IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 26. Hypersensitivity - Type IV

DISEASES ASSOCIATED WITH TYPE IV HYPERSENSITIVITY GRANULOMATOUS REACTIONS

There are numerous chronic human diseases characterized by type IV hypersensitivity. The majority of these are caused by infectious agents, such as mycobacteria, Protozoa, and Fungi; however, in certain granulomatous conditions like sarcoidosis and Crohn's disease, the inducing agent remains unidentified.

The most important disorders of this type include:

✵ leprosy,

✵ tuberculosis,

✵ Schistosomiasis,

✵ sarcoidosis,

✵ Crohn's disease.

A common feature of these infections and infestations is the persistence of the pathogenic agent, which acts as a chronic antigenic stimulus. While macrophage activation by lymphocytes can help contain the infection, persistent stimulation may lead to tissue damage resulting from the release of various macrophage products, including highly reactive oxygen metabolites and hydrolytic Enzymes. Although delayed-type hypersensitivity indicates T-Cell activation, it does not always eradicate the infection; in other words, protective Immunity and delayed-type hypersensitivity do not necessarily coincide. Consequently, some individuals exhibiting delayed-type hypersensitivity may remain unprotected against potential infection.

Leprosy. Clinically, leprosy is divided into three main types: tuberculoid, borderline, and lepromatous. In tuberculoid leprosy, discrete, hypopigmented patches with well-defined margins may appear on the Skin, showing intensive lymphocytic and epithelioid infiltration, but lacking microorganisms. In contrast, lepromatous leprosy presents as multiple, coalescing skin lesions containing vast numbers of rod-shaped Bacteria, foamy macrophages, and only sparse lymphocytes. Borderline leprosy exhibits features of both preceding forms (Fig. 26.19). Protective immunity in leprosy is typically mediated by cellular responses, but across the spectrum from tuberculoid to lepromatous forms, these responses wane, and the titre of non-protective Antibodies against M. leprae increases.

Class="center">

Fig. 26.19. Clinical manifestations of leprosy range from tuberculoid (with small lesions and minimal bacterial presence) to lepromatous, characterized by multiple lesions and uncontrolled bacterial proliferation. This spectrum reflects the immune status of the host, assessed by specific cellular and antibody responses to M. leprae infection, as well as tissue cytokine expression.

Borderline leprosy is a classic example of delayed-type hypersensitivity. Borderline reactions develop either spontaneously or following drug therapy. During such reactions, the hypopigmented skin lesions containing M. leprae Cells swell and become inflamed (Fig. 26.20), indicating the onset of a delayed-type hypersensitivity reaction. Histologically, the reaction closely resembles the tuberculoid form, featuring infiltration by IFNγ-secreting lymphocytes. The process may affect peripheral nerves, with M. leprae present in their Schwann cells; this is a major cause of nerve destruction in the disease. The lesions of borderline leprosy represent a typical granulomatous form of hypersensitivity (Fig. 26.20). In patients with tuberculoid-type reactions, T-cell sensitization can be assessed in vitro using the lymphocyte stimulation test (see Ch. 29), employing intact or sonicated M. leprae cell preparations as Antigens (Fig. 26.21).

Fig. 26.20. Borderline reaction in leprosy. 1. Small nerve almost entirely replaced by granulomatous infiltrate. 2. Lepromatous leprosy showing a high bacterial load. (Micrographs kindly provided by Dr Phillip McKee.) 3. Borderline leprosy showing large, infiltrated, inflamed plaques with well-demarcated borders. (Photograph kindly provided by Dr S. Lucas.)

Fig. 26.21. In borderline leprosy reactions, the lymphocyte response to M. leprae stimulation increases, decreasing after successful corticosteroid Treatment. Data show lymphocyte stimulation by sonicated M. leprae cell preparations (measured by ³H-thymidine incorporation) in 17 patients: (a) before anti-leprosy treatment (baseline); (b) during the reaction; and (c) after successful steroid therapy. Horizontal bars indicate median values.

Tuberculosis. In tuberculosis, a delicate balance exists between the effects of activated macrophages: on the one hand, they combat the infection, while on the other, they cause tissue damage in infected Organs. Granulomatous reactions in the Lungs lead to cavity formation and the spread of infection. Such reactions are frequently accompanied by extensive fibrosis, as visible on patients' chest radiographs (Fig. 26.22).

Fig. 26.22. Chest radiograph of a patient with Pulmonary Tuberculosis. Pronounced lung parenchyma marking (predominantly in the apices) is evident. Such changes are typical of chronic bilateral pulmonary tuberculosis. Some cardiomegaly is also observed.

The histological picture of a tuberculous lesion is a classic granulomatous reaction featuring central caseous (cheesy) necrosis (Fig. 26.23), surrounded by epithelioid cells and a small number of giant cells. The periphery of the lesion is infiltrated by mononuclear cells.

Fig. 26.23. Histological section of a tuberculous lung. An epithelioid cell granuloma (E) with giant cells (G) is visible, along with mononuclear cell infiltration (M) and an area of marked caseation and necrosis (N). Haematoxylin and eosin stain, × 75.

Schistosomiasis. In schistosomiasis — a disease caused by parasitic schistosome worms — the host Organism becomes sensitized by helminth eggs, leading to a typical granulomatous reaction in the affected tissue (Fig. 26.24; see also Ch. 18).

Fig. 26.24. Histological appearance of the Liver in schistosomiasis. Epithelioid-cell granuloma surrounding a schistosome egg (E). Hematoxylin and eosin stain, x 300. (Micrograph kindly provided by Dr. Phillip McKee.)

Sarcoidosis. Sarcoidosis is a chronic disease of unknown Etiology characterized by the accumulation of activated macrophages forming granulomas in multiple Tissues, frequently accompanied by fibrosis (Fig. 26.25). The lesions are primarily localized in lymphoid tissue, and chest radiographs often reveal enlarged Lymph Nodes (Fig. 26.26). No specific infectious agent has been successfully isolated from patients, though mycobacteria are suspected because they induce similar morphological changes.

Fig. 26.25. Histology of sarcoidosis in a lymph node biopsy. A typical sarcoidal granuloma consisting of epithelioid (E) and multinucleated giant cells (G), but lacking caseous necrosis. Only sparse mononuclear cell infiltration (M) is visible at the periphery of the granuloma. Hematoxylin and eosin stain, x 240.

Fig. 26.26. Chest radiograph of a patient with sarcoidosis. Enlarged lymph nodes are visible adjacent to The Heart (H) and in the paratracheal Regions of the lungs (L), accompanied by characteristic diffuse infiltration of the pulmonary tissue.

A clinical immunology paradox is that patients with this disease typically exhibit depressed delayed-type hypersensitivity both in vivo and in vitro. The tuberculin skin test yields negative results in sarcoidosis patients. However, if cortisone is co-administered intradermally with tuberculin, the test converts to positive, highlighting The Role of cortisone-sensitive T-suppressor cells in the genesis of anergy. Under normal conditions, cortisone would be expected to suppress delayed-type hypersensitivity.

Granulomas in sarcoidosis can develop in various organs, most frequently in the lungs, lymph nodes, bones, neural tissue, and skin. The disease may present with high fever and malaise; patients with pulmonary involvement subsequently develop dyspnea associated with pulmonary fibrosis. The Diagnosis is frequently suspected based on Clinical presentation and radiological findings, and confirmed by biopsy. Elevated serum levels of angiotensin-converting enzyme (ACE) and calcium are occasionally detected, as activated macrophages serve as a source of both ACE and 1,25-dihydroxycholecalciferol (the active metabolite of vitamin D₃).

Crohn's disease. This is another condition characterized by granuloma formation. In Crohn's disease (chronic inflammation of the ileum and colon), lymphocytes and macrophages accumulate throughout all layers of the intestinal wall. The granulomatous reaction and subsequent fibrosis lead to bowel strictures and The formation of fistulae penetrating into adjacent organs. The Nature of the antigens or infectious agents that initiate and sustain this granulomatous reaction remains unknown.

Attempts to assess the role of food allergy in this condition through elimination diets have proven effective in a significant percentage of patients. However, it remains unclear whether the diet itself or alterations in the intestinal microflora are responsible for the clinical improvement.

Questions for Consideration

■ How can the same cytokines that empower macrophages to destroy intracellular parasites also cause tissue damage?

■ Which other immunological reactions might be blocked by antibodies against cytokines?

■ How do irritants and contact hypersensitivity trigger the same morphological form of skin reaction?

■ Which types of type IV hypersensitivity cause the most severe tissue damage?

■ How can an IgE-mediated late-phase reaction be distinguished from type IV hypersensitivity reactions?

■ How do the number and function of T cells influence the manifestations of tuberculin-type hypersensitivity?

■ Could alternative immunological mechanisms exacerbate the reactions characteristic of borderline leprosy?

■ Can ultraviolet B exposure be utilized to elucidate the MECHANISMS OF TYPE IV hypersensitivity?

Introduction/47.html">Further Reading

Baadsgaard O., Wang T. 1991. Immune regulation in allergic and irritant skin reactions. Int. J. Dermatol. 30: 161-72.

Bevilacqua M.P. 1993. Endothelial-leukocyte adhesion molecules. Annu. Rev. Immunol. 11: 767-804.

Bjone G., Barnetson T., Ridley D.S. et al. 1976. Lymphocyte transformation test in leprosy: correlation of the response with inflammation of tesions. Clin. Exp. Immunol. 25: 85-94.

Britton W.J. 1993. Immunology of leprosy. Trans. Roy. Soc. Trop. Med. Hyg. 87: 508-14.

Cooper A.M., Flynn J.L. 1995. The protective Immune Response to Mycobacterium tuberculosis. Curr. Opin. Immunol. 7: 512-16.

Enk A.H., Katz S.l. 1995. Contact hypersensitivity as a model for T-cell activation in skin. J. Invest. Dermatol. 105: 805-35.

Flynn J.L., Chan J., Triebold K.J. et al. 1993. An essential role for interferon-y in resistance to Mycobacterium tuberculosis infection. J. Exp. Med. 178: 2249-54.

Friedmann P.S. 1991. The immunology of allergic contact dermatitis: the DNCB story. Adv. Dermatol. 5: 175-96.

Gaspan A.A. 1993. Advances in the understanding of contact hypersensitivity. Am. J. Cont. Derm. 4: 138-49.

Gawkrodger D.J., McVittie E., Carr M.M. et al. 1986. Phenotypic characterisation of the early cellular responses in allergic and irritant contact dermatitis. Clin. Exp. Immunol. 66: 590-98.

Gawkrodger D.J., Carr M.M., McVittie E. et al. 1987. Keratinocyte expression of MHC class II antigens in allergic sensitisation and challenge reactions and in irritant contact dermatitis. J. Invest. Dermatol. 88: 11-16.

HoefakkerS., Canbo M., van’t Erre EHM. etal. 1995. In vitro cytokine profiles in allergic and irritant contact dermatitis. Contact Dermatitis 33: 258-66.

Kaufmann S.H.E. 1994. Bacterial and protozoal infection in genetically disrupted mice. Curr. Opin. Immunol. 6: 518-25.

Kindler V., Sappino А-P., Gran G.E. et al. 1989. The inducing role of tumour necrosis factor in The Development of bactericidal granulomas during BCG infection. Cell 56: 731-40.

Lowes J., Lewell D. 1990. Immunology of inflammatory bowel disease. Vol. 12. Springer Semin. Immunopathol. 180: 251-68.

Munro C.S., Campbell D.A., Codings L.A. et al. 1987. Monoclonal Antibodies distinguish mactophages and epithelioid cells in sarcoidosis and leprosy. Clin. Exp. Immunol. 68: 282-87.

Sauder D.N. 1986. Allergic contact dermatitis. In: Thiers B.H., Dobson R.L. (eds.). Pathogenesis of Skin Diseases. New York: Churchill Livinqstone: 3-12.

Schwarzenberger K., Udey M.C. 1976. Contact allergens and epidermal promflammatory cytokines modulate Langerhans cell E-cadherin expression in situ. J. Invest. Dermatol. 106: 553-8.

Trinchieri G. 1993. Interleukin-12 and its role in the generation of Th1 cells. Immunol. Today 14: 335-8.

Yamamura M., Uyemura K., Deans R.J. et al. 1991. Defining protective immune responses to pathogens: cytokine profiles in leprosy lesions. Science 254: 277-9.