Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

4.Montan PG, Ekstrom K, Hedlin G, van Hage-Hamsten M, Hjern A, Herrmann B. Vernal keratoconjunctivitis in a Stockholm ophthalmic centre-epidemiological, functional, and immunologic investigations. Acta Ophthalmol Scand 1999; 77:559–563.

5.Secchi AG, Tognon MS, Leonardi A. Topical use of cyclosporine in the treatment of vernal keratoconjunctivitis. Am J Ophthalmol 1990; 110:641–645.

6.Foster CS, Calonge M. Atopic keratoconjunctivitis. Ophthalmology 1990; 97:992–1000.

7.Tuft SJ, Kemeny MD, Dart JKG, Buckley RJ. Clinical features of atopic keratoconjunctivitis. Ophthalmology 1991; 98:150–158.

8.Hingorani M, Moodaley L, Calder VL, Buckley RJ, Lightman S. A randomized, placebo-controlled trial of topical cyclosporin A in steroid-dependent atopic keratoconjunctivitis. Ophthalmology 1998; 105:1715–1720.

9.Allansmith MR, Ross RN. Giant papillary conjunctivitis. Int Ophthalmol Clin 1988; 28:309–316.

10.Buckley RJ. Vernal keratoconjunctivitis. Int Ophthalmol Clin 1989; 28:303–308.

11.Allansmith MR, Korb DR, Greiner JV, Henriquez AS, Simon MA, Finnemore VM. Giant papillary conjunctivitis in contact lens wearers. Am J Ophthalmol 1977; 83:697–708.

12.Anderson DF, Macleod JDA, Baddeley SM, Bacon AS, McGill JI, Holgate ST, et al. Seasonal allergic conjunctivitis is accompanied by increased mast cell numbers in the absence of leucocyte infiltration. Clin Exp Allergy 1997; 27:1060–1066.

13.Friedlaender MH. Conjunctival provocation testing: overview of recent clinical trials in ocular allergy. Curr Opin Allergy Clin Immunol 2002; 2:413–417.

14.Ahluwalia P, Anderson DF, Wilson SJ, McGill JI, Church MK. Nedocromil sodium and levocabastine reduce the symptoms of conjunctival allergen challenge by different mechanisms. J Allergy Clin Immunol 2001; 108:449–454.

15.Trocme SD, Sra KK. Spectrum of ocular allergy. Curr Opin Allergy Clin Immunol 2002; 2:423–427.

16.Metz DP, Bacon AS, Holgate ST, Lightman S. Phenotypic characterization of T cells infiltrating the conjunctiva in chronic allergic eye diseases. J Allergy Clin Immunol 1996; 98:686–696.

17.Maggi, E., P. Biswas, G. Del Prete, P. Parronchi, D. Macchia, C. Simonella, et al. Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J Immunol 1991; 146:1169–1174.

18.Metz DP, Hingorani M, Calder VL, Buckley RJ, Lightman SL. T cell cytokines in chronic allergic eye disease. J Allergy Clin Immunol 1997; 100:817–824.

19.Seder RA, Paul WE, Ben-Sasson SZ, LeGros GS, Kagey-Sobotka A, Finkelman FD, et al. Production of interleukin-4 and other cytokines following stimulation of mast cell lines and in vivo mast cells/basophils. Int Arch Allergy Appl Immunol 1991; 94:137–140.

20.Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, et al. Interleukin-4, -5, and -6 and tumour necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Molec Biol 1994; 10:471–480.

21.Moqbel R, Ying S, Barkans J, Newman TM, Kimmitt P, Wakelin M, et al. Identification of messenger RNA for IL-4 in human eosinophils with granule localization and release of the translated product. J Immunol 1995; 155:4939–4947.

22.Calder VL, Jolly G, Hingorani M, Adamson P, Leonardi A, Secchi AG, et al. Cytokine production and mRNA expression by conjunctival T-cell lines in chronic allergic eye disease. Clin Exp Allergy 1999; 29:1214–1222.

23.Avunduk AM, Avunduk MC, Tekelioglu Y. Analysis of tears in patients with atopic keratoconjunctivitis, using flow cytometry. Ophthalmic Res 1998; 30:44–48.

24.Uchio E, Ono SY, Ikezawa Z, Ohno S. Tear levels of interferon-gamma, interleukin (IL) -2, IL-4 and IL-5 in patients with vernal keratoconjunctivitis, atopic keratoconjunctivitis and allergic conjunctivitis. Clin Exp Allergy 2000; 30:103–109.

25.Leonardi A, DeFranchis G, Zancanaro F, Crivellari G, De Paoli M, Plebani M, et al. Identification of local TH2 and Th0 lymphocytes in vernal conjunctivitis by cytokine flow cytometry. Invest Ophthalmol Vis Sci 1999; 40:3036–3040.

26.Irani AM, Butrus SI, Tabbara KF, Schwartz LB. Human conjunctival mast cells: distribution of mast cellT and mast cellTC in vernal conjunctivitis and giant papillary conjunctivitis. J Allergy Clin Immunol 1990; 86:34–40.

27.Baddeley SM, Bacon AS, McGill JI, Lightman SL, Holgate ST, Roche WR. Mast cell distribution and neutral protease expression in acute and chronic allergic conjunctivitis. Clin Exp Allergy 1995; 25:41–50.

28.MacLeod JD, Anderson DF, Baddeley SM, Holgate ST, McGill JI, Roche WR. Immunolocalization of cytokines to mast cells in normal and allergic conjunctiva. Clin Exp Allergy 1997; 27:1328–1334.

29.Zhang S, Anderson DF, Bradding P, Coward WR, Baddeley SM, MacLeod JD, et al. Human mast cells express stem cell factor. J Pathol 1998; 186:59–66.

30.Anderson DF, Zhang S, Bradding P, MclGill JI, Holgate ST, Roche WR. 2001 The relative contribution of mast cell subsets to conjunctival TH2-like cytokines. Invest Ophthalmol Vis Sci 2001; 42:995–1001.

31.Abelson MB, Chambers WA, Smith LM. Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 1990; 108:84–88.

32.Bacon AS, Ahluwalia P, Irani AM, Schwartz LB, Holgate ST, Church MK, et al. Tear and conjunctival changes during the allergen-induced earlyand late-phase responses. J Allergy Clin Immunol 2000; 106:948–954.

33.Ciprandi G, Buscaglia S, Pesce G, Villaggio B, Bagnasco M, Canonica GW. Allergic subjects express intercellular adhesion molecule-1 (ICAM-1 or CD54) on epithelial cells of conjunctiva after allergen challenge. J Allergy Clin Immunol 1993; 91:783–792.

34.Bacon AS, McGill JI, Anderson DF, Baddeley S, Lightman SL, Holgate ST. Adhesion molecules and relationship to leukocyte levels in allergic eye disease. Invest Ophthalmol Vis Sci 1998; 39:322–330.

35.Allansmith MR, Hahn GS, Simon MA. Tissue, tear, and serum IgE concentrations in vernal conjunctivitis. Am J Ophthalmol 1976; 81:506–511.

36.Dombrowicz D, Capron M. Eosinophils, allergy and parasites. Curr Opin Immunol 2001; 13:716–720.

37.Walsh GM. Eosinophil granule proteins and their role in disease. Curr Opin Hematol 2001; 8:28–33.

38.Lamkhioued B, Gounni AS, Gruart V, Pierce A, Capron A, Capron M. Human eosinophils express a receptor for secretory component. Role in secretory IgAdependent activation. Eur J Immunol 1995; 25:117–125.

39.Montan P, van Hage-Hamsten M. Eosinophilic cationic protein in tears in allergic conjunctivitis. Br J Ophthalmol 1996; 80:556–560.

40.Secchi A, Leonardi A, Abelson M. The role of eosinophilic cationic protein and histamine in vernal keratoconjunctivitis. Ocular Immunol Inflamm 1995; 3:3–8.

41.Trocme SD, Kephart GM, Allansmith MR, Bourne WM, Gleich GJ. Conjunctival deposition of eosinophil granule major basic protein in vernal keratoconjunctivitis and contact lens-associated giant papillary conjunctivitis. Am J Ophthalmol 1989; 108:57–63.

42.Jose PJ, Griffiths-Johnson DA, Collins PD, Walsh DT, Moqbel R, Totty NF, et al. Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. J Exp Med 1994; 179:881–887.

43.Rot A, Krieger M, Brunner T, Bischoff SC, Schall TJ, Dahinden CA. RANTES and macrophage inflammatory protein 1 alpha induce the migration and activation of normal human eosinophil granulocytes. J Exp Med 1992; 176:1489–1495.

44.Schall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 1990; 347:669–671.

45.Weller PF. Updates on cells and cytokines: human eosinophils. J Allergy Clin Immunol 1997; 100:283–287.

46.Lamkhioued B, Gounni AS, Aldebert D, Delaporte E, Prin L, Capron A, et al. Synthesis of type 1 (IFN gamma) and type 2 (IL-4, IL-5, and IL-10) cytokines by human eosinophils. Ann N Y Acad Sci 1996; 796:203–208.

47.Woerly G, Roger N, Loiseau S, Dombrowicz D, Capron A, Capron M. Expression of CD28 and CD86 by human eosinophils and role in the secretion of type 1 cytokines (interleukin 2 and interferon gamma): inhibition by immunoglobulin a complexes. J Exp Med 1999; 190:487–495.

48.Hingorani M, Calder VL, Buckley RJ, Lightman SL. The role of conjunctival epithelial cells in chronic ocular allergic disease. Exp Eye Res 1998; 67:491–500.

49.Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7:145–173.

50.Abu el-Asrar AM, Geboes K, al-Kharashi SA, al-Mosallam AA, Tabbara KF, al-Rajhi AA, et al. An immunohistochemical study of collagens in trachoma and vernal keratoconjunctivitis. Eye 1998; 12:1001–1006.

51.Leonardi A, Brun P, Tavolato M, Abatangelo G, Plebani M, Secchi AG. Growth factors and collagen distribution in vernal keratoconjunctivitis. Invest Ophthalmol Vis Sci 2000; 41:4175–4181.

52.Leonardi A, Cortivo R, Fregona I, Plebani M, Secchi AG, Abatangelo G. Effects of TH2 cytokines on expression of collagen, MMP-1, and TIMP-1 in conjunctival fibroblasts. Invest Ophthalmol Vis Sci 2003; 44:183–189.

53.Kumagai N, Fukuda K, Ishimura Y, Nishida T. Synergistic induction of eotaxin expression in human keratocytes by TNF-alpha and IL-4 or IL-13. Invest Ophthalmol Vis Sci 2000; 41:1448–1453.

54.Leonardi A, Jose PJ, Zhan H, Calder VL. Tear and mucus eotaxin-1 and eotaxin-2 in allergic keratoconjunctivitis. Ophthalmology 2003; 110:487–492.

55.Abu El-Asrar AM, Struyf S, Al-Kharashi SA, Missotten L, Van Damme J, Geboes

K.Chemokines in the limbal form of vernal keratoconjunctivitis. Br J Ophthalmol 2000; 84:1360–1366.

56.Abu El-Asrar AM, Struyf S, Al-Mosallam AA, Missotten L, Van Damme J, Geboes

K.Expression of chemokine receptors in vernal keratoconjunctivitis. Br J Ophthalmol 2001; 85:1357–1361.

57.Hamrah P, Zhang Q, Liu Y, Dana MR. Novel characterization of MHC class IInegative population of resident corneal Langerhans cell-type dendritic cells. Invest Ophthalmol Vis Sci 2002; 43:639–646.

58.Hamrah P, Liu Y, Zhang Q, Dana MR. The corneal stroma is endowed with a significant number of resident dendritic cells. Invest Ophthalmol Vis Sci 2003; 44:581–589.

59.Kunkel EJ, Butcher EC. Chemokines and the tissue-specific migration of lymphocytes. Immunity 2002; 16:1–4

60.Baudouin C, Bourcier T, Brignole F, Bertel F, Moldovan M, Goldschild M, et al. Correlation between tear IgE levels and HLA-DR expression by conjunctival cells in allergic and nonallergic chronic conjunctivitis. Graefes Arch Clin Exp Ophthalmol 2000; 238:900–904.

61.Abu El-Asrar AM, Struyf S, Al-Kharashi SA, Missotten L, Van Damme J, Geboes

K.Expression of T lymphocyte chemoattractants and activation markers in vernal keratoconjunctivitis. Br J Ophthalmol 2002; 86:1175–1180.

62.Bielory L, Mongia A. Current opinion of immunotherapy for ocular allergy. Curr Opin Allergy Clin Immunol 2002; 2:447–452.

63.Varney VA, Hamid QA, Gaga M, Ying S, Jacobson M, Frew AJ, et al. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest 1993; 92:644–651.

64.Varney VA, Edwards J, Tabbah K, Brewster H, Mavroleon G, Frew AJ. Clinical efficacy of specific immunotherapy to cat dander: a double-blind placebo-controlled trial. Clin Exp Allergy 1997; 27:860–867.

65.Norman PS, Ohman JL Jr, Long AA, Creticos PS, Gefter MA, Shaked Z, et al. Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med 1996; 154:1623–1628.

66.Barnes PJ. Cytokine modulators for allergic diseases. Curr Opin Allergy Clin Immunol 2001; 1:555–560.

67.Feldmann M, Brennan FM, Elliott MJ, Williams RO, Maini RN. TNF alpha is an effective therapeutic target for rheumatoid arthritis. Ann N Y Acad Sci 1995; 766:272–278.

68.Takei S, Groh D, Bernstein B, Shaham B, Gallagher K, Reiff A. Safety and efficacy of high dose etanercept in treatment of juvenile rheumatoid arthritis. J Rheumatol 2001; 28:1677–1680.

69.Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000; 343:1594–1602.

70.D’haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999; 116:1029–1034.

71.Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gottlieb AB. Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 2001; 357:1842–1847.

72.Braun J, de Keyser F, Brandt J, Mielants H, Sieper J, Veys E. New treatment options in spondylo-arthropathies: increasing evidence for significant efficacy of anti-tumor necrosis factor therapy. Curr Opin Rheumatol 2001; 13:245–259.

73.Fujishima H. Respiratory syncytial virus may be a pathogen in allergic conjunctivitis. Cornea 2002; 21(suppl 1):S39–S45.

replacement, such as the central nervous system, have limited regenerative capacity. Cells of some organs, such as the liver or kidney, may remain fairly static, but will proliferate in response to stimuli or injury. Tissues with a constant turnover of cells, such as epithelia or the hematopoietic system, are highly proliferative and continuously replenish populations of mature, differentiated cells. Adult corneal and conjunctival stem cells represent the earliest progenitor cells responsible for the homeostasis and regeneration of the ocular surface. An intricate balance of intrinsic and extrinsic factors modulates stem cell proliferation and differentiation, eventually resulting in terminally differentiated cells.

Stem cells are a small, quiescent subpopulation of cells within a given tissue. Upon a demand for tissue regeneration, for example, following injury, they are stimulated to divide and differentiate into transient amplifying cells. Transient amplifying cells increase rapidly in number to replace injured or dead cells within a tissue. After amplification, they cease division, becoming postmitotic cells, which then differentiate and display the final phenotypic characteristics of the tissue as terminal differentiated cells (Fig. 1).

The ocular surface is an ideal region to study epithelial stem cell biology because of its unique spatial arrangement of stem cells and transient amplifying cells. Corneal epithelial stem cells are compartmentalized within the limbus, providing a valuable opportunity to study the behavior of stem cells and transient amplifying cells, including their responses to various growth stimuli and the mechanisms that modulate their growth and differentiation.

II.PROPERTIES OF STEM CELLS

Characteristics defining stem cell nature and behavior in all body tissues are derived mostly from studies of hematopoietic cells:

1.Stem cells comprise a small subpopulation, from 0.05% to 10%, of all cells in a tissue [1,2].

2.Stem cells are small, blastlike, poorly differentiated, with a high nuclear–cytoplasmic ratio, and are ultrastructurally unspecialized.

3.Stem cells are pluripotent, able to differentiate along several lineages.

4.Stem cells are highly proliferative and self-renewing, able to maintain the steady-state population of cells within tissues for the life span of the organism.

5.At steady state, stem cells remain fairly dormant and replicate infrequently, but when the need for tissue regeneration arises, proliferation may be induced rapidly. Relative dormancy minimizes the possibility of replication errors during cell division, which can result in mutations.

6.Stem cells give rise to transient amplifying cells that proliferate rapidly, ensuring prompt regeneration of the tissue. Transient amplifying

corneal epithelium. Schermer et al. found a 64-kDa keratin, called K3, among differentiated corneal epithelial cells [22]. This cornea-specific keratin was expressed in differentiated cells in the suprabasal limbal layer, and throughout the corneal epithelium. K3 was essentially absent among limbal basal cells, suggesting that they represented a more primitive, nondifferentiated subpopulation that did not express this cytokeratin. K3 expression was reduced in the conjunctiva, consistent with the notion that corneal progenitor cells did not originate in the conjunctiva. Kurpakus et al. demonstrated that the cornea-specific keratin K12, also expressed in the suprabasal cells of the limbus and throughout the entire corneal epithelium, was absent from the limbal basal cells [23,24]. They also demonstrated that stem or stemlike cells found throughout the basal layer or the limbal and corneal epithelium during embryonic development were later sequestered in the limbus [23–25].

No molecular markers specific for stem cells have yet been identified, significantly limiting study of their characteristics and behavior. An indirect method to identify stem cells was developed that exploited their slow growth [26,27]. Continuous administration of tritiated thymidine for a prolonged period labels replicating DNA in all cells that undergo a cell division, including slow-cycling cells. During a prolonged chase period in the absence of tritiated thymidine, radioactive label in the DNA of rapidly dividing cells is diluted by incorporation of nonradioactive thymidine. Slow-cycling cells, presumably stem cells, retain most of the previously incorporated isotope during the chase period [26,27]. Using this technique, Cotsarelis et al. observed retention of tritiated thymidine in limbal basal cells, evidence that corneal stem cells might be present [28].

This small subpopulation of normally slow-cycling limbal basal epithelial cells has a significantly greater proliferative response to wounding and to stimulation by tumor-promoting compounds than cells of the peripheral or central cornea (Fig. 3) [13,16,28]. The limbal cells’ ability to respond was maintained over a prolonged period, demonstrating a significant proliferative reserve. No cells with these properties were found in the central corneal epithelium. The labelretaining cells present in the limbus exhibited properties expected of stem cells.

Exactly how a population of stem cells is maintained is unclear. A stem cell may divide symmetrically, giving rise to a transient amplifying cell and producing a daughter stem cell, replenishing the stem cell pool. Alternatively, regeneration of stem cells could occur by de-differentiation of early transient amplifying cells back to stem cells.

Stem cells have the highest growth potential for culture in vitro, and regions enriched in stem cells display greater numbers of colony-forming cells. They can continue to divide in vitro for at least 120–160 generations [29,30]. Limbal epithelial cells display greater in-vitro proliferative capacity than central and peripheral corneal cells, consistent with the presence of stem cells in the limbus [31–41]. Culture conditions in vitro do not entirely mimic the original