Zusammenfassender Bericht Blur, Band 34, Seit 317-328 (1977) Department of Internal Medicine, Section of Hematology and Oncology, Kantonsspital, St. Gallen

Disorders of the Mononuclear Phagocyte System. An Analytical Review Gerhard Meuret The present paper reviews and analyzes the disorders of the mononuclear phagocyte system (MPS) on the basis of the current pathophysiologic concepts. Disorders with changes in the MPS cover a broad spectrum since the MPS is involved in numerous biologic processes including host defense mechanisms, scavenger activities, interactions with bone and connective tissue formation and destruction. Terminology The term mononuclear phagocyte system is equivalent with monocyte macrophage system and monocyte macrophage complex. Macrophage and histiocyte are synonyms [23]. Every cell belonging to MPS may be termed mononuclear phagocyte apart from its specific designation, e.g. monoblast, promonocyte, blood monocyte, etc. The term macrophage comprises all kinds of cells originating from blood monocytes, irrespective of its localization in the organism, its age, morphology and function. Some pathophysiologic aspects of MPS

Genealogy of mononudear j)hagocytes The pertinent knowledge concerning the life cycle and genealogy of mononuctear phagocytes is integrated into the concept of MPS [23]. The progenitors of this cell system, i.e. differentiated stem cells [23,60], monoblasts and promonocytes, are situated in the bone marrow (Fig. 1). They produce blood monocytes which, after a short period in circulation [49], leave the vessels to migrate into the tissue, and convert into macrophages. The monocyte-derived macrophages colonize normal tissues as v. Kupffer cells, alveolar macrophages, microglial cells, etc., and they accumulate at sites of inflammatory or immunologic reactions as macrophages, epitheloid ceils and giant ceils [83]. Fibroblasts, endothelial cells, reticulum cells, sinus lining cells, and antigen binding dendritic cells are not of monocyte origin [23].

Functional interrelationshi;Os In vitro studies using mononuclear phagocytes from different animal species and man demonstrated numerous interrelationships with other cellular or humoral Eingegangen am 10. 1. 1977

G. Meuret

318 D~erenliated Stem Cells Monoblosts

-,-"l~'Macr.ophages Promonoeyles

l Histiocytesof Connective Tissue

I

1

Cells of Liver

Alveolar Free s Fixed Pleural and Micr.oglioI Macrophages Macrophages Peritoneal Cells of of Lung of Lymphoid Macrophoges Ner.vous Tissue System Mocr'ophages,Epitheloid Cells,and Giant Cells of Inflammation Kupffer.

Fig. 1: The mononuclear phagocyte system (MPS) [23]. Differentiated Stem Ceils Granu,ocytopoies~s? Monocyopoiesis ]

Ost~

Stim, FO

sled oxic ~hages

Fig. 2: Macrophage-interactions in host-defense. systems. The significance of these observations in human pathophysiology is at present only partially understood. However, several symptoms being associated with disorders of MPS indicate that interactions similar to those observed in vitro are also active in vivo. Thus, it is worthwhile to integrate the observed mechanisms into a system and use it as a background to interprete disease phenomena (Fig. 2). The different types of interactions may be grouped as follows : 1. Interrelationships between MPS and granulocytopoiesis, erythrocytopoiesis, thrombocytopoiesis. These 4 myeloid cell lines are probably coupled by virtue of their common origin, i.e. pluripotent myeloid stem cells (Fig. 3) [3, 75]. 2. Interrelationships between MPS and granulocytopoiesis. Both cell systems share similar or identical differentiated stem ceils and control systems [45,56]. 3. Interrelationships between macrophages and T-lymphocytes on the one hand and the differentiated stem cells common to granulocytopoiesis and monocytopoiesis on the other (Fig. 2). These interactions are mediated by humoral activities, the "colony stimulating factor," being secreted by macrophages [26] and by stimulated T-lymphocytes [70]. This factor is involved in regulation of stem cell proliferation and differentiation [45,46].

Disorders of the mononuclearphagocytesyslem

319

4. Macrophage-macrophage interactions. In addition to stem cell proliferation colony stimulating factor promotes macrophage proliferation [84]. At sites of inflammatory and immunologic reactions, macrophages secrete several soluble products which are either primary or secondary (by tissue destruction) [61,65, 82] chemotactic agents for blood monocytes and macrophages. This refers to complement components [68], plasminogen activator [28], lysosomal enzymes [27], collagenase and elastase [44, 87], prostaglandins [56] and other agents.

A ~ _ ~

c 9 0

9- Thrombocytes ,- Erythrocytes 9- Granulocytes " Monocytes

~

Thrombocytes Erythrocytes

Macrophages Lymphocytes

B

Macrop ages Lymphocytes

Thrombocytes Eryfhrocytes Granulocytes "~Monocytes

Thrombocytes / , / . 0Erylhrocytes •

Q~_.~ ~ D

Lymphocytes

Granulocytes Monoiytes

J Macrophages Lymphocytes

Mulfipotent Myeloid Stem Cell Differentiated Stem Cell

Fig. 3 : Classification of disorders of MPS into 4 groups : (A) diseases involving all 4 myeloid cell lines; (B) diseases involving MPS and granulocytopoiesis; (C) diseases associated with excessive macrophage-accumulation; (D) diseases involving primarily MPS and the lymphocytic system. 5. Macrophage-lymphocyte interactions which are partly mediated by cell to cell contact and partly by lympho~nes being particularly released from stimulated lymphocytes. Lymphokines recruit macrophages from blood monocytes (chemotactic factor), fix them at loci of inflammatory or immunologic reactions (migration inhibition factor), and transform macrophages into potent effector cells of these reactions (macrophage activating-, arming-, and cytotoxicity factors) [21,

22,41]. A further mode of macrophage-lymphocyte interaction is mediated by components of the complement system, the main source of which are the macrophages [69]. Complement enhances the cytotoxicity of lymphocytes and of immunocomplexes. The latter are chemotactic for blood monocytes and macrophages.

G. Meuret

320

6. By secretion of plasminogen activator [28, 86] macrophages influence coagulation. The clotting system is coupled with the kinin generating system and the complement system [13,17,64]. 7. Under pathologic conditions macrophage activity is involved in destruction of tissue, connective tissue and bone. This is caused by macrophage release of lysosomal enzymes, collagenase, by formation of cytotoxic macrophages and by osteoclast activating factor being secreted from lymphocytes upon interaction with macrophages [44,87]. 8. The accumulation of eosinophils in inflammatory cell infiltrates may be ascribed to several soluble products being released from stimulated lymphocytes, e.g. eosinophil stimulating factor which enhances eosinophil production [71], or eosinophil chemotactic factor [14].

Classification of disorders of MPS Existing classifications take into consideration exclusively those symptoms that emerge within the system itself [12,23,25]. They neglect important disease manifestations being simultaneously present in other systems which may reflect the primary cause of the disease. Many disorders of MPS cannot be understood adequately if this system is analyzed separately, disregarding its mutual relationships with other systems. Moreover, it has proven useful to group the diseases according to the cell systems primarily involved. This approach resulted in a simple classification into 4 groups each being composed of a "potpourri" of different disease entities (Fig. 3, Tab. 1): Group

Major alterations associated with

Type of disease

A

MPS (monocytopoiesis) & granulocytopoiesis & erythrocytopoiesis & thrombocytopoiesis

acute & chronic non-lymphocytic leukemias preleukemic states polycythemia vera, osteomyelofibrosis aplastic anemia

B

MPS & granulocytopoiesis

chronic granulomatous disease Chediak-Higashi syndrome, myeloperoxidase deficiency, different forms of neutropenia

C

MPS (macrophages)

a) several lipoid storage diseases (Tab. 2) b) idiopathic histiocytosis : Abt Letterer Siwe syndrome eosinophilic granuloma histiocytic medullary reticulosis familial erythrophagocytic lymphohistiocytosis

D

MPS & lymphocytes

inflammatory, infectuous, immunologic, malignant disorders

Tab. 1 : Classificationof the disorders of the mononuclear phagocyte system (MPS) according to primarily involved cell systems.

Disorders of the mononuclearphagocytesystem

321

Group A. Dysfunction including all 4 myeloid cell lines: all types of acute and chronic non-lymphocytic leukemias, preleukemic states, polycythemia vera, osteomyelofibrosis, and aplastic anemia. These diseases may hypothetically be attributed to dysfunctions of the pluripotent myeloid stem cells [8] which are assumed to be the common progenitors of erythrocytopoiesis, thrombocytopoiesis, granulocytopoiesis, and monocytopoiesis (Fig. 3).

Group B. These diseases manifest themselves primarily by alterations of MPS in combination with granulocytopoiesis: (1) chronic granulomatous disease of childhood [4] which demonstrates selective bactericidal and fungicidal defects in monocytes-macrophages and in granulocytes; (2) Chediak-Higashi syndrome, in which abnormal lysosomes and failure of the fusion with phagocytic vesicles were found in monocytes-macrophages and in granulocytes [5, 66]; (3) myeloperoxidase deficiency being present in both types of phagocytes [37,74] ; and (4) several forms of neutropenia being associated with monocytosis, e.g. infantile genetic agranulocytosis [33], familial chronic neutropenia [15,30], and cyclic neutropenia [48]. The defects occurring in the diseases mentioned, bone marrow transplantation experiments resulting in the successful transmission of cyclic neutropenia from affected to healthy dogs [89] and in the cure of mice with Chediak-Higashi syndrome [32] are in accord with the concept that MPS and granulocytopoiesis share common precursors.

Gro1~ C. Diseases with excessively enlarged macrophage pools, a symptom which is associated with several lipid storage diseases (Tab. 2) on the one hand and the group of idiopathic histiocytosis on the other. Disease

Lipid accumulated

Enzyme deficiency

Niemann-Pick Gaucher Fabry Gm-gangliosidoses Sea-blue histiocyte syndrome

sphingomyelin glucocerebroside ceramide GMi-glycopeptide phosphosphingolipids glycosphingolipids

sphingomyelinase ~-galactosidase ~-galactosidase ~-galactosidase complex

Tab. 2: Lipoid storage diseases associated with macrophage transformation into foam cells or sea-blue histiocytes, respectively.

Group D. Diseases in which MPS is involved in combination with the lymphocytic system. This refers to "reactive" macrophage-lymphocyte accumulations in inflammatory, infectious, immunologic and malignant diseases. These ceils are assumed to represent the effector cells charged with the elimination of inflammatory and/or immunogenic stimuli, or malignant cells. Specific features of certain disease entities of MPS

Acute monocytic leukemia Generally, the bone marrow is tightly packed with monoblasts and promonocytes. The leukemic cells share several functional characteristics with their normal counter-

322

G. Meuret

parts [76,77]: they contain NaF-sensitive non-specific esterase and lysozyme; adhere and spread on surfaces; bear Fc-membrane receptors for IgG and exhibit phagocytosis. Their migration potential frequently causes leukemic organ infiltration. In inflammatory exudates and in culture the leukemic blasts mature into macrophages. The proliferation activity of the leukemic cells, however, is lower than in normal monocytopoietic ceils [47].

Chronic monocytic "leukemia" This rare syndrome may persist without significant change during months and even years. It bears the following hallmarks: high susceptibility to infections; fever of unknown origin which may be attributed to monocyte-produced pyrogens [6]; extreme monocytopoietic hyperproliferation and extreme blood monocytosis; rise in plasma cells and immunoglobulins or monoclonal hypergammaglohulinemia; and absence of qualitative dysfunctions of MPS [52]. Thus, it seems equivocal whether this disorder represents a true neoplasia of MPS, or a premyeloma [58], or preleukemia [62], which is associated with an extracordinary strong reaction of MPS against an immunogenic, perhaps leukemogenic, factor affecting the organism. Marked monocytosis also occurs in about a quarter of preleukemic syndroms [73].

Myelomonocytic leukemia A preleukemic phase lasting between 1-9 years precedes 34% of myelomonocytic leukemias [72]. This type of leukemia clearly demonstrates the presence of proliferative dysfunctions in all 4 myeloid cell lines [55, 72]. They result in morphologic abnormalities, increase in sideroblasts, and discrepancies between enhanced amounts of precursors in bone marrow on the one hand and a lack of mature blood ceils on the other. Further specific features are hypergammaglobulinemia or other immunological abnormalities [10] and renal dysfunction primarily arising from lysozymuria [59, 63]. The erythromonocytic leukemia is a variant which is dominated by morphologic abnormalities, hyperproliferation, and ineffectivity of erythr0cytopoiesis [9].

Monocytopenia The isolated monocytopenia (monocyte blood counts below 100 per bd) as a seperate entity without affection of other hematopoietic cell lines seems non-existent. Monocytopenia occurs in combination with neutropenia, aplastic anemia, and hairy celt leukemia [80]. In aplastic anemia a positive correlation between monocyte and neutrophil blood counts was observed [85].

Lipoid-storage diseases Lipoid-accumulation in macrophages is caused by two basically different mechanisms (Fig. 4) : (1) by excessive lipoid ingestion due to phagocytosis of hematopoietic cells, e.g. in hemolytic anemia, thalassemia, idiopathic thrombocytopenic purpnra, chronic myeloid leukemia [1, 18], and (2) by congenital deficiencies of catalytic enzymes (Tab. 2). Lipoid storage is associated with a considerable increase in macrophage pools and with maerophage transformation into different types of storage cells, e. g. foam ceils and sea-blue histiocytes [81]. Macrophage accumulation in bone marrow may give rise to bone ratification.

Disorders of the mononudearphagocylesyslem

323

Idiopathic bistiocytosis The term idiopathic histiocytosis comprises the following disorders: Abt Letterer Siwe syndrome, eosinophilic granuloma, histiocytic medullary reticulosis [79, 88], and familial erythrophagocytic lymphohistiocytosis [43]. The Hand Schtiller Christian syndrome is not accepted as a separate disease entity because it merely represents a rare manifestation of a multifocal eosinophilic granuloma [40]. Formation of Storage Cells StorageDisease

Normal

Endom tosis

Congenital

Aquired

j ce.Stoerag II

Macrophage

jal~rr'on

~~D'e:icfive~ ~ 'Risein M..

I

J

c v

'

Exocytosis Fig. 4: Two different mechanisms give rise to the conversion of macrophages into storage

ceils:

(1) congenital defects of lipoid degradating enzymes, (2) excessive lipoid input by phagocytosis of dying hematopoietic ceils. Idiopathic histiocytoses are systemic disorders associated with progressive macrophage ( = histiocyte) infiltration of skeleton, skin, liver, spleen, lymph nodes, gastrointestinal tract, and hypophysis [35, 42]. Monocytopoiesis initially hyperproliferates and gradually converts into hypoproliferation with increasing macrophage infiltration of bone marrow [47]. Lymphocyte dysfunctions [11,38], bone ratification, and fibrosis may occur. Mortality of treated disease is highest in newborns (77%) decreasing to about 0% at the age of 3 years [24,35]. Lichtenstein speculated that eosinophilic granuloma, Abt Letterer Siwe syndrome and Hand Schtiller Christian syndrome share a common pathogenesis. This hypothetical pathogenetic principle was termed by him "histiocytosis X" [39]. Later, the same term was used by other authors in another sense, namely to designate the different types of idiopathic histiocytoses themselves, and even for other non-systemic disorders being characterized by local macrophage accumulation such as the "primary histiocytosis X of the lung" [57].

"Reactive" accumulation of macrophages Inflammatory, infectious, immunologic, and malignant disorders [19,20,29,31] are associated with "reactive" cellular tissue infiltrates containing particularly lymphocytes, macrophages, and to a less extent, neutrophils and eosinophils. Histiocytic reactions predominate in several idiopathic disorders, such as primary hisdocytosis of

G. Meuret

324

lung [57] and sinus histiocytosis with massive lymphadenopathy [36, 67, 11]. Cells of these infiltrates are recruited from the blood by the mechanisms outlined above (Fig. 2). They represent effector cells charged with the elimination inflammatory and/or immunologic stimuli [2,16]. Macrophage-consumption at the reaction site can be roughly estimated by monocytopoietic proliferation activity [51,53,54j60,78]. Macrophage demand is particularly high in acute infection (Tab. 3); it is markedly increased in several chronic inflammatory, infectuous, and malignant disorders, such as excematous diseases, tuberculosis ( = "high turnover granuloma"), Hodgkin's disease, mycosis fungoides; it is moderately increased in psoriasis vulgaris, colitis ulcerosa, Crohn's disease, breast cancer; and it is normal in sarcoidosis ( = "low turnover granuloma"), lymphosarcoma, reticulosarcoma. Macrophage consumption returns towards normal levels in Hodgkin's disease and breast cancer after therapeutically achieved remissions. At this stage, immunostimulation by BCG-scarification does not result in a measurable rise in macrophage-turnover. Diagnosis

Monocytopoietic proliferation activity *

Normal

1.0

Inflammatory diseases Psoriasis vulgaris Excematous diseases Colitis ulcerosa Gastric, duodenal nicer (U) U 13 hours after partial gastrectomy

1.7 3.8 1.8 3.2 5.7

Granulomatous diseases Sarcoidosis Crohn's disease Tuberculosis

1.1 1.8 3.5

Malignoma Breast cancer (BC) BC in remission & BCG-scarification Lymphosarcoma, reticulosarcoma Hodgkin's disease (HD) HD in remission Mycosis fungoides

2.8 1.2 0.8 3.7 1.4 5.3

* median of aH-thymidine labeling index times fraction of mononuclear phagocytes in bone marrow divided by median of healthy individuals [51, 78]. Tab. 3: Monocytopoietic proliferation activity which roughly reflects the macrophagedemand. Hodgkin's disease and disseminated malignoma may give rise to negative skin reactions of delayed type hypersensitivity despite increased monocyte production. This is attributed to high macrophage consumption by the tumor and chemotactic abnormalities of monocytes [7,82].

Disorders of the mononuclearphagocyte system

325

Macrophage action simultaneously exerts two o p p o s e d effects, namely tissuep r o t e c t i o n and tissue-destruction. In some disorders, e.g. vascular collagen diseases, inflammatory fibroxanthoma [34], Wegener's granulomatosis, etc., the tissue-agress i r e c o m p o n e n t prevails. Frequently, it is successfully d a m p e d by antiinflammatory a n d / o r i m m u n o s u p p r e s s i v e therapy. This work was supported by the Kind Philipp Donation.

References 1. Albrecht M. : ,,Gaucher"-Zeilenbei chronisch myeloischer Leuk~mie. Blur 13; 169 (1966). 2. Alexander P., Evans R. & Grant C. K. : The interplay of lymphoid cells and macrophages in tumor immunity. Ann. Inst. Past. 122, 645 (1972). 3. Aster R. H. & Enright S. E. : A platelet and granulocyte membrane defect in paroxysmal nocturnal hemoglobinuria: usefulness for the detection of platelet antibodies.J, din. Invest. 48, 1199 (1969). 4. Berendes H., Bridges R. A. & Good R. A. : A fatal granulomatosis in childhood: the clinical study of a new syndrome. Minn. Med. 40, 309 (1957). 5. Blume R. S. & Wolff S. M.: The Chediak-Higashi syndrome: Studies in four patients and a review of the literature. Medicine 51, 247 (1972). 6. Bodel P. & Atkins E. : Release of endogenous pyrogen by human monocytes. New Engl. J. Med. 276, 1002 (1967). 7. Boetcher D. A. & Leonard E. J.: Abnormal monocyte chemotactic response in cancer patients, jr. nat. Cancer Inst. 52, 1091 (1974). 8. Boggs D. R. & Boggs S. S. : The pathogenesis of aplastic anemia: a defective pluripotent hematopoietic stem cell with inappropriate balance of differentiation and self-replication. Blood 48, 71 (1976). 9. Broun O. G., Jr.: Chronic erythromonocytic leukemia. Amer. jr. Med. 47, 785 (1969). 10. CannatA. & SeligmannM. : Immunological abnormalities in juvenile myelomonocytic leukemia. Brit. reed.jr. I, 71 (1973). 11. Cederbaum S. D., Niwayama G., Stiehm E. R., Neerhout R. C., Ammann A. J. & Berman W., Jr. : Combined immunode-

ficiency presenting as the Letterer-Siwesyndrome. Pediatrics 85, 466 (1974). 12. Cline M. J. & Golde D. W.: A review and reevaluation of the histiocytic disorders. Amer. jr. Med. 55, 49 (1973). 13. Cochrane C. G., Revak S. D., Wuepper K. D., Johnston A., Morrison D. C. & Ulevitch R.: Activation of Hageman factor and the kinin forming intrinsic clotting, and fibrinolytic systems. In: Raspe G. (Ed.): Avances in the Biosciences, 12, 237 (1974). 14. Cohen S. & Ward P. A.: Lymphocytederived eosionophil chemotactic factor. f. exp. Med. 133, 133 (1971). 15. Cutting H. O. & Lang J. E.: Familial benign chronic neutropenia. Ann. inlern. Med. 61, 876 (1964). 16. Dannenberg A. M., Jr. : Macrophages in inflammation and infection. New Engl. J. Med. 293, 489 (1975). 17. Davies P. & Allison A. C. : The macrophage as a secretory cell in chronic inflammation. Agents and Actions 6, 60 (1976). 18. Dosik H., Rosner F. & Sawitsky A.: Acquired lipoidosis: Gaucher-like cells and "blue cells" in chronic granulocytic leukemia. Sem. hemat. 9, 309 (1972). 19. Evans R.: Macrophages in syngeneic animal tumors. Transplantation 14, 468 (1972). 20. Evans R.: Macrophages and the tumor bearing host. Br.J. Cancer 28, 19 (1973). 21. Evans R. & Alexander P. : Mechanisms of immunologically specific killing of tumor cells by macrophages. Nature 236, 168 (1972). 22. Evans R. & Alexander P. : Mechanisms of extracellular killing of nucleated mammalian ceils by macrophages. In: Nelson D. S. (Ed.): Immunobiology of

326 the macrophage, p. 535, Academic Press 1976. 23. Furth van R., Langevoot H. L. & Schaberg A.: Mononuclear phagocytes in human pathology-proposal for an approach to improved classification. In: Furth van R. (Ed.): Mononuclear Phagocytes in Immunity, Infection, and Pathology. Blackwell 1975, p. 1. 24. Glass A. G. & Miller R. W.: U.S. mortality from Letterer-Siwe disease. Pediatrics 42, 364 (1968). 25. Golde D . W . : Disorders of mononuclear phagocyte proliferation, maturation and function. Clin. I-Iaemat. 4, 705 (1975). 26. Golde D. W., Finlay T. N. & Cline M. J.: Production of colony-stimulating factor by hmuan macrophages. Lancet 2, 1397 (1972). 27. Gordon S., Todd J. & Cohn Z. A.: In vitro synthesis and secretion of lysozyme by mononuclear phagocytes.J, exp. Med. 139, 1228 (1974). 28. Gordon S., Unkeless J. C. & Cohn Z. A.: Induction of macrophage plasminogen activator by endotoxin stimulation and phagocytosis. Evidence for a two stage process. J. exp. Med. 140, 995 (1974). 29. Hersh E. M., Mavligit G. M., Gutterman J. U. & Barsales P. B.: Mononuclear cell content of human solid tumors Med. Pediat. Oncol. 21, 1 (1976). 30. Hitzig W. H. : Famili{re Neutropenie mit dominantem Erbgang und Hypergammaglobulin~imie. I-Ielv. reed. Acta 26, 779 (1959). 31. Husby G., Hoagland P. M., Strickland R. G. & Williams R. C., Jr. : Tissue T and B cell infiltration of primary and metastatic cancer..J, din. Invest. 57, 1471 (1976). 32. Kazmierowski J. A., Elin R. J., Reynolds H. Y., Durbin W. A. & Wolff S. M.: Chediak-Higashi syndrome: reversal of increased susceptibility to infection by bone marrow transplantation. Blood 47, 555 (1976). 33. Kostman R. : Infantile genetic agranulocytosis. Ac*a paediat. 45, Suppl. 105, l (1956). 34. Kyriakos M. & Kempson R. L.: Inflammatory fibrous histiocytoma. An aggressive and lethal lesion. Cancer 37, 1606 (1976).

G. Meuret 35. Lahey M. E.: Histiocytosis X - comparison of three treatment regims. J. Pediatr. 87II, 664 (1962). 36. Lampert F. & Lennert K. : Sinus histiocytosis with massive lymphadenopathy. Cancer 37, 783 (1976). 37. Lehrer R. I. & Cline M. J.: Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to candida infection. J. din. Invest. 48, 1478 (1969). 38. Leikin S., Puruganan G., Frankel A., Steerman R., Chandra R. : Immunologic parameters in histiocytosis X. Cancer 32, 796 (1973). 39. Lichtenstein L.: Histiocytosis X. Integration of eosinophilic granuloma of bone, "Letterer-Siwe disease," and "Schtiller-Christian disease" as related manifestations of a single nosologic entity. Arch. Palh. 56, 84 (1953). 40. Lieberman P. H., Jones C. R., Dargeon H. W. K. & Begg C. F.: A reappraisal of eosinophilic granuloma of ,bone, Hand-Schiiller-Christian Syndrome and Letterer-Siwe-Syndrome. Medicine 48, 375 (1969). 41. Lohmann-Mattes M. L.: Introduction of macrophage-mediated cytoxicity. In: Nelson D. S. (Ed.). Immunobiology of the macrophage, p. 464, Academic Press, 1976. 42. Lucaya Z. : Histiocytosis X. Amer. J. Dis. Child. 121, 289 (1971). 43. Mac Mahon H. E., Bedizel M. & Ellis C. A. : Familial erythrophagocytic lymphohistiocytosis, Pediatrics 32, 868 (1963). 44. Mergenhagen S. E., Wahl S. M., Wahl L. M., Horton J. E. & Raiz L. G.: The role of lymphocytes and macrophages in the destruction of bone and collagen. Ann. 2V. Y. Acad. Sd. 256, 132 (1975). 45; Metcalf D.: Regulation of granulocyte and monocyte-macrophage proliferation by colony stimulating factor (CSF) : a review. Ex20. Hemat. 1, 185 (1973). 46. Metcalf D. & Moore M. A. S.: In: Haematopoietic Cells. North Holland Publishing Comp., Amsterdam-London (1971). 47. Meuret G. : Unpublished observations. 48. Meuret G. & Fliedner T. M.: Neutrophil and monocyte kinetics in a case of cyclic neutropenia. Blood 44, 801 (1974). 49. Meuret G. & Hoffmann G.: Mon0cyte

Disorders of the mononucIearphagocyte syslem

50. 51.

52.

53.

54.

kinetic studies in normal and disease states. Brit. f. Haemat. 24, 275 (1973). Meuret G., Bammert J. & Hoffmann G. : Kinetics of human monocytopoiesis. Blood 44, 801 (1974). Meuret G., Schmitt E. & Hagedorn M.: Monocytopoiesis in chronic exzematous diseases, psoriasis vulgaris, and mycosis fungoides. J. Invest. Dermat. 66, 22 (1976), Meuret G., Bundschu-Lay A., Senn H. J. & Huhn D.: Functional characteristics of chronic monocytic "leukemia." Acta haemat. 52, 95 (1974). Meuret G., Schmitt E., Senn H. J. & Hoffmann G.: Monozytopoese, Makrophagenumsatz bet entztindlichen und malignen Erkrankungen. Blur, Suppl. (in press). Meuret G., Detel U., Kilz H. P., Senn H. J. & Lessen van H.: Human monocytopoiesis in acute and chronic inflammation. Acta haemat. 54, 328 (1975).

55. Miescher P. A. & IVarquet J. J. : Chronic myelomonocytic leukemia in adults. Sem. in Hemal. 11, 129 (1974). 56. Morley J.: Prostaglandins and lymphokines in rheumatoid arthritis. Prostaglandins 8, 315 (1974). 57. Nadean P. J., Ellis H. F. Jr., Harrison E. G. Jr. & Fontana R. S.: Primary pulmonary histiocytosis X. Dis. Chest. 37, 325 (1960). 58. Osserman E. F.: Clinical and biochemicai studies of plasmacytic and monocytic dyscrasias and their interrelationships. Trans. Stud. Coll. Phycns. Philad. 36, 134 (1969). 59. Osserman E. F. & Lawlor D, P.: Serum and urinary lysozyme (muramidase) in monocytic and monomyelocytic leukemia.J, exp. Med. 124, 921 (1966). 60. Pike B. & Robinson W. A.: Human bone marrow- culture in agar gel. J. cell. P&sioL 76, 77 (1970). 61. Postlethwaite A. E. & K a n g A. H.: Collagen- and collagen peptide-induced chemotaxis of human blood monocytes.J, exp. Med. 143, 1299 (1976). 62. Pretlow T. G.: Chronic monocytic dyscrasia culminating in acute leukemia. Amer. J. Med. 46, 130 (1969). 63. Pruszanski W. & Platts M. E.: Serum and urinary proteins, lysozyme (muramidase), and renal dysfunction in mono-

327 and myelomonocytic leukemia, f. din.

Invest. 49, 1694 (1970). 64. Ratnoff O. D.: Some relationships among hemostasis, fibrinolytic phenomena, immunity, and the inflammatory response. Adv. Immun. 10, 145 (1969). 65. Richardson D. L., Pepper D. S. & Kay A. B.: Chemotaxis for human monocytes by fibrinogen-derived peptides. Brit. f. Haemar 32, 507 (1976). 66. Root R. K., Rosenthal A. S. & Balestra D. J.: Abnormal bactericidal, metabolic, and lysosomal functions of Chediak-Higashi syndrome leukoeytes. J. clin. Invest. 51, 649 (1972). 67. Rosai J. & Dorfman R. F. : Sinus histiocytosis with massive lymphadenopathy a pseudolymphomatous benign disorder. Cancer 30, 1174 (1972). 68. Ruddy S., Gigli I. & Austen K. F.: The complement system of man. New Engl. J. IVied. 287, 489 (1972). 69. Ruddy S., Gigli I. & Austen K. F. : The complement system of man. New EngL f. Med. 287, 545 (1972). 70. Ruscetti F. W. & Chervenick P. A.: Release of colony stimulating activity from thymus-derived lymphocytes, f. din. Invest. 55, 520 (1975). 71. Ruscetti F. W., Cypess R. H. & Chervenick P. A. : Specific release of neutrophilic- and eosinophilic-stimnlating factors from sensitized lymphocytes. Blood 47, 757 (1976). 72. Saarni M. T. & Linman J. W.: Myelomonocytic leukemia: disorderly proliferation of all marrow cells. Cancer 27, 1221 (1971). 73. Saarni M. T. & Linman J. W.: The hematologic syndrome preceding acute leukemia. Amer.J. Med. 55, 38 (1973). 74. Salmon S. E., Cline M. J., Schulz J. & Lehrer R. I.: Myeloperoxidase deficiency: a genetic leukocyte defect. 2Vew EngL ar. Med. 282, 250 (1970). 75. Sandberg A, A. & Hossfeld D. K.: Chromosomal abnormalities in human neoplasia. Ann. Rev. Med. 21, 379 (1970). 76. Schmalzl F. : Unreifzellige Monozytenleukiimien. Blur 22, 157 (1972). 77. Schmalzl F., Huhn D., Asamer H., Abbrederis K. & Braunsteiner H.: Atypical (monomyelocytic) myelogenous leukemia. Acta haemat. 48, 72 (1972). 78. Schmitt E., Menret G. & Stix L.:

328 Monocyte recruitment in tuberculosis and sarcoidosis. Brit. ar. tgaemat. 35, 11 (1977). 79. Scott R. B. & Robb-Smith A. H. T.: Histiocyte medullary reticulosis. Lancet 237, 194 (1939). 80. Seshadri R. S., Brown E. J. & Zipursky A. : Leukemic reticuloendotheliosis. A failure of monocyte production. New EngL J. Med. 295, 181 (1976). 81. Silverstein M. N. & Ellefson R. D.: The syndrome of the seablue histiocyte. Sere. I-temat. 9, 299 (1972). 82. Snyderman R. & Mergenhagen S. E.: Chemotaxis of macrophages. In: Nelson D. S. (Ed.).: Immunobiology of the macrophage. Academic Press, New York, San Francisco, London, p. 232 (1976). 83. Spector W. G. & Mariano M.: Macrophage behaviour in experimental granulomas. In: (Furth R. van, Ed.) Mononuclear Phagocytes in Immunity Infection, and Pathology. Blackwell, OxfordEdinburgh, p. 927 (1975).

G. Meuret 84. Stanley E. R., Cifone M., Heard P. M. & Defendi V. : Factors regulating macrophage production and growth: identity of colony-stimulating factor and macrophage growth factor, f. exp. Med. 143, 631 (1576) . 85. Twomey J. J., Douglass C. C. & Sharkey O., J r . : The monocytopenia of aplastic anemia. Blood 41, 187 (1973). 86. Unkeless J. C., Gordon S. & Reich E.: Secretion of plasminogen activator by stimulated macrophages, jr. exp. Med. 139, 834 (1974). 87. Wahl L. M., Wahl S. M., Mergenhagen S. E. & Martin R. R.: Collagenase production by lymphokine activated macrophages. Science 187, 261 (1975). 88. Warnke R. A., Kim H. & Dorman R. F. : Malignant histiocytosis (histiocytic medullary reticulosis). Cancer 35, 215 (1975). 89. Weiden P. L., Robinett B., Graham T. C., Adamson J. & Storb R.: Canine cyclic neutropenia: a stem cell defect. J. din. Invest. 53, 950 (1974).

Author's address : PD Dr. G. Meuret, Department of Internal Medicine, Section of Hematology and Oncology, Kantonsspital St. Gallen, Switzerland.