J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from J Clin Pathol 1983;36:723-733 Review article Granulomatous inflammation- a review GERAINT T WILLIAMS, W JONES WILLIAMS From the Department ofPathology, Welsh National School ofMedicine, Cardiff SUMMARY The granulomatous inflammatory response is a special type of chronic inflammation characterised by often focal collections of macrophages, epithelioid cells and multinucleated giant cells. In this review the characteristics of these cells of the mononuclear phagocyte series are considered, with particular reference to the properties of epithelioid cells and the formation of multinucleated giant cells. The initiation and development of granulomatous inflammation is discussed, stressing the importance of persistence of the inciting agent and the complex role of the immune system, not only in the perpetuation of the granulomatous response but also in the development of necrosis and fibrosis. The granulomatous inflammatory response is Macrophages and the mononuclear phagocyte ubiquitous in pathology, being a manifestation of system many infective, toxic, allergic, autoimmune and neoplastic diseases and also conditions of unknown The name "mononuclear phagocyte system" was aetiology. Schistosomiasis, tuberculosis and leprosy, proposed in 1969 to describe the group of highly all infective granulomatous diseases, together affect phagocytic mononuclear cells and their precursors more than 200 million people worldwide, and which are widely distributed in the body, related by http://jcp.bmj.com/ granulomatous reactions to other irritants are a morphology and function, and which originate from regular occurrence in everyday clinical the bone marrow.' Macrophages, monocytes, pro- histopathology. A knowledge of the basic monocytes and their precursor monoblasts are pathophysiology of this distinctive tissue reaction is included, as are Kupffer cells and microglia. Label- therefore of fundamental importance in the under- ling studies with tritiated thymidine have shown that standing of many disease processes. granuloma cells, including both epithelioid cells and Granulomatous inflammation is best defined as a multinucleated giant cells, are also of the same special variety of chronic inflammation in which cells lineage2-5 and it is claimed that monocytes in tissue on October 1, 2021 by guest. Protected copyright. of the mononuclear phagocyte system are pre- culture may develop into epithelioid cells and giant dominant and take the form of macrophages, cells.6 epithelioid cells and multinucleated giant cells. In The origin of tissue macrophages (histiocytes) most instances these cells are aggregated into well from bone marrow precursors via circulating mono- demarcated focal lesions called granulomas, cytes is now well established,7 the maturation pro- although a looser, more diffuse arrangement may be cess being accompanied by progressive morphologi- found. In addition there is usually an admixture of cal and functional changes which continue even other cells, especially lymphocytes, plasma cells and when macrophages enter the tissues.8 The produc- fibroblasts. tion of monocytes is under positive and negative Before considering the pathogenesis of feedback control, with peripheral macrophages and granulomatous inflammation it is essential to review lymphocytes secreting factors that are both our knowledge of the three fundamental cells stimulatory and inhibitory to stem cell proliferation involved, namely the macrophage, the epithelioid in the marrow.9 Recruitment and localisation of cell and the multinucleated giant cell. monocytes into inflammatory lesions is aided by two groups of substances. The emigration of monocytes from the circulation is promoted by chemotactic Accepted for publication 14 March 1983 agents including microbial products, complement 723 J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from 724 Williams, Williams components, fibrin degradation products and antibodies, similar to those presently available for lymphokines while the immobilisation of lymphocyte subsets'9 is the most hopeful approach. macrophages within a lesion is aided by other The ability to ingest a wide variety of substances lymphokines including migration inhibition and into membrane bound vacuoles (endocytosis) is a macrophage adhesion factors.'0 " Although distinctive but not unique property of mononuclear immigration from the circulation seems to be by far phagocytes. Two mechanisms are involved, the most important source of macrophages in the pinocytosis and phagocytosis. Macrophages take up inflammatory reaction, local macrophage mitosis fluids and soluble proteins, immune complexes, does occur.'2 However, perhaps due to hormones, lectins and other macromolecules by chromosomal instability, this seems to be limited to pinocytosis20 21 whereas larger particles are engulfed very few divisions."3 by phagocytosis. The process is initiated by interac- Light microscopy of routine haematoxylin and tion between a particle and a surface receptor which eosin stained sections does not allow macrophages then triggers intracytoplasmic contractile proteins, to be distinguished from other mononuclear cells in including actin and myosin, to create membrane an inflammatory infiltrate unless they contain movement and pseudopodial ingestion.20 22-24 recognisable ingested material. Macrophages may Macrophage surface receptors are of many types be round, oval or spindle shaped in outline with a and specificity. Particles opsonised by cytoplasm which varies from eosinophilic and finely immunoglobulin G and E interact with Fc granular to clear and vesicular. The nucleus has a receptors25 26 while those attached to the third com- smooth or sometimes indented membrane with ponent of complement bind to C3b receptors.27 marginated heterochromatin and usually a single Both Fc and C3b receptors may also react with nucleolus. On ultrastructural examination the cell immune complexes while non-immunological membrane is irregular, being thrown into folds and receptors exist for lectins,28 alternative pathway processes. Cytoplasmic organelles vary greatly complement activators29 and other particles. according to the functional activity of the cell8 and Particulate ingestion is followed by phagosome- include endoplasmic reticulum (rough and smooth), lysosome fusion allowing intracellular degradation mitochondria, Golgi complexes, microtubules, and microbial killing. Digestion of particulate mater- microfilaments and membrane bound vesicles, the ial and dead organisms is accomplished by lysosomal latter including primary and secondary lysosomes enzymes'3 but killing of micro-organisms depends and residual bodies. However, in the absence of on other methods, in particular the production of obviously phagocytosed material there is no ultra- superoxides, hydrogen peroxide and hydroxyl radi- structural feature that is absolutely diagnostic for cals30 and other microbicidal substances. The pro- http://jcp.bmj.com/ the macrophage. cess is aided by the presence of antibody, IgG for Enzyme histochemistry is more valuable in the bacteria, IgE for metazoa." tissue identification of cells of the mononuclear Intracellular killing of micro-organisms is greatly phagocyte series, but suffers from the disadvantage enhanced by the phenomenon of macrophage of requiring specially prepared material. activation,32 a change which is accompanied by Macrophages typically contain non-specific ester- morphological8 and many other functional altera- ases diffusely in the cytoplasm, and the presence of tions including the secretion of a range of different on October 1, 2021 by guest. Protected copyright. membrane bound lysosomal enzymes, especially substances, enhanced phagocytic capacity, and an acid phosphatase and lysozyme is also useful in their ability to recognise and kill tumour cells."' Activa- recognition. Furthermore, variations in the tion can be accomplished by immunoglobulins, cytoplasmic distribution of peroxidase correspond to immune complexes, activated complement compo- different stages in macrophage differentiation.'4 nents, lymphokines, and by non-immunological 5-nucleotidase, leucine aminopeptidase and alkaline agents such as bacterial endotoxin." phosphodiesterase I are cell membrane-associated Extracellular secretion by activated macrophages macrophage enzymes which have also been used as is now recognised as a most important function34 35 macrophage markers.'5 Intracellular localisation of and some idea of the myriad of secretory products macrophage products, notably alpha-i -antitrypsin,'6 can be obtained from the Table. It can be seen that also has a role in cell identification. However, it is among the factors produced are those with essen- the development of monoclonal antibodies to tially opposing effects, for example collagenase and specific cell types that holds the most promise for the fibrogenic substances, suggesting that there are very identification of mononuclear phagocyte cells.7 18 If subtle controls over secretion which at present are the various stages of functional differentiation of almost a complete mystery. Nevertheless it is known these cells are to be recognised morphologically that activation is not an "all or none" phenomenon, then immunohistology with specific monoclonal and that the function of activated macrophages can J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from Granulomatous inflammation-a