Plasmacytoid monocytes (so-called plasmacytoid T cells) in granulomatous lymphadenitis

Plasmacytoid Monocytes (So-Called Plasmacytoid T Cells) in Granulomatous Lymphadenitis FABIO FACCHEllI, MD, CHRIS DE WOLF-PEETERS, PHD, RITA DE VOS, PHD, JOOST J. VANDENOORD, PHD, KAREN A. F, PULFORD, PHD, AND VALEER J. DESMET, PHD Immuoohistochemical evidence that the plasmacytoid T cell is closely related to the blood mooocyte has been reported, and the term plasmacytoid mooocyte has been proposed to describe this cell. The present study was undertaken to analyze the presence lymph nodes showing epithelioid cell reactions. Numerous plasmacytoid mooocytes (detected by a panel of moooclonal antibodies) were found in the majority of tbe lymph nodes studied, usum&nucleated giant cells. The present findings suggest that plasmacytoid mooocytes may give rise to epitltelioid cells. This is further supported by the ultrastructural similarities between plasmacytoid mooocytes and plasmacytoid epithelioid cells, a cell type that has been identified previously in granulomas and considered a direct precursor of the classical epithelioid cell. HUM PATHOL 20:58fL593. 0 1989 by W.B. Saunders Company.

Plasmacytoid T cells are mononuclear cells commonly found in the interfollicular and paracortical areas of the lymph node. Iv2 Their identification was formerly based on purely morphological criteria, such as medium size, round to slightly indented nuclear shape, and a well-defined cytoplasm that stains blue-grey on Giemsa staining and contains a welldeveloped rough endoplasmic reticulum. lx3s4 More recently, the recognition of plasmacytoid T cells was facilitated by their labeling with some monoclonal antibodies reactive in paraffin-embedded material.2*5 Plasmacytoid T cells are considered to represent a special subset of CD4’ T lymphocytes6 Recently, we demonstrated5 that these cells not only express the CD4 molecule known to be present also on monocytes/macrophages, but that they react with other, well-defined antigenic markers that label monocytes and mononuclear phagocytes, such as CD36 and CD15. In addition, plasmacytoid T cells were found to react with several antibodies, not well characterized in terms of target antigen, but highly selective for macrophages in tissue sections, such as EBM/l 1, Y l/ 82A, KiM6, KiM7, and KPl.‘-I1 This study provided From the Department of Pathology, Catholic University of Leuven, Leuven, Belgium; and the Nuffield Department of Pathology, University of Oxford, Oxford, United Kingdom. Accepted for publicationJanuary 3, 1989. Key words: monocytes, granulomas, lymphadenitis, immunohistochemistry. Address correspondence and reprint request to Fabio Facchetti, MD, Department of Pathology, Laboratorium voor Histo/ Cvtochemie. Universitv Hospital. Catholic Universitv of Leuven, Minderbroedesstraat li, 3060 Leuven, Belgium. 0 1989 by W.B. Saunders Company. 0046-8 177/89/2006-0008$5.00/O

strong evidence for the monocyte-related origin of plasmacytoid T cells, and the term plasmacytoid monocyte was proposed to describe these cells.5 Because monocytes and monocyte-derived cells play an essential role in granuloma formation,12-14 we have undertaken a study of the presence and distribution of plasmacytoid monocytes in granulomatous lymphadenitis. MATERIALS AND METHODS Tissues Thirty-three lymph nodes containing epithelioid cells were selected for this study. The diagnoses are given in Table 1. Epithelioid cells occurred in small nests (group A, 13 cases) and/or in well-developed granulomas (group B, 20 cases) (Table 1). All tissue specimens had been fixed in B5 and embedded in paraffin.

Lectin Staining and lmmunohistochemistty Five micron serial sections were used for conventional hematoxylin and eosin staining, and for staining with concanavalin A (Con-A) and with monoclonal antibodies. Peroxidase-conjugated Con-A was applied overnight at 4”C, in a dilution of 50 pg/mL in phosphate buffered saline, pH 7.2. For immunohistochemistry, an Avidin-Biotin Complex (ABC) immunoperoxidase technique (Dakopatts, Copenhagen, Denmark) was used. The monoclonal and polyclonal antibodies and their specificities are listed in Table 2. The peroxidase reaction product was developed using a solution of diaminobenzidine-H,O, and sections were then counterstained with Mayer’s hematoxylin.

Electron Microscopy Tissue from two cases that had been fixed in glutaraldehyde and processed for electron microscopy was investigated. One micron thick sections were used to select small nests of epithelioid cells and areas from well-developed granulomas. Subsequently, serial ultrathin sections were studied by transmission electron microscopy.

RESULTS Histological and Immunohistochemical

Findings

Small epithelioid cell nests were found scattered in the subcapsular, interfollicular, and paracortical areas. Granulomas composed of epithelioid cells and variable numbers of multinucleated giant cells occurred in the same location in partially involved

PLASM.4CYTOlD MONOCYlES IN GRANULOMAS (Facchetiiet al)

TABLE I.

Epithelioid Cell Distribution, Plasmacytoid Monocyte Occurrence, and Diagnosis In Reactive Lymph Nodes Used in This Study Plasmacytoid Monocytes

Epithelioid Cell Distribution

Cases

Group A, small nests Group B, granulomas

Absent

Diagnosis

8

1

5 4

4* 2*

Piringer-Kuchinka lymphadenitis Polymorphic pulp hyperplasia Sarcoidosis Tuberculosis

C+A+S

A+S

13

3

11 9

2 3

12 1 11 9

Abbreviations: C, clusters; A, loose aggregates; S, singular cells. * Lymph node parenchyma completely involved by granulomas.

lymph nodes. In extensively involved lymph nodes, granulomas progressively replaced the paracortex and were surrounded by remnants of B cell follicles. Epithelioid and multinucleated giant cells showed cytoplasmic positivity with antibodies LN2, VICY-1, KPl, and with Con-A, and, on the cell membrane, with antibodies MT1 and TAL-lB5. A minority of epithelioid cells were reactive with antibody Mac-387. Large numbers of plasmacytoid monocytes were recognized in most of the cases in this study, in the interfollicular and paracortical areas. They were easily identified in immunostained sections by their membrane-associated reactivity with monoclonal antibody MT1 and by their cytoplasmic reactivity with TABLE2.

Reagents MB2 MT1

LNl LN2

VICY-1 TAL-185 KPl’ Mac387t S-100$

Con A

Reactivity of the Antibodies and Lectin Used in the Present Study Specificities All B cells (not plasma cells) T cells; myeloid cells: monocytes and macrophages; interdigitating reticulum cells and Langerhans cells Follicle center cells; red cells and precursors B cells; monocytes and macrophages; interdigitating reticulum cells and Langerhans cells (HLA-DR related, cytoplasmic) HLA-DR. y-chain HLA-DR, a-chain Macrophages Macrophages; granulocytes Interdigitating reticulum cells; dendritic reticulum cells; Langerhans cells; subpopulation of T lymphocytes Macrophages; plasma cells

Source (Reference) B (15) B (18)

B (17) B (17)

VK ICRF ox D D

(18) (19) (11) (20) (21)

P (22)

Abbreviations: B, Biotest Seralc Brussels, Belgium; VK, Dr W. Knapp, Vienna, Austria; ICRF, Dr WF Bodmer, Imperial Cancer Research Fund, London, UK; OX, Dr DY Mason, Oxford, UK; D, Dakopatts, Copenhagen, Denmark; P, Polysciences, Warrington, PA. * KPl is a monoclonal antibody that has been shown to selectively label the cytoplasm of most cells of mononuclear phagocyte origin, myeloid precursors, occasional granulocytes, and rare interdigitating reticulum cells, in paraffin sections after trypsinization. It does not stain lymphoid cells in these sections.” t Mac387 staining was performed after trypsinization of the sections. $ Polyclonal antibody.

antibodies LN2, VICY-1, and KPl. In addition, they were reactive with the lectin Con-A; variable numbers of these ceils were stained by antibody TAL-IBS in their cytoplasm and/or on their plasma membrane. Plasmacytoid monocytes occurred as large clusters and/or loose aggregates and as single cells (for details, see Table 1). Epithelioid cells and multinucleated giant cells were seen to lie within loose aggregates of plasmacytoid monocytes and, occasionally, within plasmacytoid monocyte clusters (Figs 1 and 2). In seven of the 13 cases containing small nests of epithelioid cells (group A), the majority of these cell nests were associated with plasmacytoid monocytes. However, in five cases only a few epithelioid cell nests were surrounded by plasmacytoid monocytes, and in the remaining case no plasmacytoid monocytes were found. The lymph nodes in these six cases did not differ from the other lymph nodes of the same group with regard to the size or morphology of the epithelioid cell nests or to the reactive changes in the lymphoid parenchyma. In cases containing well-developed granulomas (group B), these regions were surrounded by variable numbers of plasmacytoid monocytes, the largest number being present around the smallest, poorly organized granulomas. Plasmacytoid monocytes were almost absent around granulomas showing fibrosis and hyalinization (Fig 3). Plasmacytoid monocyte clusters as well as epithelioid cell nests and granulomas were surrounded by variable numbers of dendritic cells, strongly stained by S-100, LN2, VICY-1, and TAL- lB5, and recognizable as interdigitating reticulum cells. They were intermingled with MTl-positive T lymphocytes and MB2-positive B lymphocytes. MTl-positive T lymphocytes were also observed within plasmacytoid monocyte clusters and in the granulomas.

Electron Microscopic Findings On electron microscopy, epithelioid cell nests and granulomas were composed of a heterogeneous cell population. They contained small to medium sized plasmacytoid monocytes, characterized by abundant rough endoplasmic reticulum with parallel arrangement of the cisternae, by a well-developed Golgi apparatus, and by rare small lysosomes (Fig 4, left). The medium-to-large sized epithelioid cells showed long and slender cytoplasmic processes, interdigitating with each other; their cytoplasm contained many

HUMAN PATHOLOGY

Volume 20, No. 6 [June 1989)

FIGURE 1. Piringer-Kuchinka lymphadenitis, illustrating immunoreactivity of small epithelioid cell nests [arrows) and of the numerous surrounding plasmacytoid monocytes. (ABC immunoperoxidase for KPI, counterstained with hematoxylin; magnification x 380.)

organelles. The multinucleated giant cells occasionally contained lysosomes, phagosomes, or long Birbeck granules. some of the epithelioid cells (Fig 4, right) and multinucleated giant cells contained large amounts of rough endoplasmic reticulum, equal in density to that seen in plasmacytoid monocytes. In addition, macrophages with numerous and heterogeneous lysosomes and phagosomes, typical interdigitating reticulum cells, small lymphocytes, fibroblasts, myofibroblasts, and small venules were found in the granulomas.

DISCUSSION In this study, numerous plasmacytoid monocytes (so-called plasmacytoid T cells) were shown to be present in reactive lymph nodes containing small epithelioid cell nests and well-developed granulomas, and, as previously pointed out,i their presence was unrelated to the etiology of the granulomatous process. An important observation was that plasmacytoid monocytes tended to be present in the same distribution pattern as both epithelioid cell nests and well-

FIRIJRE 2. Granulomatous iymphadenitls, showing a small granuloma within a cluster of plasmacytoid monocytes. Several intensely stained interdigitattng reticulum cells surround the cluster (arrows). (ABC immunoperoxidase for LN2 counterstained with hematoxylin; magnification x 380.)

PLASMACYTOID MONOCYES

IN GRANULOMAS (Facchetti et al]

FlRlJRE 3. Granulomatous tymphadenitis showing two adjacent granulomas. The granuloma on the right shows significant fibrosis. Many plasmacytoid monocytes are in close association with the nonfibrotic granuloma (left). [ABC immunoperoxidase for KPI, counterstained with hematoxylin; magnification x 380.)

between these cells. This suggests that these cell populations share a common lineage. The present study also indicates that plasmacytoid monocytes are actively engaged in granuloma formation and may represent the precursor cell population that transforms into epithelioid cells. Our preliminary observations on the ultrastructure of granulomas support this hypothesis, since plasmacytoid

In keeping with previous developed granulomas. observatiorq5 where several monocyte/macrophage associated markers (such as CD4, EBMll, Y1/82A, KiM6, KiM’7, CD15, and CD36) were demonstrated on epithelioid cells and multinucleated giant cells on the one hand, and on plasmacytoid monocytes on the other, the present immunohistologic analysis shows further similarities in antigen and lectin expression

FIRURE + Ultrastructural examination reveals the cytoplasmic similarities of plasmacytoid monocytes and plasmacytoid epjthelloid cells. (Left) An lllu.stration of a typical plasmacytoid monocyte in a case of granulomatous lymphadenitls. (Magnification x 6,035.) (Right) Part of a typical plasmacytold epithelloid cell characterized by long and slender cytoplasmic processes, and showing large amounts of rough endoplasmlc reticulum as in the plasmacytold monccytes. Part of a small lymphocyte in the upper left comer is visible. (Magnification x 6,035.)

591

HUMAN PATHOLOGY

Volume 20, No. 6 (June 1989)

proliferation in response to foreign antigen or induce a suppressor T cell population.43z44 If OKM5positive, OKMl-negative plasmacytoid monocytes have a similar functional capacity, they may play a role in modulating the granulomatous reaction, either by amplifying the immune response or by generating a suppressor cell population which is involved in the control and restriction of the inflammatory process.45 In conclusion, the results of this study indicate that numerous plasmacytoid monocytes are present in granulomatous lymphadenitis and suggest that, in this circumstance, they may transform into epithelioid cells. Isolation of plasmacytoid monocytes from lymphoid tissues and characterization of their changes in morphology and function in an in vitro tissue culture system is a challenging prospect for the future in order to provide definitive evidence on their role in the formation of epithelioid cell granulomas.

monocytes show cytoplasmic similarities to those epithelioid cells characterized by a conspicuous amount of rough endoplasmic reticulum. The latter correspond to cells previously referred to as “plasmacytoid” epithelioid cells,23-27 which have been considered to represent nonphagocytosing cells with secretory function,23,25,27 and whose presence is a feature of early granulomas.26~28 Heterogeneity in the cytochemical profile of epithelioid cells in granulomas has been reported and has been related to the chronology of granuloma formation and to the topographic distribution of epithelioid cells.2g~30 The positivity of epithelioid cells for acid phosphatase and the absence of other lysosomal enzymes,2g*30 observed during the early stages of granuloma formation and at the periphery of welldeveloped granulomas, corresponds well with the cytochemical characteristics of plasmacytoid monocytes (so-called plasmacytoid T cells31,32) which, as noted in this study, occur in the same location. The presence of numerous plasmacytoid monocytes in T cell lymphomas and in Hodgkin’s disease,32 two conditions in which epithelioid cell reactions are frequently observed, might indicate that in these circumstances plasmacytoid monocytes also may transform into epithelioid cells. On the other hand, the extensive cell death occurring within large plasmacytoid monocyte clusters in histiocytic necrotizing lymphadenitis (Kikuchi’s disease)6 might explain the absence of an epithelioid cell reaction in this peculiar lymphadenitis.33 In addition to playing a role as the precursors of epithelioid cells, plasmacytoid monocytes may also function in the immunopathogenesis of granuloma formation. Immunologic granulomas result from the interaction between T lymphocytes and antigenpresenting cells,34-37 with recruitment of monocytederived cellsSs that transform under lymphokine stimulation into epithelioid and multinucleated cells.s6*3g~40The antigen-presenting function in granulomas is classically attributed to interdigitating reticulum cells, which we and others37*41 observed around the granulomas. Because plasmacytoid monocytes strongly express the y-chain of HLA-DR and, variably, the a-chain of this molecule (recognized by monoclonal antibodies VICY-1 and TAL-lB5, respectively), these cells may also be capable of the processing and presentation of antigen. If plasmacytoid monocytes transform into epithelioid cells under the influence of activated T lymphocytes, their variability in number and their absence in some epithelioid cell clusters and granulomas may be related to different functional stages in the evolution of the granulomas. The lack of plasmacytoid monocytes around advanced fibrosing and hyalinizing granulomas supports this hypothesis. Plasmacytoid monocytes show a peculiar OKM5positive, OKMl-negative phenotype.5 This phenotype characterizes blood monocytes involved in the autologous mixed lymphocyte reaction.42 These cells are capable of stimulating T lymphocytes by selfantigen presentation and may either facilitate their

Acknowledgment. Monoclonal antibodies VICY-1 and TAL- 1B5 were kindly provided by Dr W. Knapp and by Dr W. F. Bodmer, respectively. The authors thank P. Aertsen, B. Smets, and L. Vanryckel for excellent technical assistance, and M. Rooseleers for preparation of the photographs.

REFERENCES 1. Vollenweider R, Lennert K: Plasmacytoid T-cell clusters in non-specific lymphadenitis. Virchows Arch (B) 44: l-14, 1983 2. Facchetti F, De Wolf-Peeters C, van den Oord JJ, et al: Plasmacytoid T cells: A cell population normally present in the reactive lymph node. An immunohistochemical and electronmicroscopic study. HUM PATHOL 19:1085-1092, 1988 3. Lennert K, Remmele W: Karyometrische Untersuchungen an Lymphknotenzellen des Menschen: I. Mitt.-Germinoblasten, Lymphoblasten und Lymphozyten. Acta Haematol (Basel) 19:99113, 1958 4. Mtiller-Hermelink HK, Kaiserling E, Lennert K: Pseudofollikulare Nester von Plasmazellen (eines besonderen Typs?) in der paracorticalen Pulpa menschlicher Lymphknoten. Virchows Arch (B) 14:47-56, 1973 5. Facchetti F, De Wolf-Peeters C, Mason DY, et al: Plasmacvtoid T cells. Immunohistochemical evidence for their monocvtemacrophage origin. Am J Pathol 133:15-21, 1988 6. Feller AC, Lennert K, Stein H, et al: Immunohistology and aetiology of histiocytic necrotizing lymphadenitis. Report orthree instructive cases. Histonatholos?v 7:825-839. 1983 7. Kelly PMA, Bliis E, Mozon JA, et ah Monoclonal antibody EBM/l 1: High cellular specificity for human macrophages. J Clin Path01 41:510-515, 1988 8. Davey FR, Cordell JL, Erber WN, et al: A monoclonal antibody (Y1/82A) with specificity toward peripheral blood monocytes and tissue macrophages. J Clin Path01 41:753-758, 1988 9. Parwaresch MR, Radzun HJ, Kreipe H, et al: Monocyte/ macrophage-reactive monoclonal antibody Ki-M6 recognizes an intracytoplasmic antigen. Am J Path01 124:141-151, 1986 10. Kreipe H, Radzun HI, Parwaresch MR, et al: Ki-M7 monocbnaf antibody specific fo; myelomonocytic cell lineage and macrophage in human. J Histochem Cytochem 35:1117-l 126, 1987 11. Pulford K, Rigney E, Jones M, et al: KPl-A new monodonal antibody detecting a monocyte/macrophage associated antigen in routinely processed tissue sections. J Clin Path01 (in press) 12. Sutton JS, Weiss L: Transformation of monocytes in tissue culture into macrophages, epithelioid cells and multinucleated giant cells. J Cell Biol 28:303-332, 1966

592

PLASM4CYlOlD MONOCYTES IN GRANULOMAS (Facchetti et al] BCG granulomas for pair of enzymes. Am J Path01 99: 195-212, 1980 30. Veress B, Malmskold K: The distribution of SlOO and lysozyme immunoreactive cells in the various phases of granuloma development in sarcoidosis. Sarcoidosis 4:33-37, 1987 31. Carbone A, Manconi R, Volpe R, et al: Enzyme- and immunohistochemical study of a case of histiocytic necrotizing lymphadenitis. Virchows Arch (A) 408:637-647, 1986 32. Miiller-Hermelink HK, Steinman G, Stein H, et al: Malignant lymphoma of plasmacytoid T-cells. Morphologic and immunologic studies characterizing a special type of T-cell. Am J Surg Path01 7:849-862, 1983 33. Pileri S, Kikuchi M, Dagmar H, et al: Histiocytic necrotizing lymphadenitis without granulocytic infiltration. Virchows Arch (A) 395:257-271, 1982 34. Adams DO: The granulomatous inflammatory response, Am J Path01 84:163-190, 1976 35. Miiller-Hermelink HK, Kaiserling E: Epithelioidzellreaktionen im lymphatischen Gewebe, in Dohm G (ed): Verhandl Deut;c71;oesellschaft Pathol. Stuttgard, Gustav Fisher Verlag, 1980, pp

13. Epstein WL, Krasnobrod H: The origin of epithelioid cells in experimental granulomas in man. Lab Invest 18: 190-195, 1968 14. Adams DO: The structure of mononuclear phagocytes differentiating in vivo. I. Sequential fine and histologic studies of the effect of Bacillus Calmette-Guerin (BCG). Am J Path01 76: 1748, 1974 15. Hall PA, D’Ardenne AJ, Butler MC, et al: New marker of B lymphocytes, MBZ: Comparison with other lymphocyte subset markers active in conventionally processed tissue sections. J Clin Path01 40:151-156. 1987 16. Poppema S, Hollema H, Visser L, et al: Monoclonal antibodies (MTl. MT2. MBl. MB2 MB3) reactive with leukocvte subsets in paraffin-embedded tissue sections. Am J Path01 127:418429, 1987 17. Epstein AL, Marder RJ, Winter JN, et al: Two new monoclonal antibodies (LNl, LN2) reactive in B5 formalin-fixed, paraffin-embedded tissues with follicular center and mantle zone human B lymphocytes and derived tumors. J Immunol 133:10281036, 1984 18. Quaranta V, Majdic 0, Sting1 G, et al: A human Ia cytoplasmic determinant located on multiple forms of invariant chain (y, y2, ~3). J Immunol 132:1900-1905, 1984 19. Adams TE, Bodmer JG, Bodmer WF: Production and characterization of monoclonal antibodies recognizing the chain subunits of human Ia alloantigens. Immunology 50:613-624, 1983 20. Flavell DJ, Jones DB, Wright DH: Identification of tissue histiocytes on paraffin sections by a new monoclonal antibody. J Histochem Cytochem 35:1217-1226, 1987 21. Takahashi K, Isobe T, Ohtsuki Y, et al: Immunohistochemical localization and distribution of S-100 protein in the human lymphoreticular system. Am J Path01 116:497-503, 1984 22. Hsu S-M, Ree HJ: Histochemical studies on lectin binding in reactive lvmnhoid tissue. .,I Histochem Cvtochem 31:538-546. 1983 ’ ’ 23. Gusek W: Formale Pathogenese der hyalinen Transformation des Sarkoidosegranuloms. Virchows Arch (A) 345:264-275, 1968 24. Elias PM, Epstein WL: Ultrastructural observations on experimentally induced foreign-body and organized epithelioid-cell granulomas in man. Am J Path01 52: 1207-1223, 1968

36. Boros DL: Granulomatous inflammation. Prog Allergy 24: 184-276, 1978 37. Martin AG, Kleinhenz ME, Elmets CA: Immunohistologic identification of antigen-presenting cells in cutaneous sarcoidosis. 1 Invest Dermatol 86:525-629, 1986 38. Hunninghake GW, Gadek E, Young RC, et al: Maintenance of granuloma formation in pulmonary sarcoidosis by T lymphocytes within the lung. N Engl J Med 302:594-598, 1980 39. Warfel AH, Hadden JW: Macrophage fusion factor elicited from BCG-sensitized lymphocytes. Am J Path01 93:753-770, 1978 40. Yoshida T: Role of Lymphokines in the induction and maintenance of the granuloma, in Boros DL, Yoshida T (eds): Basic and Clinical Aspects of Granulomatous Diseases. Amsterdam, Elsevier, 1980, pp 81-94 41. Pineiro-Maceira JM, Fukuyama K, Epstein WL, et al: Immunohistochemical demonstration of S-100 protein antigencontaining cells in Berillium-induced, Zirconium-induced and Sarcoidosis granulomas. Am J Clin Path01 81:563-568, 1984 42. Shen HH, Talle MA, Goldstein G, et al: Functional subsets of human monocytes defined by monoclonal antibodies: A distinct subset of monocytes contains the cells capable of inducing the autoloeous mixed lvmnhocvte culture. 1 Immunol 130:698-705. 1983 23. Bensus&n A, Meuer SC, Schlossman SF, et al: Delineation of an immunoregulatory amplifier population recognizing autologous Ia molecules. Analysis with human T cell clones. J Exp Med 159:559-576, 1984 44. Battisto JR, Ponzio NM: Autologous and syngeneic mixed lymphocyte reactions and their immunological significance. Prog Allergy 28:160-192, 1981 45. van den Oord JJ, De Wolf-Peeters C, Facchetti F, et al: Cellular composition of hypersensitivity-type granulomas: Immunohistochemical analysis of tuberculous and sarcoidal lymphadenitis. HUM PATHOL 15:559-565, 1983

25. Jones Williams W, James EMV, Erasmus DA, et al: The fine structure of sarcoid and tuberculous granulomas. Postgrad Med 46:496-500, 1970 26. Williams G: Isolated epithelioid cells from disaggregated BCG granulomas. An ultrastructural study. J Path01 136: 1-13, 1982 27. Turk JL, Narayanan RB: The origin, morphology and function of epithelioid cells. Immunobiology 161:274-282, 1982 28. Turk JL: The mononuclear phagocyte system in granulomas. Br J Dermatol 113s:49-54, 1985 29. Suga M, Dannenberg AM, Higuchi S: Macrophage functional heterogeneity in vivo: Macrolocal and microlocal macrophage activation, identified by double-staining tissue sections of

593