The Langerhans Cell*

Tne JOURNAL OF INVESTIOATIVR DERMATOLOOY

Copyright

Vol. 44, No. 3

1965 by The Williarris & Wilkins Co.

Printed in U.S.A.

THE LANGERHANS CELL* ALVIN S. ZELICKSON, M.D.

Since Langerhans (1) first described the

MATERIALS AND METHODS

presence of gold-positive dendritic cells in the epidermis, their nature has been an unsettled question. These cells, which morphologically resemble inelanocytes, are free of pigment and

All specimens used in this study were obtained

by means of a punch biopsy from the extensor surface of the left upper arm of caucasian males. The tissue was immediately fixed in buffered 1%

tetroxide and embedded in either Vestopal are not seen when stained for melanin nor osmium W or Epon 812. The preparations were then secwhen the dopa stain is used; but they can be tioned with an LKB ultrotome and the sections

demonstrated with gold chloride methods. Mas- were stained with uranyl acetate. An RCA EMU

son (2) regards them as effete or wornout 3F electron microscope was used to examine the

melanocytes which are being exfoliated with grids. The study extended over a four year period from January 1959 through December 1963.

the neighboring epidermal cells, while Ferreira-

Marques (3) is of the opinion that they are Schwannian cells and that their dendritic

RESULTS

Location and Morphology. When studied

processes are nerve fibers.

with the electron microscope, Langerhans cells Recently, the ultrastructure of the melano- are found not only in the superficial portions cyte and the Langerhans cell has been examined of the epidermis but are also located on the in detail (4—11). The melanocyte of the human basement membrane and in the dermis (Fig. 1). epidermis is readily distinguishable from the Langerhans cells, on occasion, are noted breakother cells of the epidermis. It is easily recog- ing through the basement membrane into the nized by its clear cytoplasm, its lack of desmo- dennis. This suggests that the epidermalsomes, and the presence of melanin granules dermal cells "drop-off" to the dermis rather within its cytoplasm. Mitochondria are abun- than migrate to the epidermis. The cell is dant and a well-developed Golgi complex sur- dendritic in nature and its nucleus is markedly rounds the nucleus. The Langerhans or high- convoluted, often having one indentation which level clear cell is also clearly separable from is deeper than the others (Fig. 2). The cytothe surrounding keratinocytes. Its cytoplasm is plasm is relatively clear although there are a clear due to a relative absence of filaments; it few cytoplasmic filaments present. Pores are

is dendritic in nature and also lacks desmo- present in the nuclear membrane forming a somes. The Golgi zone is well-developed and direct communication between the nucleus and mitochondria are numerous. The Langerhans cytoplasm. The mitochondria are numerous cell is distinguished from the melanocyte by its characteristic cytoplasinic granule and by the convoluted appearance of its nucleus. Using the technics of electron microscopy to study these cells further, this paper will demoji—

and appear normal. The endoplasmic reticulum

aureophilic, dendritic cells.

organelles. The lysosomes become more numer-

is well-developed as is the Golgi complex. Centrioles are often seen and are located in the region of the Golgi zone (Fig. 2). Signifi-

cantly, the Langerhans cell contains many strate the existence of a transitional cell in lysosomes (Fig. 3). These are round, dense human epidermis, one which contains the bodies which are limited by a single membrane. melanin granule typical of the melanocyte as Their structural pattern varies, but basically well as the specific Langerhans cell granule consists of a concentric series of membranes. and will also point out the nature of these At times a helical pattern is noted within these ous and more prominent as the cell assumes a more superficial position in the epidermis. Also

Received for publication April 24, 1964.

* From the Division of Dermatology, University of Minnesota Medical School, Minneapolis, Minnesota.

present within the cells at this point are nu-

Aided by research grant Ca-05887 from the merous cytoplasmic lipid droplets (Fig. 3). In U.S.P.H.S. and by research grants M-388 and cells high in the epidermis the plasma memB-782 from the National Institute of Mental brane is deeply convoluted, thus giving the cell Health and the National Institute for Neurologic Diseases and Blindness, U.S.P.H.S. a vacuolated appearance (Fig. 4). 201

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202

FIG. 1. Contrary to the generally-held view, Langerhans cells are found in the dermis as well as in the epidermis. The cell contains numerous Langerhans granules (L) and is surrounded by collagen (c). mitochondrion (m); nucleus (N). X 18,960.

A Specific Granule. The characteristic gran- of the granule is variable, the handle at times ules within the Langerhans cell are shaped like being up to two microns in length. The number, a tennis racket with the handle portion having a as well as the size, of the Langerhans granules linear, striated lamella midway between its two is also variable. The granules tend to increase in limiting membranes (Fig. 5). The striations, size as they move toward the periphery of the similar to those found in melanosomes, have a cell and into the dendritic processes. Signifi-

50 Aigstrom periodicity. The racket portion cantly, typical melanosomes and/or melanin of the granule is limited by a wide membrane granules are also found in a few of these cells, which surrounds a clear zone. In occasional especially in those removed from the basement sections, there is a cross-striated pattern within

the clear zone of the granule (Figs. S and 6).

membrane (Figs. 7—9).

Method of Granule Secretion. The specific

The granules are usually found in close proxim- granules of the Langerhans cell are not seity to the Golgi complex and are formed by an creted into neighboring cells as are the melanin

outpouching of the smooth-walled vesicles of granules. The Langerhans cell granule moves the Golgi apparatus. The size of each portion from the Golgi zone toward the cell mem-

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THE LANGERHANS CELL

FIG. 2. The nucleus (N) of the epidermal Langerhans cell is characteristically indented. A centriole (c) is present within the Golgi zone (g) which in turn is surrounded by many typical granules (L).

x 11,808.

brane, attaches to it, and then opens to the

DISCUSSION

extracellular space rather than being passed to Although similar in many ways, the Langera neighboring cell. Either end of the granule hans cell and the melanocyte differ in that may reach the cell membrane first, although, the each has a characteristic cytoplasmic granule. "racket" portion usually does so, thus leaving The Langerhans cell granule lacks pigment the "handle" portion remaining within the and differs morphologically from the melanin cytoplasm with one end open to the surround- granule. At present, the consensus is that both ing milieu (Fig. 10). Because the granules are the endoplasmic reticulum and the Golgi comreleased in this manner and are not "injected" plex play a major role in melanogenesis. Alinto other cells, the Langerhans cell granule is terations in either or both of these organelles not seen in any cell but the Larigerhans Cell.

might account for the relatively different

204

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FIG. 3. A higher magnification shows the close association of the Golgi zone (g) to the numerous Langerhans cell granules (L). Also present is a lysosome (ly) and several lipid droplets (d). X 40,320.

structure of the granule. It is necessary for neural or neurohormonal function nor that it is both the endoplasinic reticulum and the Golgi complex to function normally if the cell is to

in any way related to a Schwannian cell. The

latter is in full agreement with the electron furnish a normal, mature granule. As it is microscopic findings of other authors (6). The next question to be considered, after postulated that the Langerhans cell is a transitional cell, it is quite conceivable that abnor- relating the two cells, is whether or not the malities exist in either of these two organelles Langerhans cell is an effete melanocyte. The which could result in this granule difference. cell is capable of mitotic division as witnessed As shown here, the Langerhans cell can by the numerous centrioles present and of proproduce both Langerhans granules and melano- tein synthesis, as demonstrated by the large somes, thus demonstrating a clearcut relation- number of granules it is producing; therefore, ship between these two cells. Although the it certainly should not be considered "wornpossibility of the Langerhans cells phagocytizing

melanin particles cannot be ruled out, there was no evidence to support this viewpoint.

out." The Langerhans cell is most likely a transitional cell. That it is a transitional cell and does not re-convert to a melanocyte is

The present study revealed no evidence which suggested by its production of an "incomplete" would suggest that the Langerhans cell has a granule which it is unable to pass to its neigh-

THE LANGERHANS CELL

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membrane. L, Langerhans cell granule; N, nucleus. X 17.020.

bors, and by the presence of both lysosomes and lipid deposits, both of which are often present shortly before the onset of cell degeneration (see later). As with keratinocytes,

another melanocyte or a Langerhans cell, while

a Langerhans cell may only produce other

Langerhans cells. The latter in turn will eventually become effete dendritic cells. If

the melanocyte probably engages in an irrever- these findings can be corroborated, the present sible process, proceeding from a inelanocyte to a cell system will be established as a most intransitional cell (Langerhans cell) to a truly triguing model for the differentiation of nonworn out cell.

embryonic cells.

More than likely, the Langerhans cell may reproduce itself and a point may be reached when, as in vitiligo, there is the formation of only this cell type. This too, is evident in the Syrian hamster where cells with Langerhans granules are unresponsive to the melanogenic and tumor-inducing effects of 7, 12-dimethylbenz (a) anthracene (10). If this is correct, a melanocyte may divide and produce either

The effete form of the cell is probably related to the presence of lysosornes, especially in those cells near the surface. Lysosomes have been associated with the hydrolytic enzymes of the cell and cell death (12). The enzymes are

isolated from the rest of the cytoplasm by a single membrane. When the lysosornal membrane ruptures releasing these enzymes, lysis of the cell occurs. This in fact happens and the

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

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FIG. 5.The granules have a 50 Angstrom periodicity in longitudinal section (L). When seen face on, the Langerhans granules have a similar periodicity, but in a cross-striated pattern. X 65,600.

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THE LANGERHANS CELL

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6. The characteristic cross-striations are clearly evident when the "racket" portion of the

granule is seen face-on (F). Again note the close association of the granules with the Golgi zone (g).

THE JOURNAL OF INVESTIGATIVE DERMATOLOGY

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Rio. 7. Melanin granules (M) and Langerhans granules (L) in the same cell. They are located in the cytoplasm in close approximation to the indented portion of the nucleus (N). X 73,710.

THE LANGERHANS CELL

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FIG. 8. Langerhans granules (L) and melanin granules (M) in the same cell. lysosome (ly). X 57,330.

210

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FIG. 9. Another Langerhans cell demonstrating both melanin and specific granules. X 82,628.

THE LANGERHANS CELL

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FIG. 10. An interesting series of micrographs demonstrating the manner in which the Langerhans cell granule (L) opens to the extracellular space. The granules move from the Golgi zone (g) to the cell surface. They then attach to the cell membrane (cm) and, in some manner, open to the surrounding milieu. From X 45,990.

212

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cells present in the upper regions of the epidermis become vacuolated and stop producing granules as the lysosomes disintegrate. SUMMARY

It has been shown that the Langerhans cell can produce both Langerhans granules and melanosomes, thus demonstrating a clearcut

4. ZELICKSON, A. S. AND HARTMAN, J. F.: The

fine structure of the melanocyte and melanin granule. J. Invest. Derm., 36: 23, 1961.

5. BIRBECIC, M. S., BREATHNACH, A. S. AND

EVERALL, J. D.: An electron microscopic study of basal melanocytes and high-level

clear cells (Langerhans) in vitiligo. J.

Invest. Derm., 37: 51, 1961. 6. BREATHNACH, A. S., BIRBECK, M. S. AND

EVERALL, J. D.: Observations on Langer-

hans cells in leprosy. Brit. J. Derm., 74: 243, 1962.

relationship between these two cells. The exact nature of this association is discussed in detail.

7. BREATHNACH, A. S., BJRBECK, M. S. AND

The variable location of the Langerhans cell and the manner of granule secretion is also

and melanocytes. Ann. N.Y. Acad. Sci.,

EVERALL, J. D.: Observations bearing on the relationship between Langerhans cells 100: 223, 1963.

8. BREATHNACH, A. S.: A new concept of the

described.

Addendum

Since submission of this manuscript Breathnach (J. Anat. 98: 265, 1964) has also described lysosomes in Langerhans cells.

relation between the Langerhans cell and the melanocyte. J. Invest. Derm., 40: 279, 1963.

9. MOYER, F. H.: Genetic effects on melanosome

fine structure and ontogeny in normal and malignant cells. Ann. N.Y. Acad. Sci., 100: 584, 1963.

10. RAPPAPORT, H., NAKAI, T. AND SwiFT, H.:

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melanin granule. Electron Microscopy of

Skin and Mucous Membrane, p. 96. Springfield Ill. Chas. C Thomas, 1963.

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24. Wynn, C. H. and Iqbal, M.: Isolation of rat

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44. Janoff, A. and Zweifach, B. W.: Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J. Exp. Med., 120: 747, 1964.

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