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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 - 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 , epithelioid cells and multinucleated giant cells. In this review the characteristics of these cells of the mononuclear 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 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, and , 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 .' Macrophages, , pro- histopathology. A knowledge of the basic monocytes and their precursor are pathophysiology of this distinctive tissue reaction is included, as are Kupffer cells and . Label- therefore of fundamental importance in the under- ling studies with tritiated thymidine have shown that standing of many disease processes. 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 () most instances these cells are aggregated into well from bone marrow precursors via circulating mono- demarcated focal lesions called , 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 , plasma cells and when macrophages enter the tissues.8 The produc- . 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 proliferation involved, namely the , the epithelioid in the marrow.9 Recruitment and localisation of cell and the multinucleated . 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 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 . Two mechanisms are involved, the most important source of macrophages in the pinocytosis and . 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 , 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 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 review 725

Secretory products ofmacrophages Enzymes Bioactive lipids Neutral proteases-for example, collagenase, elastase, , thromboxanes, leukotrienes plasnunogen activator, converting activators enzymne, enzymes denatunngangiotensinproteoglycans and myelin. Binding proteins Acid hydrolases-for example, phosphatases, sulphatases, Transferrin, B12 binding protein, fibronectin proteases, ribonucleases. Cyclic AMP Lysozyme Factors stimulating proliferation of: Esterases Lymphocytes (T and B) Enzyme inhibitors Myeloid precursors (colony stimulating factors) Alpha-1-antitrypsin Erythroid precursors inhibitors Fibroblasts Complement components Small vessels Cl, C2, C3, C4, C5 Factors inhibiting proliferation of: Properdin, Factors B, D Lymphocytes Oxygen metabolites Tumour cells Superoxides, hydrogen peroxide, hydroxyl radical Viruses (interferon) Endogenous pyrogens

be varied according to the nature of the activating EpithelHoid cells stimulus.36 Furthermore there is increasing evidence Epithelioid cells are mononuclear cells with finely that macrophages do not form a homogeneous granular eosinophilic cytoplasm, vesicular nuclei, group of cells, but that they are markedly and indistinct cell boundaries which are usually heterogeneous, different populations having differ- found aggregated into clusters within certain ent characteristics and functions.37 38 The tumorici- granulomas. Their mononuclear phagocyte origin is dal effect of activated macrophages is only poorly not in doubt,2-5"4 but there remains controversy understood. It is likely that macrophage-tumour cell over the mechanisms by which epithelioid cells are contact is necessary in some instances313539 while formed, and in particular the role of cell-mediated macrophage , especially peroxides, are immunity. Epithelioid cells have been considered to important in others.40 be a hallmark of delayed Macrophages have complex interactions with granulomas,45 a fact well illustrated in the pathology

lymphoid cells at different phases of the immune of leprosy, where epithelioid cells only occur with http://jcp.bmj.com/ response.4'43 Induction of immunity probably the appearance of cell-mediated immunity to the requires the initial presentation of an antigen to T causative organism.46 However there are now lymphocytes which can then initiate cell-mediated reports of epithelioid granuloma formation in con- immunity or generate "helper" functions for genitally athymic "nude" animals47 48 suggesting that antibody-producing B lymphocytes. Macrophages T cell function is not essential. Furthermore, are responsible for this presentation, but only after although lymphokines induce dramatic changes in they have endocytosed the antigen and "processed" macrophages in vitro, the changes are not quite it. Macrophage-T cell interaction is restricted to those of epithelioid transformation.4950 on October 1, 2021 by guest. Protected copyright. cells bearing surface HLA-DR (or Ia) molecules Ultrastructural examination of epithelioid and hence is under the control of immune response cells5l-55 reveals closely applied and often genes. Cell-to-cell contact is usually necessary at the interdigitating cell membranes which, in the onset, but growth and differentiation factors which experience of most workers, lack any junctional cause T cell proliferation and differentiation and specialisation. Nevertheless some authors56 have which are secreted by macrophages ("monokines") illustrated desmosome and hemidesmosome-like are also involved. Mention has already been made of structures. The nuclei are regular and ovoid with the role of macrophages as effectors of the immune marginated heterochromatin, and the complex cyto- response. Lymphokines, antibodies and immune plasm contains numerous mitochondria and an complexes cause macrophage and active Golgi apparatus. Some epithelioid cells con- activation, allowing ingestion and final elimination tain rough surfaced endoplasmic reticulum resembl- of the antigen, a process that is enhanced by opson- ing that of plasma cells or fibroblasts52-54 (type A or isation with antibody and complement. It is clear, plasmacytoid epithelioid cells) while others have therefore, that macrophages have properties which numerous cytoplasmic single membrane-bound make them highly suited to their central role in vesicles containing electron-lucent or weakly granulomatous inflammation which is the defence of osmiophilic material (type B or vesicular epithelioid the host from exogenous or endogenous irritants. cells). There is now good evidence that these two J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from

726 Williams, Williams cytoplasmic appearances represent the two ends of a contents into the extracellular space.56 Considerable morphological spectrum, intermediate forms having attention has been given to the secretion of rough endoplasmic reticulum and vesicles in varying angiotensin-converting enzyme by epithelioid cells, proportions.5357 The proportions of the different cell not only to the immunocytochemical localisation of types vary in different granulomas according to the the enzyme69 but also to the use of serum aetiology,53 but generally speaking plasmacytoid angiotensin-converting enzyme activities in the clin- epithelioid cells are predominant in the early phase ical diagnosis of granulomatous diseases.70 The role of granulomatous inflammation while the vesicular of angiotensin-converting enzyme in the granuloma cells become numerous at a later stage, suggesting is highly speculative but there is preliminary evi- that plasmacytoid cells mature with time into vesicu- dence to suggest that it inhibits the migration of lar cells, presumably with a progressive modification macrophages and leucocytes.7' Furthermore its sec- of function." retion by the can be controlled by T One of the consistent features of the epithelioid lymphocytes.72 It is highly likely that epithelioid cells cell is the virtual absence of recognisable endocyt- secrete many more substances, similar to and in osed material, either on light or electron keeping with, macrophages. However, details are microscopy, suggesting that the cell is not actively not known at present. phagocytic. Nevertheless, a common finding is the As secretory cells, epithelioid cells share features intracellular Schaumann body, a complex of in common with activated macrophages. Indeed, crystalline calcium salts and conchoidal bodies pro- some workers consider the two terms to be bably derived from autophagocytic residual synonymous, but this is surely an oversimplification. lysosomal bodies.58 59 Functional studies on Most reports of activated macrophages describe epithelioid cells have, until recently, only been poss- increasing phagocytic capacity and expression of ible on "facsimile" epithelioid cells, that is, cells surface receptors, but epithelioid cells exhibit the produced artificially from macrophages by opposite. Nevertheless it is possible that epithelioid experimental manipulation.6'62 Although having transformation could be a specialised type of many of the morphological features, these facsimiles macrophage activation, perhaps by a distinct sub- are not identical to epithelioid cells and their population of mononuclear phagocytes. The lack of authenticity has been questioned.63 However, viable any evidence of phagocytosis, recent or past, in epithelioid cells have recently been isolated from epithelioid cells raises the possibility that these cells granulomas produced in vivo, allowing functional do not arise from phagocytic tissue macrophages4"

studies to be made.' Both facsimile and isolated but develop directly from monocytes entering the http://jcp.bmj.com/ "true" epithelioid cells are, as would be expected lesion which are already destined to mature into from t8heir morphology, poorly phagocytic, and epithelioid cells.63 " The factors which initiate this there is a blanket inhibition of endocytosis by both process, however, remain a complete mystery. immunological and non-immunological receptors. The epithelioid cell is, therefore, best regarded as Moreover, there is evidence that the expression of a very specialised type of mononuclear phagocyte, surface immune receptors (Fc and C3b) is reduced immobilised in the granuloma, whose function has in epithelioid cells compared with macrophages, been diverted away from phagocytosis to extracellu- although there is some dispute over the detailed lar secretion. on October 1, 2021 by guest. Protected copyright. changes.6466 It appears therefore that the epithelioid cell is not specialised to interact with Multinucleated giant cells extracellular particulate matter. Nevertheless recent studies in indicate that epithelioid cells Multinucleated giant cells are a regular feature of express surface HLA-DR (Ta) antigens67 and con- granulomatous inflammation. There is now over- sequently have the potential to interact immunolog- whelming evidence that they are macrophage ically with activated T lymphocytes in their vicin- polykaryons, produced by the fusion of ity.42 macrophages, rather than by nuclear mitosis without Electron microscopy suggests that epithelioid cells cytoplasmic division.25 6 73 74 Traditionally have important biosynthetic properties. Enzyme inflammatory giant cells have been divided into the histochemistry has shown the presence of acid Langhans (tuberculous) type, in which up to 20 phosphatases, ,3-galactosidase, lysozyme and non- nuclei are distributed centrally or around the specific esterase, while ultrastructural cytochemistry periphery of the cell, and the foreign-body type with has revealed a mucoglycoprotein, not yet further often very numerous haphazardly arranged nuclei characterised, within the vesicles of type B cells." throughout the cytoplasm. However it is now clear Some of these vesicles have been seen to fuse with that there is no fundamental difference between the plasmalemma, presumably discharging their these two cell types, and there is no diagnostic J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from

Granulomatous inflammation-a review 727 significance. Both types are commonly found to simultaneous endocytosis theory, in that the cells coexist in the same lesion, transitional forms have often contain ingested material or the products of its been described, and studies in tissue culture have degradation, residual bodies with myelin figures.8' shown that type giant cells "mature" Prominent microfilaments are also present, espe- into Langhans type cells, probably by movements of cially in the periphery of the cytoplasm and these the intracellular cytoskeleton.5 '3 sometimes fuse together to produce the star-shaped Mechanisms whereby macrophages fuse to pro- asteroid bodies seen on light microscopy.82 More duce giant cells have been widely studied. Fusion centrally there is an active Golgi apparatus and induced by viruses occurs in many cell types numerous mitochondria, lysosomal bodies and some throughout the body, including macrophages,2' but membrane-bound vesicles. The giant cells of is of limited significance in the granulomatous epithelioid cell granulomas are different, however. environment. Three main ideas have been suggested They rarely contain microfilaments or any recognis- for inflammatory giant cell formation. First, it was able ingested material. Instead they have an ultra- proposed that fusion may be an immune-mediated structure similar to that of epithelioid cellss15383 and phenomenon, giant cell production being stimulated some authors have described giant cells with the by lymphokines.7576 However, the evidence for this cytoplasmic features of both type A and type B has been questioned," macrophage fusion occurs in epithelioid cells.55 The way by which these cells vitro in the absence of immune factors and giant cell could be formed is a mystery-the poor phagocytic formation occurs equally well in normal and athymic capacity of epithelioid cells" would make their mice." The second suggestion is that fusion occurs fusion by simultaneous endocytosis very unlikely between "young" macrophages and "older" cells, unless the cytoplasm did not develop its epithelioid the latter having existed for some time in the appearance until after cell fusion had occurred. granulomatous environment acquiring chromosomal There is now some electron microscopical evidence abnormalities and changes in the macrophage to suggest that fusion of epithelioid-like cells may surface.5 The recognition of the altered and abnor- follow the development of specialised desmosome- mal cell surface by young macrophages is the like intercellular junctions between adjacent stimulus for cell fusion, and the process is regarded ceUs.56 84 as a means whereby altered, effete and senescent The functions of multinucleated giant cells are cells can be removed. Hovever, other studies have only speculative. While their formation in foreign failed to produce giant cells by altering macrophage body granulomas may be only an accident of surfaces in vitro, or by coculturing macrophages of simultaneous endocytosis the process does have the http://jcp.bmj.com/ different genetic makeup.78 The third proposal is advantage of successfully interiorising particles that giant cells form as a result of simultaneous which would otherwise be too large for endocytosis attempted phagocytosis,' during which two by a single cell. Moreover there is no reason to macrophages attempt to ingest the same particle. suspect that intracellular digestion by giant cells is The endosome margins of one macrophage, instead inferior to that by mononuclear macrophages. The of fusing together around the particle, fuse with the ultrastructure of giant cells, especially those in endosome margins of a second result- epithelioid granulomas, suggests that they too could macrophage, on October 1, 2021 by guest. Protected copyright. ing in fusion of the two cells. There is considerable have important biosynthetic and secretory functions circumstantial and experimental evidence to support similar to mononuclear epithelioid cells. this theory, including the relatively poor phagocytic capacity of giant cells79 which can be explained at Pathogenesis of granulomas least partly by the interiorisation of surface membrane receptors during the original fusion pro- Granuloma formation is usually regarded as a means cess.80 Although ingested foreign material can of defending the host from persistent irritants of frequently be found within giant cells this is not either exogenous or endogenous origin. The causa- always the case, and this is one of the possible tive agent is walled off and sequestered by cells of anomalies of the simultaneous endocytosis theory. macrophage lineage allowing it to be contained, if The proponents of the idea suggest that this can be not destroyed altogether. Experimental models of explained by the fact that the granulomatous granulomatous inflammation have provided much of environment itself produces endocytogenic material our present knowledge of the pathogenesis of from endogenous macromolecules, independently of granulomas.85 Such studies have shown that both the the initial irritant.367380 nature of the irritant and host factors are important Ultrastructural examination of multinucleated in governing the type of reaction that is produced. giant cells from granulomas produced by foreign All injected substances cause an initial influx of material provides some evidence to support the mononuclear cells by the phenomenon of J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from

728 Williams, Williams chemotaxis. However, what happens next depends difficult to achieve agreement among different on the resistance of the irritant to degradation by observers as to the presence or absence of macrophages. If it is a soluble substance that is easily epithelioid cells. digested then the macrophages move away once A second classification of granulomas is based on degradation is complete.'3 However if it is poorly cell kinetics.'392 Within any lesion there is a con- soluble, persistent and undegradable a granuloma is tinuous turnover of macrophages, dying cells being formed. The exception to this rule is that soluble replaced either by new recruits from the circulation materials can produce granulomas if they combine or by local mitosis. However, there are striking with endogenous macromolecules to form insoluble, variations in the turnover rate between different undegradable compounds, a mechanism considered granulomas. "Low turnover" granulomas are those important in granuloma formation by certain soluble with little macrophage death, immigration or metal salts such as beryllium.85 Experimental mitosis. They are typically produced by agents granulomas can also be produced by soluble irritants which, although poorly degradable, are relatively complexed either with insoluble inert materials86 or inert and non-toxic to the cells-for example, with antibodies to form insoluble immune com- carrageenan, barium sulphate. The macrophages plexes.87 present are long lived and contain large amounts of Why poorly soluble, undegradable material the irritant.93 Epithelioid cells are not found, and causes immobilisation of macrophages and their lymphoid cells are unusual, suggesting that immune organisation into a granuloma is unknown, although mechanisms are of minor importance in their in some instances, where there is involvement of the pathogenesis. These low turnover lesions immune system, lymphocyte-produced MIFs correspond to foreign body granulomas. "High undoubtedly have a role. The macrophages in the turnover" granulomas, on the other hand, are pro- lesions are often activated, making them particularly duced by irritants which are toxic to macrophages suited to a degradative function, but in spite of this, such as mycobacteria or silica. They are character- granuloma-producing agents often persist within ised by a high rate of recruitment and local division cells for a long time. Their resistance to degradation of macrophages to compensate for their relatively is quite unexplained in many cases, although some- short life span and high death rate within the times there is evidence that the macrophage' s lesion.94 The causative agent is present in only a armamentarium of lysosomal enzymes is small proportion of the cells and the lesions thus inappropriate to denature the chemical structure of have some features in common with epithelioid

the irritant, such as the cell walls of certain granulomas. However, not all high turnover http://jcp.bmj.com/ bacteria.88 Other irritants, such as some parasites, granulomas have epithelioid cells. Although a escape destruction by acquiring a coat of host anti- classification of granulomas by their cell kinetics is gens89 or becoming sequestered within the of considerable theoretical importance it is unfortu- macrophage cytoplasm, apparently safe from nate that in clinical practice most lesions are of the attack.90 The latter sequestration is in part due to the high turnover type and contain macrophages in vary- failure of phagosomes to fuse with lysosomes, a fea- ing degrees of activation. There is some evidence of ture of some mycobacterial .9' functional heterogeneity among the infiltrating Observations that granulomas are of differing macrophage population, not only between on October 1, 2021 by guest. Protected copyright. morphology and caused by a wide variety of irritants granulomas of different aetiology,63 but also in have led to numerous attempts to classify different zones of the same granuloma.38 granulomatous inflammation, either to help in the The characteristics of a granuloma are not only diagnosis of granulomatous disease or to further the dependent upon the properties of the causative irrit- understanding of the granulomatous process. How- ant. Host factors are also of great importance, a fact ever, none has been very successful. On a pure well illustrated in the pathology of leprosy, where morphological level, histopathologists have divided different individuals produce very different granulomas into "foreign body" and "epithelioid" granulomatous reactions to the causative bacillus, types, depending primarily on the absence or pre- with a spectrum of appearances between two sence of epithelioid cells. An inducing agent is often extremes. At one end of the spectrum is lepromat- recognisable in foreign body granulomas while it is ous leprosy in which there are ill-defined collections difficult or impossible to find in epithelioid lesions. of foamy macrophages containing large numbers of Moreover the two lesions are said to contain either bacilli-features associated with foreign body foreign body or Langhans type giant cells respec- granulomas. At the other end is tuberculoid leprosy tively. This classification is very unsatisfactory, how- with organised epithelioid granulomas in which ever; the two types of giant cell are not distinct, as bacilli are difficult to find. It is now clear that the has been alluded to earlier, and in practice it is often most important factor governing the type of reaction J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from

Granulomatous inflammation-a review 729 is the degree of immunological resistance to the formation it is also essential to take account of organism developed by the host. Patients with high changes in the circulation. These have been studied immunity develop tuberculoid reactions while those recently in sarcoidosis where the high density of with low immunity have the lepromatous form." helper T cells at the site of granuloma formation is Similar findings have been found in experimental accompanied by a reduction in the proportion of zirconium granulomas in guinea pigs.9596 A third helper cells in the circulation and an increase in the classification of granulomas, therefore, is based on proportion of suppressor T cells.'08 Moreover there the immunological dependence of the lesions,97 with is evidence that the serum of many patients with granulomas being divided into immunological and sarcoidosis contains T cell suppressant factors, some non-immunological types. In view of the close of which are probably immune complexes.'09 interactions of lymphocytes and macrophages The idea that immune mechanisms can initiate described earlier it is not surprising that both cell- granulomatous inflammation has not gained univer- mediated and antibody-mediated immunity have sal acceptance. Epstein,63 11 while stressing the role their role in the accumulation and differentiation of of immune mechanisms in amplifying the mononuclear phagocytes that is granuloma forma- granulomatous response, has cast doubt on the sole tion. Nowhere has this been studied more than in importance of immunity in the initiation of the reac- experimental schistosomiasis, where it is interesting tion and has suggested the existence of a specific that different species of the parasite apparently pro- type of hypersensitivity leading to epithelioid duce immunological granulomas by different means. granuloma formation which he terms granulomatous The reaction to Schistosoma mansoni is largely a hypersensitivity. He states that the nature of this cell-mediated, T lymphocyte dependent reac- reaction is a mystery but suggests that it might be a tion,85 98 whose progression is controlled by the bal- specific function of the mononuclear phagocyte ance of T cell subsets (helper and suppressor cells) system. Other workers"' have extended this idea by and possibly by the antibody response to the para- postulating that a specialised subgroup of mono- site.99- 101 Schistosoma japonicum, on the other nuclear phagocyte cells can act as memory cells, hand, produces immunological granulomas by a being primed on first exposure to a granuloma- method that appears to be independent of cell- producing agent. Subsequent exposure is then mediated immunity, but whose initiation and control followed by proliferation of these memory cells to requires the presence of antibody.'02 103 Cell- produce epithelioid cells and giant cells. There is no mediated immunity is also involved in the good evidence to support this hypothesis, but in fact granulomatous reaction of tuberculosis and the concept of granulomatous hypersensitivity is berylliosis,85 while antibodies, especially when com- very difficult to prove or disprove. However some http://jcp.bmj.com/ bined with antigen in the form of immune com- support for its existence comes from the production plexes, not only produce granulomas in the of epithelioid granulomas in immune deficient ani- experimental model,87 but are also probably impli- mals and from the development of zirconium cated in the granulomatous reaction of extrinsic granulomas in man in the absence of demonstrable allergic alveolitis,'0 primary biliary cirrhosis,'05 and cell mediated immunity to this metal."2 If even in mycobacterial infections.'06 Recent studies granulomatous hypersensitivity occurs at all as an using monoclonal antibodies to identify lymphocyte entity, its effects are greatly amplified by the con- on October 1, 2021 by guest. Protected copyright. subtypes have highlighted the importance of cell ventional immune response. mediated immunity in the genesis of epithelioid granulomas. In the granulomas of sarcoidosis67 and Complications of granulomatous inflammadon: tuberculoid leprosy,'0' the great majority of the necrosis and fibrosis lymphocytes present are T cells. Furthermore, helper T cells greatly outnumber suppressor/ Granulomatous inflammation, like any inflammat- cytotoxic subsets, the ratio of helper to suppressor ory reaction, frequently results in tissue damage dur- cells in sarcoidosis increasing with the clinical activ- ing the active phase and fibrosis during the healing ity of the disease. Helper T cells in sarcoidosis are process. It is not surprising, in view of the nature of distributed uniformly throughout the granuloma67 some macrophage secretions (Table), that tissue while in tuberculoid leprosy they are concentrated in necrosis is a frequent complication of some a cuff around the central epithelioid cell zone.'07 The granulomas, especially towards the centre of lesions number of T lymphocytes in the non-epithelioid containing highly activated cells which are continu- granulomas of lepromatous leprosy, on the other ally dying and releasing their toxic contents. Such hand are small, the cells present being predomin- necrosis may take the form of caseation and cavita- antly of the suppressor/cytotoxic subset. tion, as occurs classically in tuberculosis, or it may In considering immune mechanisms in granuloma appear as a microabscess containing polymorphs. In J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from

730 Williams, Williams addition to autodigestion by macrophage enzymes, fibroblasts and collagen degradation, chiefly by tissue necrosis may also be produced by the direct neutral proteases. Macrophages have the potential toxic action of a causative agent, especially in the to affect both sides of this balance. Their presence is case of infectious micro-organisms. There is also highly desirable for successful wound healing"'7 and, evidence that the process is augmented by the when cultured under appropriate conditions they immune response, both by its cellular and humoral secrete substances which increase hydroxyproline arms. Cavitation in tuberculous granulomas has production'8 or stimulate proliferation in fibro- been associated with strong delayed hypersensitivity blasts. 119 Interleukin- 1, a macrophage product to the tubercle bacillus."3 However recent studies which is closely related to endogenous pyrogen, is with experimental mycobacterial infections in rats probably one such substance,'20 while fibronectin, a have shown that necrosis in granulomas is under glycoprotein secreted by macrophages with much more subtle immunological influence."4 It has important roles in cellular adhesion, is a chemotactic been suggested that the main stimulus to necrosis in agent for fibroblasts.'2' On the other hand, this model is the formation of immune complexes macrophage supernatants which inhibit collagen between antibodies and excess antigen synthesis have been described,'22 and collagenase (mycobacteria) in the centre of the lesion. This secretion by activated macrophages is well situation develops when cell-mediated immunity, established.34 Lymphocytes also have the potential initially strong, begins to decline for unknown for affecting fibrosis by their secretion of reasons, allowing the mycobacteria to proliferate, lymphokines which can induce migration, out of macrophage control. If cell-mediated immun- proliferation and collagen synthesis.'23 124 Studies on ity then improves again the number of bacilli whole granulomas have also found them to contain diminishes and immune complexes will form in anti- substances that induce fibroblast proliferation.'25 126 body excess causing epithelioid granuloma forma- They probably originate from macrophages or tion instead of necrosis.87 Support for this theory has lymphoid cells. Moreover, a study of explanted been obtained from experimental studies with granulomas of different types has found that col- mycobacteria coated with antibodies in differing lagen synthesis is most active in immunological proportions.'06 It may have important clinical rele- granulomas and lowest in foreign body lesions,'27 vance in the understanding of infective granulomat- corresponding with findings in vivo described above. ous diseases, particularly the "reactivation" of This suggests that cell-mediated immunity is of con- tuberculosis and the timing of BCG vaccination."4 siderable importance in controlling fibrogenesis but

Fibrosis is a common and important complication whether this is achieved by a direct action of http://jcp.bmj.com/ of granulomatous inflammation because it is often lymphoid cell products, or by an indirect effect of responsible for permanent tissue damage even after macrophage activation is uncertain. Epithelioid cells the causative agent has been eliminated. Thus hepa- have been suggested as having a role in fibrosis,45 tic and pulmonary fibrosis are important long-term and while to date there is no direct evidence for this, complications of schistosomiasis and sarcoidosis the degree of fibrosis in mycobacterial granulomas respectively. However, until very recently, does correlate with their content of epithelioid knowledge of how granulomas lead to fibrosis was cells.128 very scanty. It is clear that permanent fibrosis is not on October 1, 2021 by guest. Protected copyright. inevitable-most pathologists have seen lung Conclusion with florid granulomatous inflammation being followed by apparent complete resolution and Granulomatous inflammation represents a distinc- some granulomas, such as those of lepromatous tive tissue reaction to an irritant in which the central leprosy or carrageenan 115 116 are associated with cell is the mononuclear phagocyte cell, but which little fibrosis. Generally speaking, non- can be modified by other phenomena, especially immunological, low tumover, foreign body type hypersensitivity. The last 25 years have seen granulomas appear to stimulate the least amount of tremendous improvement in our knowledge of cell collagen production. Nevertheless, the granulomat- biology, and macrophage function but ous process can also be damped down by in spite of this many mysteries continue to surround immunological mediators, particularly by suppressor the pathogenesis of organised granulomas and the T cells.99-'0' function and significance of their two distinctive cell Experimental studies have illuminated many types, epithelioid cells and giant cells. Continued mechanisms whereby fibrosis within granulomas can research into granulomatous inflammation is essen- be controlled by the secretions of endogenous cells. tial, not only for its theoretical value, but also for its The degree of collagenisation is govemed by the important potential clinical implications. Better balance between collagen synthesis by activated knowledge of the granulomatous process will both J Clin Pathol: first published as 10.1136/jcp.36.7.723 on 1 July 1983. Downloaded from

Granulomatous inflammation-a review 731 help to elucidate the causes of so-called idiopathic 41 Van Der Meer JWM, Beelen RHJ, Fluitsma DM, van Furth R. granulomatous diseases, such as sarcoidosis, Crohn's Ultrastructure of mononuclear phagocytes developing in liquid bone marrow cultures: a study on peroxidatic activity. J Exp disease or primary biliary cirrhosis, and also Med 1979;149:17-26. improve opportunities for therapeutic intervention. ,s Van Furth R. Cells of the mononuclear phagocyte system: If the destructive properties of granulomas can be nomenclature in terms of sites and conditions. In: van Furth R, reduced while the beneficial functions are amplified, ed. Mononuclear phagocytes, functional aspects. The Hague: Martinus Nijhoff, 1980:1-30. there will be immense scope for preventing the 16 Isaacson P, Jones DB, Millward-Sadler GH, Judd MA, Payne S. long-term complications, especially fibrosis, of many Alpha-1-antitrypsin in human macrophages. 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