Fine structural alterations of corneal endothelium during experimental

Hajime Inomata and George K. Smelser

Uveitis was produced in albino rabbits by intravitreal injection of bovine serum albumin. By this often-used technique, a uveitis became manifest about 7 days after the antigen injection. Inflammation was most severe in the anterior portion of the but also involved the , which became thickened and hazy. Blood vessels invaded the anterior stroma from the limbus and in advanced cases reached half way to the center of the cornea and the middle, as well as the anterior layers of the stroma. Marked haze teas noted in the anterior chamber, and evidence of cells and fibrin clots could be seen by slit lamp examina- tion. Structural changes of the endothelium included mononuclear cell infiltration and vacuolization. The cells were lymphocytes and plasma cells. Although polymorphonuclear leukocytes were observed in the anterior chamber, none was found invading the endothelium. The actual invasion itself consisted of the cells entering between endothelial cells, so that they came to lie first in the inter endothelial cell space and finally under the endothelium, between it and Descemet's membrane. During this process the endothelial cell cytoplasm showed little evidence of change. Their cytoplasmic organelles were well preserved, but there was a remarkable change in the dilation of the intercellular space. The functional complexes which characterized the anterior chamber aspect of these cells appeared intact, even though lymphocytes and plasma cells lay under them and between endothelial cells, and apparently had passed through these junctions. The changes which have been described were more pronounced in the inferior aspect of the cornea where massive keratic precipitates occurred. In no instance did inflammatory cells invade Descemet's membrane. It is concluded, therefore, that they were derived entirely from the anterior chamber, which they had presumably entered from the of .

Key words: allergic uveitis, experimental production, corneal endothelium, corneal stroma, Descemet's membrane, corneal vascularization, corneal infiltrate, corneal inflammations, histopathology, ultrastructure, rabbits.

From the Department of Ophthalmology, Columbia .he histopathology of experimental University, New York, N. Y. uveitis has been studied1"11 since zur Nid- This investigation was supported, in part, by den first demonstrated that an ocular in- National Institutes of Health Research Grant No. 8 RO-1EY-00190-13, from the National flammation was elicited when a foreign Institute, and, in part by Public Health Service blood serum was injected into the vitreous Research Career Program Award No. 5-K6-NB- body of a rabbit eye. Corneal involvement 19-609-06 from the National Institute of Neuro- was observed in addition to the hyper- logical Diseases and Stroke, and by a Fight for sensitivity reaction of uveal tissue, and it Sight Post-Doctoral Research Fellowship No. was shown that corneal opacification occurs F-210 (G-2) financed by Fight for Sight, New 12 York City. in with uveitis. Keratic precipitates, Manuscript submitted Nov. 21, 1969; manuscript which are found by slit lamp examination accepted Dec. 29, 1969. in the clinic as deposition of precipitates 272

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on corneal endothelium, are an important Azure II, were made for light microscopy. Thin sign of uveitis. sections were cut with glass and diamond knives 5 7 on a Porter-Blum ultramicrotome and mounted Very few histological studies " have on Parlodion-coated copper mesh, doubly stained been made on the corneal changes ac- with uranyl acetate and lead citrate, and examined companying experimental uveitis, and in a Siemens Elmiskap 1. these have been confined to light micros- Observations copy. The present study is concerned with the histopathology of the corneal endo- Light microscopy thelium in experimental uveitis at the level Early stage. Although the major part of the electron microscope, and with com- of the cornea still remained clear, the parison to that which is known in clinical periphery of the inferior quadrant was conditions. vascularized and turbid, and the aqueous humor contained a small quantity of pre- Materials and methods cipitates. Several sections from different An immune uveitis was produced by injection parts of the cornea were made. of 0.1 ml. of 20 per cent sterile aqueous bovine Neither edematous changes nor cell serum albumin solution* into the vitreous humor infiltration was detected in any part of of adult albino rabbits. After 1 to 2 weeks, during which the cornea, as well as the rest of the eye, the epithelium. Vascularization of the sub- was free of visible symptoms, pericorneal vascular epithelial layer of the stroma was accom- injection appeared. The aqueous humor became panied by slight edematous swelling and turbid and contained cells, as seen by slit lamp cell infiltration in the periphery of the examination. The cornea became vascularized, lateral and inferior quadrants of the cor- and precipitates were noted on its posterior sur- face. When inflammation was fully advanced, the nea. Descemet's membrane was completely cornea became extremely turbid and the anterior free of inflammatory cells. The endothelium chamber contained masses of cells, a hypopyon. in the inferior quadrant, where corneal The iris was severely hyperemic, and the animals vascularization and turbidity were most were photophobic. and aqueous pronounced, was irregular in thickness, humor turbidity became less pronounced when the uveitis subsided. in several stages due to the infiltration of many inflamma- of this inflammation were prepared for electron tory cells. A small amount of cellular microscopy. infiltration in the endothelium was also Rabbits were anesthesized by intravenous injec- seen in the lateral, but was absent in the tion of sodium pentobarbital solution,! 12 mg. superior quadrant. Precipitates in the per pound of body weight. Immediately after enucleation a coronal incision was made at the anterior chamber consisted of a small equator of the and the anterior half of number of mononuclear cells such as plas- the eye was immersed in fixative. Under observa- ma cells, lymphocytes, and monocytes, tion with a binocular dissecting microscope, the within a thick network of fibrin. Some and iris were gently removed while the cells were found close to the endothelial anterior segment was still immersed in the fixative. The cornea was cut into several large sections surface as keratic precipitates in the in- and the was removed with sharp razor ferior quadrant (Fig. 1). blades. Great care was taken to prevent mechan- Advanced stage. A few days later, more ical damage to the endothelial surface. The severe responses were recognizable (Fig. fixative was 1 per cent osmium tetroxide buffered 2). The cornea became extremely turbid with 0.15M sodium cacodylate, pH 7.4, at 4° C, in which the tissue was kept for one hour, then and the anterior chamber contained a mas- dehydrated rapidly through a graded series of sive hypopyon. In spite of the extreme alcohols. The large corneal segments were trimmed turbidity of the cornea as a whole, the into pieces 1 by 2 mm. in 80 per cent alcohol, epithelium remained free from edema. and embedded in Epon 812 after treatment in Considerable changes, however, were seen propylene oxide. Thick sections, stained with in the stroma and the endothelium. Newly formed blood vessels in the anterior cor- "Nutritional Biochemical Corp., Chargin Falls, Ohio. fNemhutal, Abbott Laboratories, North Chicago, 111. neal stroma reached halfway from the

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rig. J.. renpnerai (jurnea at eariy stage 01 lnuammauuii. lniiainmaiory etuis are aireauy seen on the endothelial surface as keratic precipitates before stromal change becomes manifest. See also Fig. 6. Ep, Epithelium; V, vessel; St, stroma; AC, anterior chamber. (x200.) Fig. 2. Peripheral cornea in advanced stage showing pronounced neovascularization and cellular infiltration of the entire cornea. Vacuolization is seen in the endothelial cell layer. Ep, Epithelium; V, vessel; St, stroma; AC, anterior chamber. (xl30) Fig. 3. Epithelium (Ep) shows little change through all stages of the inflammation; only small edematous vacuoles (arrows) and a few cell infiltrations in the basal portion, in advanced stage. S£, stroma; V, vessel. (x400.)

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limbus to the center and were also present filtration were limited to the periphery in the middle layers of the periphery, par- and no epithelial edema was detected. ticularly in the inferior quadrant. Edem- The endothelium seemed to be almost atous swelling was very great in the intact. The central, superior quadrant of anterior third and posterior third layers the cornea was free from cellular infil- of the stroma and slightly less in the middle tration. layer. Mononuclear cells were scattered Electron microscopy. The fine structural through almost the entire stroma, much observations were concentrated on the en- more around the newly formed blood dothelium. Since the structure of inflam- vessels than in the other regions. Most matory cells seen in the cornea is quite cells were identified as plasma cells, lym- identification of individual cells is easy by phocytes, or monocytes. Only a few poly- different from that of the endothelium, the morphonuclear leukocytes were present in electron microscopy. the stroma. Descemet's membrane was Rabbit corneal endothelium normally free of cellular infiltration. The endothe- contained a flattened nucleus with diffuse lium showed vacuolization and infiltration slightly stainable nucleoplasm when fixed by mononuclear cells. The massive hypo- in osmium. The cytoplasm of these cells pyon in the anterior chamber consisted of was rich in organelles such as mitochon- a large number of mononuclear, as well dria, rough-surfaced endoplasmic reticu- as polymorphonuclear cells within a dense lum, Golgi complexes, vesicles of various network of fibrin. sizes, free RNA particles, and centrioles. Latest stage. Occasionally corneal opac- The region occupied by a network of fine ity seen during the course of uveitis be- fibrils at the apex of the endothelial cell, came less pronounced when the uveitis called the terminal web, had fewer cyto- subsided. The intensity of histological plasmic organelles than the rest of the cell. changes in this later stage seemed to be A narrow intercellular space occurred be- closely related to the region of endothelial tween adjacent endothelial cells, and junc- damage and keratic precipitates. The cor- tional complexes were present in the api- neal swelling and histological changes cal region of opposing cell membranes. A were most remarkable in the periphery marginal fold extended into the anterior of the inferior quadrant with keratic pre- chamber (Fig. 4). cipitates. The epithelium showed small Early stage. A large number of mono- edema vacuoles and a few cells which nuclear cells, such as lymphocytes and infiltrated only into the basal layer (Fig. plasma cells, infiltrated the endothelial cell 3). The anterior half of the stroma was layers, particularly in the inferior quadrant considerably swollen, and inflammatory where keratic precipitates were seen on the cells were scattered throughout almost the endothelial surface. Lymphocytes and entire region. The cells were identified as plasma cells were found at the intercellular plasma cells, lymphocytes, monocytes, and junctions between adjacent endothelial polymorphonuclear leukocytes. The vac- cells, pushing them aside so that the en- uolated endothelium was infiltrated by dothelial cell and nucleus were deformed mononuclear cells, and its anterior surface (Figs. 4, 5, and 11). However, even after was uneven. Excrescences in Descemet's infiltration of these cells, the endothelium membrane which are not normally seen still contained well-preserved cytoplasmic protruded toward the endothelium. The organelles such as mitochondria, rough- anterior chamber contained plasma cells surfaced endoplasmic reticulum, and Golgi and lymphocytes which were mostly lo- complexes. Neither mitochondria nor en- cated on the endothelial surface as keratic doplasmic reticulum showed swelling or precipitates (Fig. 12). In the lateral quad- dilation. The surface membrane of the en- rants, the stromal edema and cellular in- dothelium was not disrupted. The inter-

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N

-MvB En

MF AC

En

AC

Fig. 4. Endothelial cell Jayer in early stage. An infiltrated lymphocyte {L) lies under endo- thelium (En) between it and Descemet's membrane (DM). The structure in the endothelial cell seems to be nonnal excepting that the cell is deformed by lymphocytic infiltration. Even after cellular infiltration the endothelial cells preserve junctional complexes (JC) at the apical region of the cells, from which a marginal fold (MF) protrudes into the anterior chamber (AC). N, Nucleus; C, centriole; Gt Golgi; MvB, multivesicular body. (xl0,000.) Fig, 5. Endothelial cell layer infiltrated by lymphocytes (L) in early stage. The anterior basal surface of endothelial cells (En) is irregular and undulating and spaces between Descemet's membrane (DM) and undulating endothelium are filled with fibrous material in the matrix of Descemet's membrane-like structure (Ex). N, Nucleus; AC, anterior chamber. (xll,000.)

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St - DM

AC r

Fig. 6. A slightly higher magnification of endothelial cell layer in Fig. 1 showing that round mononuclear and plasma cells reach the endothelial surface (En), St, Stroma; DM, Descemet's membrane; AC, anterior chamber. (x400.) Fig. 7. An electron micrograph of a resting plasma cell (PC) on the endothelial surface as seen in Fig. 6. Note a tiny process of the plasma cell extending toward the intercellular junctional area (JC) of adjacent endothelial cells (En). Descemet's membrane (DM) shows remarkable excrescence (Ex) toward the endothelial cell layer, N, Nucleus; G, Golgi; DB, dense body; AC, anterior chamber. (x9,200.)

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DM Ex Ex

H N

En En

AC

B

pf;

Figs. 8 and 9. Serial section of an invading plasma cell (PC) in the intercellular space between adjacent endothelial cells (En) opening the junction between them. DM, Descemet's membrane; Ex, excrescence; A?, nucleus; Q, Golgi; AC, anterior chamber; DB, dense body. (Fig. 8, xl53000; Fig. 9, x22,000.)

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cellular space between endothelial cells thelium was not observed even in these and infiltrated cells was about 150 to 200 stages. Endothelial cells preserve many of A in width, and no dilated spaces were their mitochondria, and much of their observed between them. Besides infiltration rough-surfaced endoplasmic reticulum, of these cells, a noticeable change occurred Golgi complexes, and the terminal web in the basal or anterior surface of the cell, in the apical rim of the cell. Some slight which became undulating. Gaps varying dilation of endoplasmic reticulum was in shape and size appeared between the found. The most remarkable change in the endothelium and Descemet's membrane, in advanced stage was vacuolization of the which Descemet's membrane-like material endothelial cell layer (Figs. 12 to 15). and fine fibrils were seen forming an ex- Electron microscopy reveals that these vac- crescence. In the normal rabbit corneas uoles are dilations of the intercellular used as controls, such excrescences of spaces. The vacuoles were almost always Descemet's membrane were not seen. The empty, showing variety in size and shape, lymphocytes and plasma cells which had and sometimes opened toward the Des- infiltrated the endothelium were sur- cemet's membrane. Sometimes they con- rounded by very thin cytoplasmic processes tained excrescences of Descemet's-like ma- of adjacent endothelial cells, and were not terial. At the apical region, however, the exposed to the anterior chamber. However, endothelium still preserved the junctional the junctional complexes were well formed complexes even when mononuclear cells in the apical region where processes of were in the dilated intercellular spaces adjacent endothelium were in contact with (Fig. 15). The excrescences of Descemet's each other and surrounded the infiltrated membrane were more clearly seen in these cells. At the basal part of this layer, in- stages than in earlier ones because of the filtrated cells were separated from Des- large intercellular spaces. They protruded cemet's membrane by thin processes of en- toward the endothelium, and in some dothelium in some places, while in others places were directly attached to an in- they rested directly on excrescences of filtrated cell (Fig. 14). Descemet's membrane. Several stages of plasma cell infiltration Discussion from the anterior chamber into the endo- The pathological changes found in this thelial cell layer were demonstrated (Figs. experimentally produced keratitis approxi- 6 to 11). When a plasma cell in the an- mate those found clinically, and add in- terior chamber reached the endothelial formation not available with light micros- surface (Figs. 6 and 7), it inserted a pseu- copy used in clinical studies. Epithelial dopodium-like process in the junction be- changes were not remarkable, showing tween the endothelial cells, and entered mild cellular infiltration and edema con- into the intercellular space (Figs. 8 and sisting of widened intercellular spaces. The 9). More and more cytoplasm apparently stromal changes consisted of cellular in- flowed into the intercellular space between filtration, including mono- and polymor- the endothelial cells. The plasma cell then phonuclear leukocytes and neovasculariza- pushed the endothelial cells aside (Fig. tion. The most interesting comparison with 10) and finally the whole cell body the clinical cases, as described in standard squeezed into the endothelial cell layer. texts,13'14 is with changes in the endothe- After infiltration, thin processes of endo- lium. In the condition studied, the kera- thelium at the apical region (Fig. 11) may titis was an extension of the uveitis pres- close over the invading cells and the junc- ent in these eyes. The source of the cellu- tional complex may re-form. lar infiltrate was the anterior chamber, Advances and latest stages. Severe dam- originating from the iris and . age to cytoplasmic organelles in the endo- The concentration of pathological changes

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DM Ex \

En

1/ En

Ex

AC En __

Fig. 10. Advanced stage ot a plasma cell invasion. More of tlie plasma cell [fLJJ cytoplasm has entered tlie endothelial cell layer pushing the endothelial cells (En) aside. DM, Descemet's membrane; Ex, excrescence; JC, junctional complex; N, nucleus; AC, anterior chamber. (x25,000.) Fig. 11. A plasma cell (PC) has finally squeezed the whole cell body into the endothelial cell layer. After the infiltration, the junctional complex (JC) reformed between adjacent endothelial cells (En). DM, Descemet's membrane; Ex, excrescence; L, lymphocyte; N, nucleus; DB, dense body; AC, anterior chamber. (x7,500.)

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Fig. 12. Endothelial cell layer in advanced stage. Keratic precipitates (KP) consisting of a group of mononuclear cells (lymphocytes and plasma cells) are present in the anterior chamber (AC). Endothelial cell layer appears to be irregular with vacuolization and cellular infiltration. No inflammatory cells are detected in Descemet's membrane (DM). Stromal (St) infiltration seems not to be coincident with the change in endothelium. (x800.) Fig. 13. An electron micrograph of endothelial cell layer in advanced stage. The vacuoles of the endothelial cell layer are dilations of intercellular spaces (IS) between endothelial cells (En). However, functional complexes (JC) at the posterior region of the cells are still intact. An excrescence (Ex) of Descemet's membrane (DM) is seen extending toward the dilated intercellular space. St, Stroma; TW, terminal web; AC, anterior chamber. (x4,500.)

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En

En IS •#•

JC MF

En AC

Fig. 14. A lymphocyte (L) in the dilated intercellular space f/S) between endothelial cells (En), The lymphocyte rests directly on the excrescence (Ex) of Descemet's membrane (DM). (x24,000.) Fig. 15. A higher magnification of the posterior surface region of vacuolated endothelial cell layer. The junctional complexes (JC) are well preserved between endothelial cells (EN) even after infiltration of a lymphocyte (L) and dilation of intercellular space (IS). MF, Marginal fold; AC, anterior chamber. (x27.,500.)

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in the lower quadrant, presumably due to inflammatory cells in the endothelium is gravity, is found clinically. The greatest different from that in the stroma. The in- changes in the endothelium occurred flammatory cells are presumably derived where precipitates were attached to, or from the uveal tract, iris, and ciliary body. lying on the endothelium. The endothelial This was recently demonstrated by Segawa changes associated with the formation of and Smelser11 in the same type of experi- keratic precipitates, as usually reported in mental uveitis, where mononuclear cells clinical cases, may be supposed to have an were shown to pass from the capillaries etiology basically similar to the experi- and through the epithelium of the ciliary mental model. The nature of endothelial processes. There have been many theories edema, or "bedewing," was clear in the concerning the pathogenesis of the late cases studied. The vacuoles were inter- opacification of corneal grafts, which oc- cellular, consisting of dilated intercellular casionally become edematous and turbid spaces. The successive steps in the process several weeks following an apparently suc- of cellular infiltration showed clearly how cessful transplantation. It is important, this was accomplished, but the final posi- therefore, to elucidate the routes of invad- tion of the infiltrating cells confirmed the ing cells in the endothelial cell layer, be- older clinical reports.15'1G It is especially cause the infiltration of cells gives rise to noteworthy that the junctional complexes severe damage of the endothelium, result- of the apex of the endothelial cells were ing in turbidity of corneal transplants in shown to be very labile, opening to admit the rejecting reaction. There are 2 possible an invading cell and re-forming after it routes by which inflammatory cells may had entered. Such cells were often en- enter the endothelial cell layer. One is closed by extremely thin endothelial cell from the newly formed blood vessels in processes which could not be observed by the stroma through the scar portion be- earlier methods. It is also of interest that tween host and graft, and the other is from only lymphocytes and plasma cells entered the anterior chamber.19 the endothelial cell layer; nevertheless, the In the present study it was established massive hypopyon in the anterior chamber that inflammatory cells in the endothelial consisted of a large number of polymor- cell layer came exclusively from the an- phonuclear, as well as mononuclear, cells terior chamber, since there was no possi- with a dense network of fibrin. bility that inflammatory cells in the stroma The presence of excrescences on Des- could reach the endothelial cell layer, as cemet's membrane, and the speed with no gaps in Descemet's membrane were which they formed, are impressive. They present. We may conclude, therefore, that were associated with areas in which both in corneal graft rejection damage to the infiltrating and endothelial cells were pres- endothelium may be caused by infiltrating ent. In view of the evident abnormality of inflammatory cells derived both from the the endothelium as a whole, the absence newly formed stromal blood vessels of great intracellular pathology is astonish- through the graft scar and from the an- ing and may serve to explain why the cor- terior chamber. However, it is clear that nea recovers a clinically normal appear- the damage to the endothelium may be ance rapidly once the inflammation of the caused only by cells infiltrating from the uveal tract subsides. anterior chamber when Descemet's mem- In contrast to the cellular infiltrate in brane is intact, as in well-established the stroma, the cells in the endothelium grafts. were only mononuclear cells. Inflammatory From the point of view of immunology, cells, furthermore, were never found in the mononuclear response is typical of the Descemet's membrane in any part of the delayed hypersensitivity lesion, while poly- cornea. This indicates that the origin of morphonuclear infiltration is seen in the

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acute passive Arthus reaction.20 Silverstein 4. Woods, A. C, Friedenwald, J. S., and Wood, and Zimmerman6 reported that a diffuse R. M.: The histopathology of the acute and keratitis might accompany uveitis produced chronic ocular hypersensitive reactions in the experimental rabbit, Amer. J. Ophthal. 40: by the antibody-mediated Arthus mech- 631, 1955. anisms, as well as by a delayed hypersen- 5. Wakeman, B. H., and Bullington, S. J.: A sitivity mechanism, and suggested that im- quantitative study of the passive Arthus munogenic keratitis could be induced reaction in the rabbit eye, J. Immunol. 76: either primarily or secondarily by inflam- 441, 1956. matory processes in the uveal tract. 6. Silverstein, A. M., and Zimmerman, L. E.: Immunogenic endophthalmitis produced in The endothelial lesions in the present the guinea pig by different pathogenetic experiment were an extension of hyper- mechanisms, Amer. J. Ophthal. 48: 435, 1959. sensitivity reaction in the uveal tract re- 7. Zimmerman, L. E., and Silverstein, A. M.: sulting from mononuclear cell infiltration. Experimental ocular hypersensitivity. Histo- logic changes in rabbits receiving a single Similarly, the deposition of lymphocytes injection of antigen into the vitreous, Amer. and plasma cells on the endothelium, di- J. Ophthal. 48: 447, 1959. rectly correlated with response of the an- 8. Fernando, A. N.: Immunological studies with terior chamber, was reported to occur in I131 labeled antigen in experimental uveitis, the rabbit cornea intralamellarly injected Arch. Ophthal. 63: 515, 1960. with bovine serum albumin.21 9. Larsen, G.: Experimental uveitis. A histo- logic study with special reference to the mast Descemet's membrane is universally ac- cell, Acta Ophthal. 39: 231, 1961. cepted as formed by the corneal endothe- 10. Silverstein, A. M.: Ectopic antibody forma- lium.22"24 Excrescences on Descemet's mem- tion in the eye: Pathologic implications, in brane have been demonstrated histopatho- Maumenee, A. E., and Silverstein, A. M., editors: Immunopathology of uveitis, Balti- logically in endothelial-epithelial dystrophy more, 1964, The Williams & Wilkins Com- (Fuchs' dystrophy) and as a senile change, pany, p. 83. 2S> 29 particularly in the extreme periphery. 11. Segawa, K., and Smelser, G. K.: Electron In the experimental uveitis reported here microscopy of experimental uveitis, INVEST. small excrescences were observed on Des- OPHTHAL. 8: 497, 1969. cemet's membrane protruding toward the 12. Polack, F. M., Smelser, G. K., and Rose, J.: Corneal grafts and ocular inflammation, endothelium and sometimes toward the INVEST. OPHTHAL. 2: 287, 1963. lacunae of the dilated intercellular space 13. Duke-Elder, S., and Leigh, A. G.: Patho- between adjacent endothelial cells. The logical changes in the endothelium, in Duke- excrescences appeared as massed of fine Elder, W. S., editor: System of ophthal- filaments within Descemet's-like material, mology, VIII, part 2, St. Louis, 1965, The C. V. Mosby Company, p. 712. and it was quite similar to that of newly 14. Hogan, M. J., and Zimmerman, L. E.: In- formed Descemet's membrane in the scar flammations of the uveal tract, in Ophthalmic 30 after . This indi- pathology: An atlas and textbook, Phila- cates that such excrescences can be very delphia, 1962, W. B. Saunders Company, p. rapidly produced by the endothelium. 373. 15. Nagano: Untersuchungen zur Pathologie des REFERENCES Hornhautendothels, Arch. f. Augenh. 76: 26, 1914. 1. zur Nidden: Bacteriologische Blutuntersuch- 16. Chi, H. H., Teng, C. C, and Katzin, H. M.: ungen bei sympatischer Ophthalmie und Histopathology of corneal endothelium. A anderen Formen von Iridochoroiditis, von study of 176 pathologic discs removed at Graefes Arch. Ophthal. 62: 193, 1905. keratoplasty, Amer. J. Ophthal. 53: 215, 1962. 2. Schlaegel, T. F., Jr., and Davis, J. B.: The 17. Polack, F. M.: Histopathological and histo- reaction of the rabbit eye to normal horse chemical alterations in the early stages of serum sensitization by intradermal injection, corneal graft rejection, J. Exp. Med. 116: Amer. J. Ophthal. 26: 785, 1943. 709, 1962. 3. Foss, B.: Experimental anaphylactic irido- 18. Polack, F. M.: The pathologic anatomy of cyclitis, Acta Path. Microbiol. Scand. Suppl. corneal graft rejection, Survey Ophthal. 11: 81: 3, 1949. 391, 1966.

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19. Inomata, H., Smelser, G. K., and Polack, F. 25. Chi, H. H., Teng, C. C, and Katzin, H. M.: M.: Fine structural changes in the corneal Histology of primary endothelial-epithelial endothelium during graft rejection, INVEST. dystrophy of the cornea, Amer. J. Ophthal. OPHTHAL. 4: 263, 1970. 45: 518, 1958. 20. Gell, P. G. H,, and Hinde, I. T.: Observa- 26. Feeney, M. L., and Garron, L. K.: Desce- tions on the histology of the Arthus reaction met's membrane in the human peripheral and its relation to other known types of cornea. A study by light and electron micros- hypersensitivity, Int. Arch. Allerg. 5: 25, copy, in Smelser, G. K., editor: The struc- 1954. ture of the eye, New York, 1961, Academic 21. Smolin, G.: Corneal endothelial changes dur- Press, Inc., p. 367. ing the hypersensitivity reaction, Amer. J. 27. Kayes, J., and Holmberg, A.: The fine struc- Ophthal. 65: 349, 1968. ture of the cornea in Fuchs' endothelial 22. Jakus, M. A.: Studies on the cornea. II. The dystrophy, INVEST. OPHTHAL. 3: 47, 1964. fine structure of Descemet's membrane, J. 28. Jakus, M. A.: The fine structure of the Biophys. Biochem. Cytol. 2: Suppl. 243, 1956. human cornea, in Smelser, G. K., editor: 23. Ohkura, T.: Electron microscopic observation The structure of the eye, New York, 1961, on the Descemet's membrane formation of Academic Press, Inc., p. 343. the developing chick embryo, Arch. Histol. 29. Jakus, M. A.: Further observations on the Jap. 22: 283, 1963. fine structure of the cornea, INVEST. OPHTHAL. 24. Kaye, G. I.: Studies on the cornea. VI. 1: 202, 1962. Corneal development. A fine structural study 30. Inomata, H., Smelser, G. K., and Polack, F. with particular reference to the differentia- M.: The fine structure of regenerating endo- tion corneal transport system, in Rohen, J. thelium and Descemet's membrane in normal W., editor: The structure of the eye. II. and rejecting corneal grafts, Submitted for Symposium, Stuttgart, 1965, F. K. Schat- publication. tauer-Verlag, p. 441.

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