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1 THE JOURNAL OF INVESTIGATIVE DEHMATOLOGY Copyright 1569 by The Williams & Wilkins Co. vol. 52, No. 5 Printed in U.S.A. INTRANIJCLEAR AND EXTRACELLIJLAR LANGERHANS' CELL GRANTJLES* KLAUS WOLFF, M.D. Acm BRIGITTE SOLLEREDER ABSTRACT Langerhans' cell granules were observed inside a nucleus of a histiocytic cell of a cm taneous lesion of lnstiocytosis X. These organelles were truly intranuclear and did not represent "nuclear pseudo-inclusion". It is suggested that they reached the nueleoplasm during an abnormal mitosis. Several extracellular Langerhans' cell granules were seen both in the dermis and epidermis. The most probable explanation for these findings would be to assume that the granules were released from disintegrating Langerhans' (bistiocytie) cells. In ultrathin sections Langerhans' cell granules are identified as rodshaped organdies with a striated central line and a partly expanded limiting membrane at one end (1 5). These structures represent two-dimensional profiles of disc- or cup-shaped bodies with a vesicular portion (5) and their internal structure consists of four sheets of regularly spaced particles which form a three-dimensional paracrystalline lattice (4). Originally, Langerhans' cdl granules were considered to represent unique constituents of intraepidermal Langerhans' cells (1 3) and Langerhans' cells of the oral mucosa (6, 7) but subsequently it was shown that they may be found in cells of normal dermis (3, 11), in cells of osseous, pulmonary and skin lesions of histiocytosis X (8, 9, 10), and in occasional histiocytes encountered in a variety of disorders (11, 12). These findings, together with histochemical evidence and results of experimental studies on the entire Langerhans' cell population, have led Wolff (13, 14) to postulate that Langerhans' cells are mesenchymal in nature. Recently, the same view has been expressed by Hashimoto and Tarnowski (10, 11). Langerhans' cell granules are cytoplasmic organelles which have never been found anywhere else but in the cytoplasm of cells. In the course of an eleetronmicroscopic study of cutaneous lesions of histiocytosis X we observed (a) a cell containing typical Langerhans' cell granules within its nucleus and (b) This study was supported in part by Ponds zur Forderung der wissenschaftlichen Forschung, Vienna, and Sobering AG., Berlin. Received September 12, 1968; accepted for publication October 18, * From the First Department of Dermatology, University of Vienna, School of Medicine, A-1090 Vienna, Austria. 424 Langerhans' cell granules in the intercellular space of the epidermis and the extracellular compartment of the dermis. To the best of our knowledge intranuclear and extracellular Langerhans' cell granules have not been observed so far and in view of the fact that the origin and fate of these subcellular structures are still disputed we consider it justified to report our findings. MATERIAL AND METHODS Biopsy specimens were taken from two papular cutaneous lesions of a 5 months old boy presenting with histiocytosis X of the Letterer-Siwe type. Small blocks were fixed in 1% osmiumtetroxideveronal-acetate buffer for 1½ hours, dehydrated in a graded series of alcohols, and embedded in Epon 812. Ultrathin sections were cut with glass knives on a Reichert OM U2 ultramicrotome, contrasted with uranyl acetate and lead citrate and examined with a Zeiss EM 9A electron microscope. RE5DLT5 The ultrasturctural features of the cells observed in this study corresponded to those already described in previous studies on histiocytosis X (8, 9, 10). In particular, numerous histiocytic cells were observed, both in the dermis and invading the epidermis, which contained typical Langerhans' cell granules in their cytoplasm. The specific findings to be reported here were as follows: 1) In the upper dermis a cell was seen the cytoplasm of which contained mitochondria, a large number of smooth surfaced vesicles, endoplasmatic reticulum, single membrane limited dense bodies, and Langerhans' cell granules (Fig. 1). The nucleus was highly lobulated and was surrounded by a characteristic nuclear envelope. The nuclear chromatin was granular in texture and in two areas exhibited

2 LANGERH&NS' CELL GRANULES 425 )1 c - fl Fio. 1. A cell observed within the dermal infiltrate of a lesion of histiocytosis X. The lobulated nucleus (N) contains multiple vesicles (V) and typical profiles of Langerhans' cell granules (double arrows). These organelles are not separated from the nucleoplasm by membranes and are therefore truly intranuclear. This is contrasted by the nuclear pseudo-inclusions (P) which represent cross-sections through cytoplasmic invaginations into the nucleus. The single arrows denote Langerhans' cell granules within the cytoplasm of the cell. ER: endoplasmic reticulum, M: Mitochondria. X nn accumulation of smooth surfaced vesicles, vacuoles, and flat cisternac resembling a Golgi zone. Interspersed between the vesicles there were several rod-like and vesicular profiles of Langerhans' cell granules (Fig. 1, 2, 3). There was no membrane separating these structures from the rest of the nucleoplasm. Despite a careful search of multiple sections no other examples of intranuclear granules were encountered. 2) In the epidermis numerous cells were seen exhibiting the ultrastructural characteristics of Langerhans' cells. The intercellular spaces were widened and in several sections intact Langerhans' cell granules were observed floating freely in the expanded space between adjacent keratinocytes (Fig. 4). Not infrequently, extracellular Langerhans' cell granules were also found in the dermis (Fig. 5) and were sometimes associated with other cytoplasmic struc-

3 426 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY ' 1 I 4,I :t _,j ta 3 IL-A t1 L $Y '::$ L Fm. 2. Enlargement of a nuclear portion of the cell from Figure 1. Within the nucleus (N) which is separated from the cytoplasm (C) by a typical nuclear envelope (double arrows), rod-like (R) and vesicular portions (Y) of Langerhans' cell granules are seen. X: intranuclear vesicles and vacuoles. X Fm. 3. Enlargement of the left lobule of the nucleus depicted in Figure 1. A typical Langerhans' cell granule (YR) and vesicles (N) arc seen within the nucleus (N) which is separated from the cytoplasm (C) by the nuclear envelope (double arrows). ER: endoplasmic reticulum. Single arrow: Langerhans' cell granule within the cytoplasm. X49500.

Extracellular Langerhans' cell granule (arrow) within the expanded intercellular space (IS) of the epidermis.

4 LANGERHANS' CELL GRANULES 427 : ;:t pg. - - : 4r 'Ij -S.' Is 4 - C 1 1*.: - 4'% / -. I cp._4; 0C' EC ' b C. -'-- : d -. Fia. 4. Extracellular Langerhans' cell granule (arrow) within the expanded intercellular space (IS) of the epidermis. K: Keratinocyte, ID: Desmosomes. X Fcc. 5. Langerhans' cell granules (arrows) in the extracellular compartment (EC) 01 the dermis. CP: Cytoplasmic processes of connective tissue cells. X49500.

5 428 TilE JOURNAL OF INVESTIGATIVE DERMATOLOGY tures such as mitoehondria, vesicles and lysosome-like bodies. Histiocytic cells with a ruptured cytomembrane were encountered occasionally. DIscussIoN In most instances cytoplasmic organelles, apparently inside a nucleus, represent so called 'nuclear pseudo-inclusions" (15). These are the result of cross sections of cytoplasmic invaginations into the nucleus which are always separated from the nucleoplasm by the nuclear envelope and are, of course, extranuclear (see Fig. 1,P). Truly intranuclear organelles with cytoplasmic features have been described, but such observations are extremely rare (16, 17, 15). The intranuclear vesicles and Langerhans' cell granules observed in our material did not represent "nuclear pseudo-inclusions" as they were not surrounded by a nuclear membrane and were therefore truly intranuelear. One can only speculate as to their mode of formation. Bucciarelli (17) who observed Golgi-like cisternae in a nucleus of Rous sarcoma considered the possibility that they represented cross-sections of invaginations of the internal nuclear membrane or detached sacs derived from sueb invaginations. Since our nucleus contained not only vesicles but also fully developed Langerhans' cell granules, neither alternative appears suited to explain our findings. Although we cannot exclude the possibility that the intranuclear organelles were in fact synthetized within the nucleus, we believe that the most probable explanation of our observations would be to assume that these structures were included within the nucleus during an abnormal mitosis. The presence of mitochondria in nuclei of Ieukemic cells as well as endoplasmic reticulum, cytoplasmic vesicles and mitochondria within the nucleoplasm of fibroblasts have also been ascribed to such a process (16, 17). There is still disagreement on the mode of formation of Langerhans' cell granules. Some authors maintain that they originate in the Golgi zone and move to the cell periphery where they attach to the cytomembrane and discharge their contents into the extracellular compartment (secretion theory) (2, 3, 4). Others claim that the granules are formed by an infolding (2) or a "folding back on itself" of the cytomembrane and thus represent a special form of endocytosis (10, 11). Lanthanum has been used to label Langerhans' cell granules (19) but these studies have not provided sufficient evidence to make either one of the two concepts more probable. Likewise, our observations of intranuelear and extracellular Langerhans' cell granules fail settle the problem of their origin. The fact that the intranuclear Langerhans' cell granules were associated with intranuclear vesicles resembling a Golgi zone may be considered to support the theory that they are Golgi derivatives. Regarding the origin of the extracellular granules observed in our material, two possibilities come to mind. Either the granules had been discharged from intact Langerhans' (or histiocytic) cells or they had been released from the cytoplasm of disintegrating cells. The observation of ruptured cytomembranes and the association of extracellular granules with other cytoplasmic structures favors the second alternative. REFERENCES 1. Birbeck, M. S., Breathnsck, A. S. and Everall, J. D.: An electron microscopic study of basal melanocytes and high level clear cells (Langerhans' cells) in vitiligo. J. Invest. Derm., 37: 51, Breathnach, A. S.: Observations on cytoplasmic organelles in Langerhans' cells of human epidermis. J. Anat., 98: 265, Zelickson, A. S.: The Langerhans' cell. J. Invest. IDerm., 44: 201, Wolff, K.: The fine structure of the Langerhans' cell granules. J. Cell Biol., 35: 468, Sagebiel, R. W. and Reed, T. H.: Serial reconstruction of the characteristic granule of the Langerhans' cell. J. Cell Biol., 36: 595, Schroeder, H. E. and Theilande, J.: Electron microscopy of normal human gingival epithelium. J. Periodont. Res., 1: 95, Waterhouse, J. P. and Squire, C. A.: The Langerhans' cell in human gingival epithehum. Arch. Oral Biol., 12: 341, Basset, F. et Nezelof, E.: Presence en microscopic Slectronique de structures filamenteuses originalcs dans les lesions pulmonaires et osseuses de l'histiocytose X. Etat actuel de la question. Bull. Soc. med. Hop. Paris, 117: 413, Basset, F. et Turiaf, J.: Identification par ha microscopic électronique de particulares dc nature probablement virale dans les liasons granulomateuses d'une histiocytosc X pulmonairc. C. R. Acad. Sci. (Paris), 261: 3701, Tarnowski, W. M. and Hashirnoto, K.: Langcrhans' cell granules in Histiocytosis X. Arch. Derm., 96: 298, Hashimoto, K. and Tarnowski, W. M.: Some

6 LANGERHANS' CELL GRANULES 429 new aspects of the Langerhans' cell. Arch. Derm., 97: 450, Ebner, H. und Niebauer, C.: Uber den Nachweis von Langerhanszell-Organellen ausserhaib der Epidermis. Wien. klin. Wschr., 79: 686, Wolff, K.: Die Langerhans-Zelle. Ergebnisse neuer experimenteller Untersuchungen. I. Mitteilung. Arch. klin. exp. Derm., 229: 54, Wolff, K.: Die Langerhans-Zelle. Ergebnisse neuer experimenteller Untersuchungen. II. Mitteiluog. Arch. klin. exp. Derm., 229: 76, Bernhard, W. and Grandboulan, N.: The fine structure of the cancer cell nucleus Exp. Cell Res.,9: (Suppi.) 19, Brandes, D., Schofield, B. and Anton, B.: Nuclear mitochondria. Science, 149: 1373, Bucciarelli, B.: Intranuclear cisternae resembling structures of the Golgi complex. J. Cell Biol., 30: 664, IS. Bloom, C. D.: A nucleus with cytoplasmic features. J. Cell Biol., 35: 266, Cancilla, P. A.: Demonstration of the Langerhans' granules by lanthanum. J. Cell Biol., 38: 248, 1968.

CELLS CONTAINING LANGERHANS GRANULES IN HUMAN LYMPH NODES OF DERMATOPATHIC LYMPHADENOPATHY*

THS JOURNAL OF INVEBTIOATIVR DERMATOLOGY Copyright 1969 by The Williams & Wilkins Co. Vol. 93, No. 4 Printed in U.S.A. CELLS CONTAINING LANGERHANS GRANULES IN HUMAN LYMPH NODES OF DERMATOPATHIC LYMPHADENOPATHY*