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Table of Contents
Vol. 48, No. 1, 2012
Issue release date: June 2012
Free Access
Ophthalmic Res 2012;48:43–49
(DOI:10.1159/000335982)

Road to Fulfilment: Taming the Immune Response to Restore Vision

Dick A.D.
School of Clinical Sciences and School of Cellular and Molecular Medicine, University of Bristol, Bristol, and National Institute of Health Research-Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
email Corresponding Author

Abstract

While traditionally considered to be an immune privileged site, the eye, and in particular the retina, is nonetheless endowed with immune-competent cells capable of engaging powerful immune regulatory networks. By understanding the mechanisms that promote immune well-being in the eye, we are able to generate therapies which combat undue immune-mediated damage not only by revealing mechanisms that promote tissue damage, but also by an ability to restore tissue immune homeostasis by harnessing intrinsic immune-regulatory mechanisms. The result is to maintain or restore immune health as well as combat tissue damage evoked during, for example, intra-ocular inflammatory disease (uveitis), angiogenesis (age-related macular degeneration) and retinal degenerative disorders. Immune activation and regulation is a balance that is dictated by cognate and soluble factors at both a tissue and cellular level. These continuously respond to and eradicate danger and pathogenic signals whilst maintaining tissue function by controlling, and not exclusively, vascular barriers, complement activation, macrophage activation and keeping in check local T cell proliferation. Loss of the balance between activation and inhibitory signals leads to uncontrolled tissue damage. Understanding the mechanisms has gained potential therapeutic opportunities not only to suppress on-going inflammation, but also to restore homeostasis and prevent recrudescence.


 goto top of outline Key Words

  • Experimental auto-immune uveoretinitis
  • Auto-immune response
  • Inflammation
  • Macrophage
  • Angiogenesis
  • Auto-immunity

 goto top of outline Abstract

While traditionally considered to be an immune privileged site, the eye, and in particular the retina, is nonetheless endowed with immune-competent cells capable of engaging powerful immune regulatory networks. By understanding the mechanisms that promote immune well-being in the eye, we are able to generate therapies which combat undue immune-mediated damage not only by revealing mechanisms that promote tissue damage, but also by an ability to restore tissue immune homeostasis by harnessing intrinsic immune-regulatory mechanisms. The result is to maintain or restore immune health as well as combat tissue damage evoked during, for example, intra-ocular inflammatory disease (uveitis), angiogenesis (age-related macular degeneration) and retinal degenerative disorders. Immune activation and regulation is a balance that is dictated by cognate and soluble factors at both a tissue and cellular level. These continuously respond to and eradicate danger and pathogenic signals whilst maintaining tissue function by controlling, and not exclusively, vascular barriers, complement activation, macrophage activation and keeping in check local T cell proliferation. Loss of the balance between activation and inhibitory signals leads to uncontrolled tissue damage. Understanding the mechanisms has gained potential therapeutic opportunities not only to suppress on-going inflammation, but also to restore homeostasis and prevent recrudescence.

Copyright © 2012 S. Karger AG, Basel


 goto top of outline References
  1. Forrester JV: Privilege revisited: an evaluation of the eye’s defence mechanisms. Eye (Lond) 2009;23:756–766.
  2. Forrester JV, Xu H, Lambe T, Cornall R: Immune privilege or privileged immunity? Mucosal Immunol 2008;1:372–381.
  3. Imrie FR, Dick AD: Biologics in the treatment of uveitis. Curr Opin Ophthalmol 2007;18:481–486.
  4. Sharma SM, Nestel AR, Lee RW, Dick AD: Clinical review: anti-TNF-α therapies in uveitis: perspective on 5 years of clinical experience. Ocul Immunol Inflamm 2009;17:403–414.
  5. Chi W, Zhu X, Yang P, Liu X, Lin X, Zhou H, et al: Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Invest Ophthalmol Vis Sci 2008;49:3058–3064.

    External Resources

  6. Ke Y, Liu K, Huang GQ, Cui Y, Kaplan HJ, Shao H, et al: Anti-inflammatory role of IL-17 in experimental autoimmune uveitis. J Immunol 2009;182:3183–3190.
  7. Atan D, Fraser-Bell S, Plskova J, Kuffova L, Hogan A, Tufail A, et al: Cytokine polymorphism in noninfectious uveitis. Invest Ophthalmol Vis Sci 2010;51:4133–4142.

    External Resources

  8. Atan D, Fraser-Bell S, Plskova J, Kuffova L, Hogan A, Tufail A, et al: Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF loci. Invest Ophthalmol Vis Sci 2011;52:3573–3581.
  9. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al: Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet 2010;42:703–706.
  10. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP: Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett 2011:585:3689–3698.
  11. McDermott MF: Genetic clues to understanding periodic fevers, and possible therapies. Trends Mol Med 2002;8:550–554.
  12. Scher JU, Abramson SB: The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 2011;7:569–578.
  13. Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, et al: Control of TH17 cells occurs in the small intestine. Nature 2011;475:514–518.
  14. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D: Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci USA 2011;108:11548–11553.
  15. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, et al: Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;478:250–254.
  16. Matzinger P: The danger model: a renewed sense of self. Science 2002;296:301–305.
  17. Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002;296:298–300.
  18. Nathan C: Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006;6:173–182.
  19. Medzhitov R: Origin and physiological roles of inflammation. Nature 2008;454:428–435.
  20. Chen M, Forrester JV, Xu H: Dysregulation in retinal para-inflammation and age-related retinal degeneration in CCL2 or CCR2 deficient mice. PLoS One 2011;6:e22818.
  21. Xu H, Chen M, Forrester JV: Para-inflammation in the aging retina. Prog Retin Eye Res 2009;28:348–368.
  22. Lee RW, Schewitz LP, Nicholson LB, Dayan CM, Dick AD: Steroid refractory CD4+ T cells in patients with sight-threatening uveitis. Invest Ophthalmol Vis Sci 2009;50:4273–4278.

    External Resources

  23. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DR, Willcocks LC, et al: A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 2010;16:586–591, 1 p following 591.
  24. Forrester JV, Xu H, Kuffova L, Dick AD, McMenamin PG: Dendritic cell physiology and function in the eye. Immunol Rev 2010;234:282–304.
  25. Kezic J, Xu H, Chinnery HR, Murphy CC, McMenamin PG: Retinal microglia and uveal tract dendritic cells and macrophages are not CX3CR1 dependent in their recruitment and distribution in the young mouse eye. Invest Ophthalmol Vis Sci 2008;49:1599–1608.

    External Resources

  26. Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD: Turnover of resident retinal microglia in the normal adult mouse. Glia 2007;55:1189–1198.

    External Resources

  27. Balasubramaniam B, Carter DA, Mayer EJ, Dick AD: Microglia derived IL-6 suppresses neurosphere generation from adult human retinal cell suspensions. Exp Eye Res 2009;89:757–766.
  28. Dick AD: Influence of microglia on retinal progenitor cell turnover and cell replacement. Eye (Lond) 2009;23:1939–1945.
  29. Dick AD, Carter D, Robertson M, Broderick C, Hughes E, Forrester JV, et al: Control of myeloid activity during retinal inflammation. J Leukoc Biol 2003;74:161–166.
  30. Ransohoff RM, Cardona AE: The myeloid cells of the central nervous system parenchyma. Nature 2010;468:253–262.
  31. Broderick C, Duncan L, Taylor N, Dick AD: IFN-gamma and LPS-mediated IL-10-dependent suppression of retinal microglial activation. Invest Ophthalmol Vis Sci 2000;41:2613–2622.
  32. Carter DA, Dick AD: Lipopolysaccharide/interferon-γ and not transforming growth factor-β inhibits retinal microglial migration from retinal explant. Br J Ophthalmol 2003;87:481–487.
  33. Carter DA, Dick AD: CD200 maintains microglial potential to migrate in adult human retinal explant model. Curr Eye Res 2004;28:427–436.
  34. Rao NA, Kimoto T, Zamir E, Giri R, Wang R, Ito S, et al: Pathogenic role of retinal microglia in experimental uveoretinitis. Invest Ophthalmol Vis Sci 2003;44:22–31.
  35. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM: Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 2011;14:1142–1149.
  36. Gordon S: Alternative activation of macrophages. Nat Rev Immunol 2003;3:23–35.
  37. Gordon S, Taylor PR: Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005;5:953–964.
  38. Murray PJ, Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011.
  39. Copland DA, Wertheim MS, Armitage WJ, Nicholson LB, Raveney BJ, Dick AD: The clinical time-course of experimental autoimmune uveoretinitis using topical endoscopic fundal imaging with histologic and cellular infiltrate correlation. Invest Ophthalmol Vis Sci 2008;49:5458–5465.

    External Resources

  40. Kerr EC, Raveney BJ, Copland DA, Dick AD, Nicholson LB: Analysis of retinal cellular infiltrate in experimental autoimmune uveoretinitis reveals multiple regulatory cell populations. J Autoimmun 2008;31:354–361.
  41. Robertson MJ, Erwig LP, Liversidge J, Forrester JV, Rees AJ, Dick AD: Retinal microenvironment controls resident and infiltrating macrophage function during uveoretinitis. Invest Ophthalmol Vis Sci 2002;43:2250–2257.

    External Resources

  42. Dick AD, Broderick C, Forrester JV, Wright GJ: Distribution of OX2 antigen and OX2 receptor within retina. Invest Ophthalmol Vis Sci. 2001;42:170–176.
  43. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al: Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 2000;290:1768–1771.
  44. Banerjee D, Dick AD: Blocking CD200-CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats. Ocul Immunol Inflamm 2004;12:115–125.
  45. Broderick C, Hoek RM, Forrester JV, Liversidge J, Sedgwick JD, Dick AD: Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis. Am J Pathol 2002;161:1669–1677.
  46. Jenmalm MC, Cherwinski H, Bowman EP, Phillips JH, Sedgwick JD: Regulation of myeloid cell function through the CD200 receptor. J Immunol 2006;176:191–199.
  47. Copland DA, Calder CJ, Raveney BJ, Nicholson LB, Phillips J, Cherwinski H, et al: Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis. Am J Pathol 2007;171:580–588.
  48. Broderick CA, Smith AJ, Balaggan KS, Georgiadis A, Buch PK, Trittibach PC, et al: Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis. Mol Ther 2005;12:369–373.
  49. Ferrara DC, Merriam JE, Freund KB, Spaide RF, Takahashi BS, Zhitomirsky I, et al: Analysis of major alleles associated with age-related macular degeneration in patients with multifocal choroiditis: strong association with complement factor H. Arch Ophthalmol 2008;126:1562–1566.

    External Resources

  50. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005;102:7227–7232.
  51. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.
  52. Chen M, Muckersie E, Luo C, Forrester JV, Xu H: Inhibition of the alternative pathway of complement activation reduces inflammation in experimental autoimmune uveoretinitis. Eur J Immunol 2010;40:2870–2881.
  53. Chen M, Muckersie E, Robertson M, Forrester JV, Xu H: Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp Eye Res 2008;87:543–550.
  54. Copland DA, Hussain K, Baalasubramanian S, Hughes TR, Morgan BP, Xu H, et al: Systemic and local anti-C5 therapy reduces the disease severity in experimental autoimmune uveoretinitis. Clin Exp Immunol 2010;159:303–314.
  55. Chen M, Copland DA, Zhao J, Liu J, Forrester JV, Dick AD, et al: Persistent inflammation subverts thrombospondin-1-induced regulation of retinal angiogenesis and is driven by CCR2 ligation. Am J Pathol 2011.
  56. Kerr EC, Copland DA, Dick AD, Nicholson LB: The dynamics of leukocyte infiltration in experimental autoimmune uveoretinitis. Prog Retin Eye Res 2008;27:527–535.
  57. Apte RS, Richter J, Herndon J, Ferguson TA: Macrophages inhibit neovascularization in a murine model of age-related macular degeneration. PLoS Med 2006;3:e310.

    External Resources

  58. Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS: Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Invest 2007;117:3421–3426.
  59. Wu WK, Llewellyn OP, Bates DO, Nicholson LB, Dick AD: IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia. Immunobiology 2010;215:796–803.
  60. Raveney BJ, Copland DA, Nicholson LB, Dick AD: Fingolimod (FTY720) as an acute rescue therapy for intraocular inflammatory disease. Arch Ophthalmol 2008;126:1390–1395.

 goto top of outline Author Contacts

Prof. Andrew D. Dick
Bristol Eye Hospital
Lower Maudlin Street
Bristol BS1 2LX (UK)
E-Mail a.dick@bristol.ac.uk


 goto top of outline Article Information

Received: October 31, 2011
Accepted after revision: November 30, 2011
Published online: March 6, 2012
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 0, Number of References : 60


 goto top of outline Publication Details

Ophthalmic Research (Journal for Research in Experimental and Clinical Ophthalmology)

Vol. 48, No. 1, Year 2012 (Cover Date: June 2012)

Journal Editor: Corcóstegui B. (Barcelona), Pelayes D. (Buenos Aires), Pleyer U. (Berlin)
ISSN: 0030-3747 (Print), eISSN: 1423-0259 (Online)

For additional information: http://www.karger.com/ORE


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

While traditionally considered to be an immune privileged site, the eye, and in particular the retina, is nonetheless endowed with immune-competent cells capable of engaging powerful immune regulatory networks. By understanding the mechanisms that promote immune well-being in the eye, we are able to generate therapies which combat undue immune-mediated damage not only by revealing mechanisms that promote tissue damage, but also by an ability to restore tissue immune homeostasis by harnessing intrinsic immune-regulatory mechanisms. The result is to maintain or restore immune health as well as combat tissue damage evoked during, for example, intra-ocular inflammatory disease (uveitis), angiogenesis (age-related macular degeneration) and retinal degenerative disorders. Immune activation and regulation is a balance that is dictated by cognate and soluble factors at both a tissue and cellular level. These continuously respond to and eradicate danger and pathogenic signals whilst maintaining tissue function by controlling, and not exclusively, vascular barriers, complement activation, macrophage activation and keeping in check local T cell proliferation. Loss of the balance between activation and inhibitory signals leads to uncontrolled tissue damage. Understanding the mechanisms has gained potential therapeutic opportunities not only to suppress on-going inflammation, but also to restore homeostasis and prevent recrudescence.



 goto top of outline Author Contacts

Prof. Andrew D. Dick
Bristol Eye Hospital
Lower Maudlin Street
Bristol BS1 2LX (UK)
E-Mail a.dick@bristol.ac.uk


 goto top of outline Article Information

Received: October 31, 2011
Accepted after revision: November 30, 2011
Published online: March 6, 2012
Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 0, Number of References : 60


 goto top of outline Publication Details

Ophthalmic Research (Journal for Research in Experimental and Clinical Ophthalmology)

Vol. 48, No. 1, Year 2012 (Cover Date: June 2012)

Journal Editor: Corcóstegui B. (Barcelona), Pelayes D. (Buenos Aires), Pleyer U. (Berlin)
ISSN: 0030-3747 (Print), eISSN: 1423-0259 (Online)

For additional information: http://www.karger.com/ORE


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Forrester JV: Privilege revisited: an evaluation of the eye’s defence mechanisms. Eye (Lond) 2009;23:756–766.
  2. Forrester JV, Xu H, Lambe T, Cornall R: Immune privilege or privileged immunity? Mucosal Immunol 2008;1:372–381.
  3. Imrie FR, Dick AD: Biologics in the treatment of uveitis. Curr Opin Ophthalmol 2007;18:481–486.
  4. Sharma SM, Nestel AR, Lee RW, Dick AD: Clinical review: anti-TNF-α therapies in uveitis: perspective on 5 years of clinical experience. Ocul Immunol Inflamm 2009;17:403–414.
  5. Chi W, Zhu X, Yang P, Liu X, Lin X, Zhou H, et al: Upregulated IL-23 and IL-17 in Behçet patients with active uveitis. Invest Ophthalmol Vis Sci 2008;49:3058–3064.

    External Resources

  6. Ke Y, Liu K, Huang GQ, Cui Y, Kaplan HJ, Shao H, et al: Anti-inflammatory role of IL-17 in experimental autoimmune uveitis. J Immunol 2009;182:3183–3190.
  7. Atan D, Fraser-Bell S, Plskova J, Kuffova L, Hogan A, Tufail A, et al: Cytokine polymorphism in noninfectious uveitis. Invest Ophthalmol Vis Sci 2010;51:4133–4142.

    External Resources

  8. Atan D, Fraser-Bell S, Plskova J, Kuffova L, Hogan A, Tufail A, et al: Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF loci. Invest Ophthalmol Vis Sci 2011;52:3573–3581.
  9. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T, et al: Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet 2010;42:703–706.
  10. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP: Why is PTPN22 a good candidate susceptibility gene for autoimmune disease? FEBS Lett 2011:585:3689–3698.
  11. McDermott MF: Genetic clues to understanding periodic fevers, and possible therapies. Trends Mol Med 2002;8:550–554.
  12. Scher JU, Abramson SB: The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 2011;7:569–578.
  13. Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, et al: Control of TH17 cells occurs in the small intestine. Nature 2011;475:514–518.
  14. Kriegel MA, Sefik E, Hill JA, Wu HJ, Benoist C, Mathis D: Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice. Proc Natl Acad Sci USA 2011;108:11548–11553.
  15. Lathrop SK, Bloom SM, Rao SM, Nutsch K, Lio CW, Santacruz N, et al: Peripheral education of the immune system by colonic commensal microbiota. Nature 2011;478:250–254.
  16. Matzinger P: The danger model: a renewed sense of self. Science 2002;296:301–305.
  17. Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002;296:298–300.
  18. Nathan C: Neutrophils and immunity: challenges and opportunities. Nat Rev Immunol 2006;6:173–182.
  19. Medzhitov R: Origin and physiological roles of inflammation. Nature 2008;454:428–435.
  20. Chen M, Forrester JV, Xu H: Dysregulation in retinal para-inflammation and age-related retinal degeneration in CCL2 or CCR2 deficient mice. PLoS One 2011;6:e22818.
  21. Xu H, Chen M, Forrester JV: Para-inflammation in the aging retina. Prog Retin Eye Res 2009;28:348–368.
  22. Lee RW, Schewitz LP, Nicholson LB, Dayan CM, Dick AD: Steroid refractory CD4+ T cells in patients with sight-threatening uveitis. Invest Ophthalmol Vis Sci 2009;50:4273–4278.

    External Resources

  23. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DR, Willcocks LC, et al: A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 2010;16:586–591, 1 p following 591.
  24. Forrester JV, Xu H, Kuffova L, Dick AD, McMenamin PG: Dendritic cell physiology and function in the eye. Immunol Rev 2010;234:282–304.
  25. Kezic J, Xu H, Chinnery HR, Murphy CC, McMenamin PG: Retinal microglia and uveal tract dendritic cells and macrophages are not CX3CR1 dependent in their recruitment and distribution in the young mouse eye. Invest Ophthalmol Vis Sci 2008;49:1599–1608.

    External Resources

  26. Xu H, Chen M, Mayer EJ, Forrester JV, Dick AD: Turnover of resident retinal microglia in the normal adult mouse. Glia 2007;55:1189–1198.

    External Resources

  27. Balasubramaniam B, Carter DA, Mayer EJ, Dick AD: Microglia derived IL-6 suppresses neurosphere generation from adult human retinal cell suspensions. Exp Eye Res 2009;89:757–766.
  28. Dick AD: Influence of microglia on retinal progenitor cell turnover and cell replacement. Eye (Lond) 2009;23:1939–1945.
  29. Dick AD, Carter D, Robertson M, Broderick C, Hughes E, Forrester JV, et al: Control of myeloid activity during retinal inflammation. J Leukoc Biol 2003;74:161–166.
  30. Ransohoff RM, Cardona AE: The myeloid cells of the central nervous system parenchyma. Nature 2010;468:253–262.
  31. Broderick C, Duncan L, Taylor N, Dick AD: IFN-gamma and LPS-mediated IL-10-dependent suppression of retinal microglial activation. Invest Ophthalmol Vis Sci 2000;41:2613–2622.
  32. Carter DA, Dick AD: Lipopolysaccharide/interferon-γ and not transforming growth factor-β inhibits retinal microglial migration from retinal explant. Br J Ophthalmol 2003;87:481–487.
  33. Carter DA, Dick AD: CD200 maintains microglial potential to migrate in adult human retinal explant model. Curr Eye Res 2004;28:427–436.
  34. Rao NA, Kimoto T, Zamir E, Giri R, Wang R, Ito S, et al: Pathogenic role of retinal microglia in experimental uveoretinitis. Invest Ophthalmol Vis Sci 2003;44:22–31.
  35. Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM: Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 2011;14:1142–1149.
  36. Gordon S: Alternative activation of macrophages. Nat Rev Immunol 2003;3:23–35.
  37. Gordon S, Taylor PR: Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005;5:953–964.
  38. Murray PJ, Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011.
  39. Copland DA, Wertheim MS, Armitage WJ, Nicholson LB, Raveney BJ, Dick AD: The clinical time-course of experimental autoimmune uveoretinitis using topical endoscopic fundal imaging with histologic and cellular infiltrate correlation. Invest Ophthalmol Vis Sci 2008;49:5458–5465.

    External Resources

  40. Kerr EC, Raveney BJ, Copland DA, Dick AD, Nicholson LB: Analysis of retinal cellular infiltrate in experimental autoimmune uveoretinitis reveals multiple regulatory cell populations. J Autoimmun 2008;31:354–361.
  41. Robertson MJ, Erwig LP, Liversidge J, Forrester JV, Rees AJ, Dick AD: Retinal microenvironment controls resident and infiltrating macrophage function during uveoretinitis. Invest Ophthalmol Vis Sci 2002;43:2250–2257.

    External Resources

  42. Dick AD, Broderick C, Forrester JV, Wright GJ: Distribution of OX2 antigen and OX2 receptor within retina. Invest Ophthalmol Vis Sci. 2001;42:170–176.
  43. Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, et al: Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 2000;290:1768–1771.
  44. Banerjee D, Dick AD: Blocking CD200-CD200 receptor axis augments NOS-2 expression and aggravates experimental autoimmune uveoretinitis in Lewis rats. Ocul Immunol Inflamm 2004;12:115–125.
  45. Broderick C, Hoek RM, Forrester JV, Liversidge J, Sedgwick JD, Dick AD: Constitutive retinal CD200 expression regulates resident microglia and activation state of inflammatory cells during experimental autoimmune uveoretinitis. Am J Pathol 2002;161:1669–1677.
  46. Jenmalm MC, Cherwinski H, Bowman EP, Phillips JH, Sedgwick JD: Regulation of myeloid cell function through the CD200 receptor. J Immunol 2006;176:191–199.
  47. Copland DA, Calder CJ, Raveney BJ, Nicholson LB, Phillips J, Cherwinski H, et al: Monoclonal antibody-mediated CD200 receptor signaling suppresses macrophage activation and tissue damage in experimental autoimmune uveoretinitis. Am J Pathol 2007;171:580–588.
  48. Broderick CA, Smith AJ, Balaggan KS, Georgiadis A, Buch PK, Trittibach PC, et al: Local administration of an adeno-associated viral vector expressing IL-10 reduces monocyte infiltration and subsequent photoreceptor damage during experimental autoimmune uveitis. Mol Ther 2005;12:369–373.
  49. Ferrara DC, Merriam JE, Freund KB, Spaide RF, Takahashi BS, Zhitomirsky I, et al: Analysis of major alleles associated with age-related macular degeneration in patients with multifocal choroiditis: strong association with complement factor H. Arch Ophthalmol 2008;126:1562–1566.

    External Resources

  50. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al: A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 2005;102:7227–7232.
  51. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al: Complement factor H polymorphism in age-related macular degeneration. Science 2005;308:385–389.
  52. Chen M, Muckersie E, Luo C, Forrester JV, Xu H: Inhibition of the alternative pathway of complement activation reduces inflammation in experimental autoimmune uveoretinitis. Eur J Immunol 2010;40:2870–2881.
  53. Chen M, Muckersie E, Robertson M, Forrester JV, Xu H: Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp Eye Res 2008;87:543–550.
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    External Resources

  58. Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS: Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Invest 2007;117:3421–3426.
  59. Wu WK, Llewellyn OP, Bates DO, Nicholson LB, Dick AD: IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia. Immunobiology 2010;215:796–803.
  60. Raveney BJ, Copland DA, Nicholson LB, Dick AD: Fingolimod (FTY720) as an acute rescue therapy for intraocular inflammatory disease. Arch Ophthalmol 2008;126:1390–1395.