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type 4 hypersensitivity

Tuesday 10 March 2009

The cell-mediated type of hypersensitivity is initiated by antigen-activated (sensitized) T lymphocytes. It includes the delayed type hypersensitivity reactions mediated by CD4+ T cells, and direct cell cytotoxicity mediated by CD8+ T cells.

It is the principal pattern of immunologic response not only to a variety of intracellular microbiologic agents, such as Mycobacterium tuberculosis, but also to many viruses, fungi, protozoa, and parasites.

So-called contact skin sensitivity to chemical agents and graft rejection are other instances of cell-mediated reactions. In addition, many autoimmune diseases are now known to be caused by T cell-mediated reactions.

Delayed Type Hypersensitivity

The classic example of delayed hypersensitivity is the tuberculin reaction, which is produced by the intracutaneous injection of tuberculin, a protein-lipopolysaccharide component of the tubercle bacillus. In a previously sensitized individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside.

Morphologically, delayed type hypersensitivity is characterized by the accumulation of mononuclear cells around small veins and venules, producing a perivascular "cuffing".

There is an associated increased microvascular permeability caused by mechanisms similar to those in other forms of inflammation. Not unexpectedly, plasma proteins escape, giving rise to dermal edema and deposition of fibrin in the interstitium.

The latter appears to be the main cause of induration, which is characteristic of delayed hypersensitivity skin lesions. In fully developed lesions, the lymphocyte-cuffed venules show marked endothelial hypertrophy and, in some cases, hyperplasia. Immunoperoxidase staining of the lesions reveals a preponderance of CD4+ (helper) T lymphocytes.

With certain persistent or nondegradable antigens, such as tubercle bacilli colonizing the lungs or other tissues, the initial perivascular lymphocytic infiltrate is replaced by macrophages over a period of 2 or 3 weeks.

The accumulated macrophages often undergo a morphologic transformation into epithelium-like cells and are then referred to as epithelioid cells. A microscopic aggregation of epithelioid cells, usually surrounded by a collar of lymphocytes, is referred to as a granuloma.

This pattern of inflammation that is sometimes seen in type IV hypersensitivity is called granulomatous inflammation.

The sequence of cellular events in delayed hypersensitivity can be exemplified by the tuberculin reaction. When an individual is first exposed to protein antigens of tubercle bacilli, naive CD4+ T cells recognize peptides derived from these antigens in association with class II molecules on the surface of antigen-presenting cells. This initial encounter drives the differentiation of naive CD4+ T cells to TH1 cells.

The induction of TH1 cells is of central importance because the expression of delayed hypersensitivity depends in large part on the cytokines secreted by TH1 cells.

Why certain antigens preferentially induce the TH1 response is not entirely clear, but the cytokine milieu in which naive CD4+ T cells are activated seems to be relevant, as discussed subsequently. Some of the TH1 cells enter the circulation and may remain in the memory pool of T cells for long periods, sometimes years.

On intracutaneous injection of tuberculin in an individual previously exposed to tubercle bacilli, the memory TH1 cells recognize the antigen displayed by antigen-presenting cells and are activated. These TH1 cells secrete cytokines, mainly IFN-γ, which are responsible for the expression of delayed-type hypersensitivity.

Cytokines most relevant to this reaction and their actions are as follows:
IL-12, a cytokine produced by macrophages and dendritic cells, is critical for the induction of the TH1 response and hence delayed hypersensitivity.

On initial encounter with a microbe, the macrophages and dendritic cells that are presenting microbial antigens secrete IL-12, which drives the differentiation of naive CD4+ helper cells to TH1 cells.

These, in turn, produce other cytokines, listed below. IL-12 is also a potent inducer of IFN-γ secretion by T cells and NK cells. IFN-γ further augments the differentiation of TH1 cells.

IFN-γ has many effects and is the key mediator of delayed-type hypersensitivity. Most importantly, it is a powerful activator of macrophages.

Activated macrophages are altered in several ways: their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II molecules on the surface, thus facilitating further antigen presentation; they secrete several polypeptide growth factors, such as platelet-derived growth factor (PDGF), which stimulate fibroblast proliferation and augment collagen synthesis; they secrete TNF, IL-1, and chemokines, which promote inflammation; and they produce more IL-12, thereby amplifying the TH1 response.

Thus, activated macrophages serve to eliminate the offending antigen; if the activation is sustained, continued inflammation and, ultimately, fibrosis result.

IL-2 causes autocrine and paracrine proliferation of T cells, which accumulate at sites of delayed hypersensitivity; included in this infiltrate are some antigen-specific CD4+ TH1 cells and many more bystander T cells that are recruited to the site.

TNF and lymphotoxin are two cytokines that exert important effects on endothelial cells:

- (1) increased secretion of prostacyclin, which, in turn, favors increased blood flow by causing local vasodilation;
- (2) increased expression of P-E-selectins, adhesion molecules that promote attachment of the passing lymphocytes and monocytes;
- (3) induction and secretion of chemokines such as IL-8.

Together, all these changes in the endothelium facilitate the extravasation of lymphocytes and monocytes at the site of the delayed hypersensitivity reaction. The process by which T cells and monocytes exit the vasculature is generally similar to that described for neutrophils.

The steps in this process are initial rolling on the endothelium, followed by activation of integrins and firm adhesion and, ultimately, transmigration through the vessel wall.

Chemokines produced by the T cells and macrophages recruit more leukocytes into the reaction site. This type of inflammation is sometimes called "immune inflammation."

T cell-mediated hypersensitivity is a major mechanism of defense against a variety of intracellular pathogens, including mycobacteria, fungi, and certain parasites, and is also involved in transplant rejection and tumor immunity. In addition to its beneficial, protective role, delayed type hypersensitivity can also be a cause of disease.

Contact dermatitis is a common example of tissue injury resulting from delayed hypersensitivity. It may be evoked by coming in contact with urushiol, the antigenic component of poison ivy or poison oak, and manifests in the form of a vesicular dermatitis.

The basic mechanism is similar to that described for tuberculin sensitivity. On repeat exposure to the plants, the sensitized CD4+ cells of the TH1 type first accumulate in the dermis, then migrate toward the antigen within the epidermis. Here they release cytokines that damage keratinocytes, causing separation of these cells and formation of an intraepidermal vesicle.

Type I diabetes and multiple sclerosis

Type I diabetes and multiple sclerosis are two diseases involving different organs in which tissue injury is caused by delayed type hypersensitivity reactions against autologous tissue antigens, mediated by the TH1 type of CD4+ T cells.

In these examples of TH1-mediated autoimmune disease, there is some evidence that CD8+ cells may also be involved. In certain other forms of delayed hypersensitivity reactions, especially those that follow viral infections, cytokine-producing CD8+ cells may be the dominant effector cells.

T Cell-Mediated Cytotoxicity

In this variant of cell-mediated hypersensitivity, sensitized CD8+ T cells kill antigen-bearing target cells. Such effector cells are called cytotoxic T lymphocytes (CTLs).

Tissue destruction by CTLs may be an important component of many T cell-mediated diseases. CTLs directed against cell surface histocompatibility antigens play an important role in graft rejection, to be discussed next.

They also play a role in resistance to virus infections. In a virus-infected cell, viral peptides associate with the class I molecules within the cell, and the two are transported to the cell surface in the form of a complex that is recognized by the TCR of cytotoxic CD8+ T lymphocytes.

The lysis of infected cells leads, in due course, to the elimination of the infection. It is believed that many tumor-associated antigens may also be similarly presented on the cell surface, and CTLs are therefore also involved in tumor immunity.

Much has been learned about the mechanisms by which CTLs kill their targets, and this knowledge may be of value in therapeutic modulation of T cell-mediated cytotoxicity in the settings of some autoimmune diseases.

Two principal mechanisms of T cell-mediated damage have been discovered: (1) perforin-granzyme-dependent killing, and (2) Fas-Fas ligand-dependent killing.

Perforins and granzymes are preformed mediators contained in the lysosome-like granules of CTLs. As its name indicates, perforin can perforate the plasma membranes of the target cells that are under attack by CD8+ lymphocytes.

At first, CD8+ T cells come in close contact with the target cells; this is followed by polymerization of the released perforin molecules and their insertion into the target cell membranes, thus "drilling holes" into the membrane. The CTL granules contain proteases called granzymes, which are delivered into the target cells via the perforin-induced pores.

Once within the cell, granzymes activate caspases, which induce apoptosis of the target cells. In addition, the perforin pores allow water to enter the cells, thus causing osmotic lysis. Fas-dependent killing also induces apoptosis of the target cells but by a different mechanism.

Activated CTLs express Fas ligand, a molecule with homology to TNF, that can bind to Fas expressed on target cells. This interaction leads to apoptosis.

See also

- transplant rejection