John L Turk, Department of Pathology, The Royal College of Surgeons of England, London, UK

The germ granuloma was introduced by Virchow in 1865 to describe certain well-circumscribed swellings consisting of what he thought was granulation tissue, found in a number of chronic infectious diseases including tuberculosis, leprosy, syphilis and leishmaniasis. Later authors, including Cohnbeim in 1877, distinguished large, swollen, epithelial-like cells. These they called epithelioid cells and differentiated them from the lymphoid elements in these lesions. In 1893, Metchnikoff formally recognized that these cells were related to the cells he had newly described as macrophages. The relation between granulomatous diseases and delayed-type hypersensitivity was recognized by Zinsser in 1925. Cells of the mononuclear phagocyte series are now considered to be the most important feature of granulomas. Although granuloma formation is generally a tissue response to particulate or fixed material in the tissues, they are not necessarily associated with infectious diseases or with delayed hypersensitivity. Hypersensitivity granulomas can be produced by the metals beryllium or zirconium and in sarcoidosis, a disease in which the role of an infectious agent has yet to be identified. Nonimmunological granulomas occur in silicosis and following the injection of metallic compounds such as aluminum hydroxide and kaolin. Nonimmunological granulomas can also occur in chronic infections where there is a specific failure of cell-mediated immunity, as in lepromatous leprosy, systemic leishmaniasis (kala-azar) and the systemic mycoses. The granulomas of tuberculoid leprosy and localized forms of leishmaniasis are examples of hypersensitivity (immunological) granulomas and are associated with strong delayed hypersensitivity reactions, as are the granulomas produced by beryllium and zirconium (Table 1).

The predominant cell that features in nonimmunological granulomas is the typical phagocytosing macrophage. In lepromatous leprosy, this foamy cell, often referred to as the 'Virchow' cell, is packed full of globi of Mycobacterium leprae. In immunological granulomas, the cells of the mononuclear phagocyte system take on the appearance of epithelioid cells. These cells are poorly phagocytic and may have a rough endoplasmic reticulum and Golgi apparatus presenting a plasmacytoid appearance (type A); other epithelioid cells (type B) present a more vacuolar and lysosomal appearance. It is generally thought that epithelioid cells have a secretory function. However, no specific secretory agent has, as yet, been identified. As well as epithelioid cells, hypersensitivity granulomas contain giant cells; these are generally of the Langhans type with peripherally placed nuclei. Giant cells as a whole do not have a rough endoplasmic reticulum. Other cell types seen include lymphocytes and fibroblasts. Collagen synthesis leading to fibrosis is a particular feature of hypersensitivity granulomas. The relation between epithelioid cell secretory function and fibroblast activation has yet to be fully defined. However, there is some evidence of increased prostaglandin and cytokine activity. Patients with immunological granulomatous diseases and silicosis are particularly associated with increased fibrosis in the area of the granulomas. Extreme examples of this are in sarcoidosis and berylliosis as well as tuberculosis. Silicosis is the only example of a nonimmunological granulomatous condition associated with epithelioid cell formation, fibroblast activation, increased collagen synthesis, and fibrosis generally in the lung.

There are two hypersensitive granulomatous states associated with a diagnostic skin test. The lepromin reaction is induced by the intradermal injection of killed M. leprae. The granuloma can be detected between 2 and 3 weeks as a nodular skin lesion which, on histological examination, shows all the features of an epithelioid cell granuloma. This reaction is positive in patients at the tuberculoid end of the leprosy spectrum, but negative at the lepromat-ous pole. In sarcoidosis the intradermal injection of an extract of spleen from a patient with sarcoidosis produces a Kveim reaction. This reaction is a nodular granuloma maximal between 4 and 6 weeks which, when examined histologically, shows all the features of an epithelioid cell granuloma.

Tissue destruction leading to caseation and cavitation is a particular feature of tuberculosis and is rarely, if at all, found in other immunological and nonimmunological granulomas. One of the agents that has been postulated as a cause of caseation is tumor necrosis factor a (TNFa), which is released from mononuclear phagocytes particularly by the action of endotoxin and can lead to vascular endothelial damage and fibrin deposition. It could be that there is increased release of TNFa by mononuclear phagocytes in patients with tuberculosis in the presence of certain components of M. tuberculosis, and this may account for the regular occurrence of caseation in this disease. Caseation may be a feature of the epithelioid cell granulomas or gummas of tertiary syphilis, and at the other end of the spectrum, absence of caseation is a diagnostic feature of sarcoidosis.

The association between epithelioid cell granuloma formation and delayed hypersensitivity in a number of diseases would explain the large number of T lymphocytes in the periphery of these lesions. Experimentally, it has been shown by transfer studies that granulomas in schistosomiasis are T lymphocyte mediated. They are also smaller in neonatally thy-mectomized animals. However, the presence of plasma cells and eosinophils in many granulomas of helminthic origin would indicate that B cells might

Table 1 Classification of granulomas

1. Immunological Tuberculosis Tuberculoid leprosy Syphilis

Schistosomiasis Sarcoidosis Zirconium Beryllium

2. Nonimmunological

Nontoxic, e.g. plastic beads, carbon particles, nontoxic metals (e.g. Fe)

Toxic, e.g. silica, talc, asbestos

Activation of C3, e.g. carageenan, kaolin, aluminum hydroxide play an important part in their formation. Immunoglobulin and complement also may accumulate around eggs, particularly in Schistosoma japotticum infection. In immunological granulomas of T cell origin, it has been found that CD8' T cells are found more peripherally in the granuloma, while CD4 T cells are found more centrally.

The term 'foreign body' granuloma is used to cover the localized response to a wide range of substances that enter the body from the exterior. Granulomatous reactions may occur around thorns or other sharp objects that penetrate the skin. Many of these reactions are immunological responses against foreign antigens, either as part of the object or on microorganisms carried in by the object. Thus, the lesions are frequently epithelioid cell granulomas with giant cells and there is also fibroblast proliferation. Frequently, these lesions resolve by fibrosis. The lesions produced by talc are similar. Although talc is not antigenic, the reaction is probably related to its silica content. Silicosis does not fit easily into the simple classification of immunological/ epithelioid cell granulomas leading to fibrosis and nonimmunological/phagocytosing macrophage granulomas without fibrosis. Silicosis is a highly fibrinogenic condition. It has been suggested that phacocytosis of silica leads to lysosomal damage. However, this is not the whole story as nonfibrino-genic granuloma-producing agents may have the same effect. It has been shown that asbestos, a silica-containing product, activates complement through the alternate pathway.

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