character, less characteristic of a cell-mediated reaction.

C. Contact Hypersensitivity in Humans

Contact hypersensitivity reactions are observed with some frequency in humans due to spontaneous sensitization to a variety of substances:

·              Plant cathecols are apparently responsible for the hypersensitivity reactions to poison ivy and poison oak.

·              A variety of chemicals can be implicated in hypersensitivity reactions to cosmetics and leather.

·              Topically used drugs, particularly sulfonamides, often cause contact hypersensitiv-ity.

·              Metals such as nickel can be involved in reactions triggered by contact with bracelets, earrings, or thimbles.

The diagnosis of contact hypersensitivity is usually based on a careful history of ex-posure to potential sensitizing agents and on the observation of the distribution of lesions that can be very informative about the source of sensitization. Patch tests using small pieces of filter paper impregnated with suspected sensitizing agents which are taped to the back of the patient can be used to identify the sensitizing substance.

D.  The Jones-Mote Reaction

Following challenge with an intradermal injection of a small dose of a protein to which an individual has been previously sensitized, a delayed reaction (with a lag of 24 hours), some-what different from a classical delayed hypersensitivity reaction, may be seen. The skin ap-pears more erythematous and less indurated, and the infiltrating cells are mostly lympho-cytes and basophils, the last sometimes predominating. The reaction has also been described, for this reason, as cutaneous basophilic hypersensitivity. Experimentally, it has been demonstrated that this reaction is triggered as a consequence of the antigenic stimu-lation of sensitized T lymphocytes.

E. Homograft Rejection

A most striking clinical manifestation of a delayed hypersensitivity reaction is the rejection of a graft. In classical chronic rejection, the graft recipient’s immune system is first sensi-tized to peptides derived from alloantigens of the donor. After clonal expansion, activated T lymphocytes will reach the target organ, recognize the alloantigen-derived peptides against which they became sensitized, and initiate a sequence of events that leads to in-flammation and eventual necrosis of the organ.

F. Systemic Consequences of Cell-Mediated Hypersensitivity Reactions

While type IV hypersensitivity reactions with cutaneous expression usually have no sys-temic repercussions, cell-mediated hypersensitivity reactions localized to internal organs, such as the formation of granulomatous lesions caused by chronic infections with My-cobacterium species may be associated with systemic reactions. Cytokines released by ac-tivated lymphocytes and inflammatory cells play a major pathogenic role in such reactions. Pro-inflammatory cytokines, particularly IL-1, induce the release of prostaglandins in the hypothalamic temperature regulating center and cause fever, thus acting as a pyrogenic fac-tor. TNF is also pyrogenic, both directly and by inducing the release of IL-1 by endothelial cells and monocytes. In addition, these two cytokines activate the synthesis of acute phase proteins (e.g., C-reactive protein) by the liver.

Prolonged release of TNF, on the other hand, may have deleterious effects since this factor contributes to the development of cachexia. Cachexia develops because TNF inhibits lipoprotein lipase, and as a consequence there is an accumulation of triglyceride-rich particles in the serum and a lack of the breakdown of triglycerides into glycerol and free fatty acids. This results in decreased incorporation of triglycerides into the adipose tissue and, consequently, in a negative metabolic balance. The cells continue to break down stored triglycerides by other pathways to generate energy, and the used triglyc-erides are not replaced. Cachexia is often a preterminal development in patients with se-vere chronic infections.

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