Lacrimal Gland, Tear Film, and Dry Eye Syndromes 3: Basic Science and Clinical Relevance Part B PDF
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Lacrimal Gland, Tear Film, and Dry Eye Syndromes 3 Basic Science and Clinical Relevance PartB ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo IRUN R. COHEN, The Weizmann Institute of Science DAVID KRITCHEVSKY, Wistar Institute ABEL LAJTHA, N. S. Kline Institute for Psychiatric Research RODOLFO PAOLETTI, University of Milan Recent Volumes in this Series Volume 500 BIOLOGICAL REACTIVE INTERMEDIATES VI: Chemical and Biological Mechanisms of Susceptibility to and Prevention of Environmental Diseases Edited by Patrick M. Dansette, Robert Snyder, Marcel Delaforge, G. Gordon Gibson, Helmut Greim, David 1. Jollow, Terrence J. Monks, and I. Glenn Sipes Volume 501 BIOACTIVE COMPONENTS OF HUMAN MILK Edited by David S. Newburg Volume 502 HYPOXIA: From Genes to the Bedside Edited by Robert C. Roach, Peter D. Wagner, and Peter H. Hackett Volume 503 INTEGRATING POPULATION OUTCOMES, BIOLOGICAL MECHANISMS AND RESEARCH METHODS IN THE STUDY OF HUMAN MILK AND LACTATION Edited by Margarett K. Davis, Charles E. Isaacs, Lars A. Hanson, and Anne L. Wright Volume 504 MYCOTOXINS AND FOOD SAFETY Edited by Jonathan W. DeVries, Mary W. Trucksess, and Lauren S. Jackson Volume 505 FLAVONOIDS IN CELL FUNCTION Edited by Bela A. Buslig and John A. Manthey Volume 506 LACRIMAL GLAND, TEAR FILM, AND DRY EYE SYNDROMES 3: Basic Science and Clinical Relevance Edited by David A. Sullivan, Michael E. Stem, Kazuo Tsubota, Darlene A. Dartt, Rose M. Sullivan, and B. Britt Bromberg Volume 507 EICOSANOIDS AND OTHER BIOACTIVE LIPIDS IN CANCER, INFLAMMATION, AND RADIATION INJURY 5 Edited by Kenneth V. Honn, Lawrence 1. Mamett, Santosh Nigam, and Charles Serhan Volume 508 SENSORIMOTOR CONTROL OF MOVEMENT AND POSTURE Edited by Simon C. Gandevia, Uwe Proske, and Douglas G. Stuart Volume 509 IRON CHELATION THERAPY Edited by Chaim Hershko A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher. Lacrimal Gland, Tear Film, and Dry Eye Syndromes 3 Basic Science and Clinical Relevance Part B Edited by David A. Sullivan Schepens E)'e Research Institute and Harvard Medical 5chool Bos/on, Massachusells, USA Michael E. Stern Al/ergon. Inc. Irvine, Califomia, USA Kazua Tsubata Tokyo Demal College and Ichikb.wa General Hospital Chiba, Japan Darlene A. Dartt Schepens Eye Research Institute and Harvard Medical Schoo/ Bos/on, Massachusells, USA Rose M. Sullivan Schepens Eye Research Institute Boston, Massachusells, USA and B. Britt Bromberg University 0/ New Orleans New Orleans, Louisiana, USA Springer·Science+Business Media, LLC Library of Congress Cataloging-in-Publicalion Data International Conference on the Lacrimal Gland, Tear Film, and Dry Eye Syndromes (3rd: 2000: Maui, Hawaii) Lacrimal gland, tear film, and dry eye syndromes 3: basic science and clinical relevanceledited by David A. Sullivan ... [eI al.l. p. ; cm. - (Advances in experimental medicine and biology; v. 506) "Proceedings of the 3rd International Conference on the Lacrimal Gland, Tear Film, and Dry Eye Syndromes: Basic Science and Clinical Relevance, November 15-18, 2000, Maui, Hawaii" - T.p. verso. Includes bibliographical references and index. ISBN 978-1-4613-5208-2 ISBN 978-1-4615-07 17-8 (eBook) DOI 10.1007/978-1-4615-0717-8 I. Dry eye syndromes-Congresses. 2. Lacrimal apparatus-Congresses. 3. Tears-Congresses. l. TitIe: Lacrimal gland, tear film, and dry eye syndromes Ihree. 11. Sullivan. David A. III. Tide. IV. Series. [DNLM: I. Lacrimal Apparatus-Congresses. 2. Dry Eye Syndromes-Congresses. 3. Tears-physiology-Congresses. WW 208 16125 20021 RE216.D78 155 2000 617 .7'64-de21 2002072992 Proceedings of the 3rd International Conference on the Lacrimal Gland. lear Film and Dry Eye Syndromes: Basic Science and Clinical Relevance, November 15-18, 2000; Maui. Hawaii ISBN 978-1-4613-5208-2 © 2002 Syrin,ger Science+Business Media New York Originally publishl'd by Klu'wr / I'lrnum I'ublishus, '\'l'\\ \'ork in 2002 Softcover reprint of the hardcover Ist edition 2002 10 9 8 7 6 5 4 3 2 1 A C.I.P. record for Ihis book is a vailable from the Library of Congress All rights reserved No part of this boole may be reproduced. stored in a retrieval system, or transmined in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without wrinen permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system. for excJusive use by the purchaser of the worle. Immunity and Inflammation I: Influence of Cytokines, Chemokines, Adhesion Molecules and Other Immunoactive Agents ROLE OF IMMUNITY AND INFLAMMATION IN CORNEAL AND OCULAR SURFACE DISEASE ASSOCIATED WITH DRY EYE l M. Reza Dana'-3 andPedram Harnrah 'Laboratory of Immunology Schepens Eye Research Institute and the Department of Ophthalmology Harvard Medical School 2Brigham and Women's Hospital 3Massachusetts Eye and Ear Infirmary Boston, Massachusetts, USA 1. INTRODUCTION Dry eye syndromes (DES) represent a common but highly heterogeneous group of ocular surface disorders (OSD) that affect millions of individuals, in particular women, in 23 the United States alone.' While efforts to better classify disease categories . and determine 24 relevant diagnostic tests for each disease subtype . continue, common features of DES are shared by the tear-deficient and non-tear-deficient (evaporative) forms of DES serving as common denominators of disease. These common denominators include ocular surface epitheliopathy, tear hyperosmolarity, an unstable preocular tear film and symptoms of dry 2 eye associated with varying degrees of inflammation. As such, an increasing number of investigators contend ocular irritation or discomfort, virtually invariable components of severe tear-deficient dry eye, are clinical correlates of ocular surface inflammation-which 5 9 at the cellular and molecular levels are requisite factors for the pathogenesis of DES. - In this brief overview, we will first examine the factors involved in the generation of immune responsiveness to antigens in the ocular surface and anterior segment. We will then critically evaluate whether the data generated to date provide a causal link between the generation of adaptive immunity and OSD in DES, or if the well-described inflammatory response in the ocular surface could be primarily a consequence of the myriad pathological Lacrimal Gland. Tear Film. and Dry Eye Syndromes 3 Edited by D. Sullivan el aI., Kluwer Academic/Plenum Publishers, 2002 729 730 M. R. Dana andP. Hamrah phenomena that characterize all forms of DES. Finally, a hypothetical model is offered that will attempt to conceptually bridge the gap relating causality and empiric evidence in relation to immunoinflammatory responses in DES. 2. GENERATION OF ADAPTIVE IMMUNITY "Adaptive immunity," whether (T) cell-mediated or humoral (antibody-mediated), represents that arm of the immune response generated de novo or secondarily to specific antigen(s). As such, it is characterized by a delayed clonal response specific to certain epitopes. In contrast, "innate immunity" refers to that segment of the immune response whose receptors and effector elements are fixed in the genome, and hence the reaction is 1O immediate and non-clonal. The latter is typified by neutrophils and macrophages and their released proteins and peptides generated in response to local perturbations-whether traumatic (e.g., as occurs in wound healing), infectious or immune (involving new antigens or epitopes). Since "immune-mediated inflammation" is increasingly being cited as a primary process in the pathogenesis of both autoimmune (e.g., Sj0gren's) and non- autoimmune (e.g., primary sicca syndrome or evaporative DES secondary to meibomian gland dysfunction) dry eye, it is important to first provide a brief outline of the processes that mediate immune responses in tissues. The first step in generation of inflammation is an inciting stimulus. This may be microbial, traumatic or due to introduction of novel antigens (e.g., as occurs in tissue allotransplantation). These stimuli may lead to the release of proinflammatory cytokines, nucleic acid fragments, heat shock proteins and various other mediators that, in the aggregate, signal the host that normal physiology and the microenvironment have been violated. In response to these signals, the second step in this cascade of events occurs when local (resident) tissue cells activate signal transduction pathways (e.g., NFK-B) that augment or downmodulate expression of cellular cytokine genes and/or cytokine receptor genes that, in turn, dictate the response of these resident cells to paracrine signals in the microenvironment by other cells in proximity. These responses are not limited to classic immunoinflammatory mediators (e.g., interleukins and interferons) but also include other ll molecular classes such as growth factors, chemokines and adhesion factors acting in a coordinated fashion to regulate the immune/inflammatory response in the tissue. Mild stimuli (e.g., a minor abrasive injury to an epithelialized tissue) may not generate a response beyond this step. However, generation of primary adaptive immune responses, mediated by stimulation of antigen-specific cells in lymphoid organs, requires recruitment and activation of bone marrow-derived cells. The latter is accomplished through the function of two classes of immunoactive agents-eell adhesion molecules (CAMs) and chemokines. CAMs represent a heterogeneous group of molecules composed of members of the immunoglobulin superfamily (e.g., ICAM-l), selectins (e.g., E-selectin) and integrins that 12 act in concert to activate leukocytes and enhance cell-cell interactions. These cell-cell interactions are critical in increasing leukocyte adhesion to vascular endothelial cells Role of Immunity and Inflammation in Corneal and Ocular Surface Disease 731 (VEC) and thereby allow them to "roll" on the VEC prior to integrin-mediated activation and finally transendothelial migration. Additionally, certain CAMs such as ICAM-I are important as costimulatory factors that provide na"ive T-cells with the requisite second (T- cell receptor-independent) signal for sensitization. In corneal immune and inflammatory 13 14 diseases, the central role of ICAM-I is now well established. • Once the process of leukocyte activation and transendothelial migration is accomplished, leukocytes, whether antigen-presenting cells (APC) or effectors, require recruitment to the primary site of inflammation. If APC (e.g., dendritic cells or macrophages), they initiate the process of antigen uptake and processing prior to T-cell priming. However, whereas transendothelial migration from the intravascular compartment to the tissue compartment is a requisite step for leukocyte function in the periphery, it is insufficient since leukocytes do not have the capacity for independent homing. This directionality is provided to leukocytes by chemotactic cytokines, also known as chemokines, which provide a chemotactic gradient for leukocytes. To date, nearly 50 chemokine species (ligands) and nearly two dozen chemokine receptors have been characterized, 15 and chemokines are now recognized as important mediators of ocular surface and corneal disease including ocular allergy, 16 corneal graft rejection,17.18 microbial l9 20 21 keratitis . and possibly DES. Examples of chemokines implicated in ocular immune disorders include RANTES, MIP-lalpha and IL-8, just to name a few. Hence, the coordinated and differential expression of select chemokines and CAMs leads to recruitment of APCs to sites of inflammation. These requisite steps in the generation of antigen-specific adaptive immunity are in turn related to upregulation in the activity of proinflammatory cytokines such as interleukin-l (IL-I). For example, in the cornea and ocular surface the expression of ICAM-I appears to be largely regulated by IL-I 13 expression. Moreover, IL-I in concert with tumor necrosis factor-alpha (TNF-a) leads to upregulation of select chemokines that in turn lead to activation and recruitment of ocular 22 dendritic (e.g., Langerhans) cells. The role of "master molecules" such as IL-I and TNF-a that are capable of (1) augmenting inflammation and innate immunity (e.g., IL-I, IL-6, TNF-a); (2) overexpressing factors involved in T helper cell differentiation, activation (e.g., IL-12, CD40) and proliferation (e.g., IL-2) and (3) APC maturation and recruitment is getting 225 increasing attention in the corneal immunology literature/ . because these molecules link innate and adaptive immune responses and may serve as therapeutic targets in a host of immune disorders. 3. OCULAR SURFACE INFLAMMATION IN DRY EYE SYNDROMES A large body of evidence suggests clinically significant, and especially (but importantly not exclusively) tear-deficient, DES is associated with variable degrees of ocular surface inflammation. The hallmark of the inflamed and irritated eye is "red eye," characterized by vascular engorgement and variable degrees of matrix (stromal) edema. Nonspecific features of this tissue inflammation include extravasation of protein and fluid 732 M. R. Dana andP. Hamrah from "leaky" vessels with impaired barrier function at the level of their VEC, loss of epithelial barrier function and infiltration of leukocytes into the tissue matrix. At the molecular level, ample histological and flow cytometric data demonstrate enhanced expression of proinflammatory cytokine (e.g., IL-I, IL-6, IL-8, TNF-a) mRNA and protein 52 by the ocular surface epithelium or tear film. . 1.26-31 Conversely, treatment of DES, either clinically or in animal models of keratoconjunctivitis sicca, with anti-inflammatory agents (e.g., cyclosporin A) has been associated with improved disease endpoints either clinically6.9.32-36 or at the level of the tissue.5.26.37 In addition to these findings, DES- associated ocular surface epitheliopathy has been associated with a significantly enhanced level of class II major histocompatibility complex (MHC) antigen (HLA DR) expression 5 by resident ocular surface epithelial cells. Since presentation of processed (foreign or autoantigen) peptides in the context of class II MHC molecules is a classic pathway for priming of CD4-positive T-cells, it has been postulated but not proven that this phenomenon enables these epithelial cells to serve as "non-professional" (since they are 39 not bone marrow-derived) APC,5.38 as has been postulated for lacrimal gland epithelia. The fact the expression of CD40 and its ligand (CD40L or CD154) is likewise significantly enhanced in OSD related to ocular sicca has similarly provided indirect support, but again no proof, these epithelial cells may have all the requisite phenotypic markers for 5 stimulating a primary T-cell response. In summary, the association between OSD in DES with immunoinflammatory markers on the one hand, and the subsequent downmodulation of these factors when dry eye is treated with anti-inflammatory/immunomodulatory treatments on the other, has provided indirect correlative evidence for the involvement of immunoactive agents in the pathophysiology of DES. 4. IS THE PATHOGENESIS OF DRY EYE SYNDROMES CAUSALLY RELATED TO IMMUNE MECHANISMS GENERATED IN THE OCULAR SURFACE? As noted above, the substantial empirical evidence linking DES with immunoinflammatory molecular and cellular markers in the ocular surface is sufficient to demonstrate a significant role for these mediators in the pathophysiology of OSD in dry eyes. The question, however, is not whether these mediators playa role, but rather whether this role is causal. Moreover, is the site of putative T-cell activation the ocular surface? If so, how would these molecular features fit with the paradigm of immunity described above, and with the various features of pathobiology described thus far in DES? We simply do not have adequate knowledge to answer any of these questions definitively. For example, the immune (HLA DR, CD40 overexpression) and inflammatory (IL-I, TNF-a, ICAM-I overexpression) features of DES may similarly be applied to non- sicca-related ocular conditions such as atopic disease,8 allograft rejection,23.40 cicatrizing 42 conjunctivitis,41 ocular surface burns and ocular graft-versus-host disease post-allogeneic
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