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Autoimmunität und Glaukom

Leitthema
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Zusammenfassung

Neben dem relevantesten Risikofaktor für das Glaukom, dem erhöhten Augeninnendruck, gibt es weitere relevant erscheinende Faktoren für die Erkrankung. Besondere Bedeutung haben hierbei Veränderungen in der autoimmunen Komponente des Immunsystems. In klinischen Studien wurden Veränderungen verschiedener Autoantikörper (AAK) bei Glaukompatienten nachgewiesen, sowohl AAK, welche in erhöhter Abundanz bzw. in einem erhöhten Titer vorliegen, als auch solche, die mit erniedrigtem Titer vorliegen. Diese AAK-Veränderungen beherbergen ein distinktes Potenzial, sowohl zur Glaukomfrüherkennnung als auch – aufgrund neuroprotektiver Eigenschaften einiger der AAK – zur Therapie dieser okulären Neuropathie. Dabei zeigten verschiedene Antiköper (AK), welche bei Glaukompatienten in geringerer Konzentration vorhanden sind, wie etwa die AK gegen 14-3-3-Protein, γ‑/α-Synuklein oder aber auch gegen saures Gliafaserprotein („glial fibrillary acidic protein“, GFAP) entweder in vitro oder in vivo neuroprotektive Effekte auf retinale Ganglienzellen. Um die Relevanz der Veränderungen im Immunsystem genauer zu untersuchen, sind neben zellkulturkorrespondierenden Methoden die „‑omics-basierten“ Analysen verschiedener okulärer Proben von besonderer Bedeutung. Dabei können nicht nur Materialien, welche aus experimentellen Ansätzen gewonnen werden, genauer hinsichtlich ihrer Protein- und insbesondere ihrer AK-Veränderungen untersucht werden, sondern auch geringe Probenmengen direkt vom Glaukompatienten (z. B. Kammerwasser, Tränenflüssigkeit, Serum oder Post-Mortem-Retina). Die proteomische Charakterisierung glaukomrelevanter Probentypen mit modernen massenspektrometrischen (MS-)Methoden wird essenzielle Beiträge zum molekularen Verständnis sowie entsprechend zur Diagnostik und Therapie des Glaukoms in den nächsten Jahren liefern.

Schlüsselwörter

Autoantikörper Neuroprotektiva Massenspektrometrie Augenerkrankungen Proteomik 

Autoimmunity and glaucoma

Abstract

In addition to the clinically most relevant risk factor for glaucoma, i.e., elevated intraocular pressure (IOP), there are other factors with high relevance for the disease. Changes in the autoimmune component of the immune system are of particular importance. Clinical studies have demonstrated alterations in different autoantibodies in glaucoma patients compared to healthy controls, some of which increase in abundance/have a raised titer, but also some which have a reduced titer. These changes have a distinct potential—not only as a tool for early glaucoma detection, but also as a therapeutic option due to the documented neuroprotective effects of some of these antibodies. Several antibodies displaying lower abundance in glaucoma patients, e.g., antibodies against 14-3-3 proteins, γ‑/α-synuclein, or also against glial fibrillary acidic protein (GFAP), show neuroprotective effects on retinal ganglion cells in vivo and in vitro. To assess the relevance of changes detected in the immune system of glaucoma patients, “‑omics-based” analyses of different ocular tissues are of particular importance alongside cell culture studies. In this manner, not only samples derived from experimental studies but also samples derived from glaucoma patients in even very small amounts (e. g., tears, aqueous humor, serum, or post-mortem retina) can be analyzed in detail in terms of protein and, in particular, antibody changes. Modern mass spectrometric proteomic characterization of relevant samples will deliver valuable information concerning the understanding of molecular disease mechanisms in the coming years, thus also improving diagnosis and treatment of glaucoma.

Keywords

Autoantibodies Neuroprotective agents Mass spectrometry Eye diseases Proteomics 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

K. Bell, S. Funke und F.H. Grus geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Literatur

  1. 1.
    Tham YC et al (2014) Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology 121(11):2081–2090CrossRefPubMedGoogle Scholar
  2. 2.
    Heijl A et al (2002) Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 120(10):1268–1279CrossRefPubMedGoogle Scholar
  3. 3.
    Naito T et al (2015) Relationship between progression of visual field defect and intraocular pressure in primary open-angle glaucoma. Clin Ophthalmol 9:1373–1378CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Osborne NN (2008) Pathogenesis of ganglion “cell death” in glaucoma and neuroprotection: focus on ganglion cell axonal mitochondria. Prog Brain Res 173:339–352CrossRefPubMedGoogle Scholar
  5. 5.
    Ito Y et al (2011) Involvement of endoplasmic reticulum stress on neuronal cell death in the lateral geniculate nucleus in the monkey glaucoma model. Eur J Neurosci 33(5):843–855CrossRefPubMedGoogle Scholar
  6. 6.
    Benoist d’Azy C et al (2016) Oxidative and anti-oxidative stress markers in chronic glaucoma: a systematic review and meta-analysis. PLoS ONE 11(12):e166915CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Bell K et al (2013) Does autoimmunity play a part in the pathogenesis of glaucoma? Prog Retin Eye Res 36:199–216CrossRefPubMedGoogle Scholar
  8. 8.
    Becker B, Coleman SL, Keates EU (1962) Gamma globulin in ocular diseases: diabetes and glaucoma. Trans Am Ophthalmol Soc 60:260–267PubMedPubMedCentralGoogle Scholar
  9. 9.
    Romano C et al (1995) Anti-rhodopsin antibodies in sera from patients with normal-pressure glaucoma. Invest Ophthalmol Vis Sci 36(10):1968–1975PubMedGoogle Scholar
  10. 10.
    Tezel G, Edward DP, Wax MB (1999) Serum autoantibodies to optic nerve head glycosaminoglycans in patients with glaucoma. Arch Ophthalmol 117(7):917–924CrossRefPubMedGoogle Scholar
  11. 11.
    Tezel G, Seigel GM, Wax MB (1998) Autoantibodies to small heat shock proteins in glaucoma. Invest Ophthalmol Vis Sci 39(12):2277–2287PubMedGoogle Scholar
  12. 12.
    Yang J et al (2001) Serum autoantibody against glutathione S‑transferase in patients with glaucoma. Invest Ophthalmol Vis Sci 42(6):1273–1276PubMedGoogle Scholar
  13. 13.
    Joachim SC et al (2008) Sera of glaucoma patients show autoantibodies against myelin basic protein and complex autoantibody profiles against human optic nerve antigens. Graefes Arch Clin Exp Ophthalmol 246(4):573–580CrossRefPubMedGoogle Scholar
  14. 14.
    Joachim SC et al (2007) Antibodies to alpha B‑crystallin, vimentin, and heat shock protein 70 in aqueous humor of patients with normal tension glaucoma and IgG antibody patterns against retinal antigen in aqueous humor. Curr Eye Res 32(6):501–509CrossRefPubMedGoogle Scholar
  15. 15.
    von Thun, Hohenstein-Blaul N et al (2015) Basic biochemical processes in glaucoma progression. Ophthalmologe 112(5):395–401CrossRefGoogle Scholar
  16. 16.
    Grus FH et al (2006) Serum autoantibodies to alpha-fodrin are present in glaucoma patients from Germany and the United States. Invest Ophthalmol Vis Sci 47(3):968–976CrossRefPubMedGoogle Scholar
  17. 17.
    Silosi I et al (2016) The role of autoantibodies in health and disease. Rom J Morphol Embryol 57(2 Suppl):633–638PubMedGoogle Scholar
  18. 18.
    Tiller T et al (2007) Autoreactivity in human IgG+ memory B cells. Immunity 26(2):205–213CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gronwall C, Silverman GJ (2014) Natural IgM: beneficial autoantibodies for the control of inflammatory and autoimmune disease. J Clin Immunol 34(Suppl 1):S12–S21CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lorenz K et al (2017) Course of serum autoantibodies in patients after acute angle-closure glaucoma attack. J Clin Exp Ophthalmol 45(3):280–287CrossRefGoogle Scholar
  21. 21.
    Bell K et al (2012) Serum and antibodies of glaucoma patients lead to changes in the proteome, especially cell regulatory proteins, in retinal cells. PLoS ONE 7(10):e46910CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Tezel G, Wax MB (2000) The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells. J Neurosci 20(10):3552–3562PubMedGoogle Scholar
  23. 23.
    Wax MB et al (2008) Induced autoimmunity to heat shock proteins elicits glaucomatous loss of retinal ganglion cell neurons via activated T‑cell-derived fas-ligand. J Neurosci 28(46):12085–12096CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bell K et al (2015) Protective effect of 14-3-3 antibodies on stressed neuroretinal cells via the mitochondrial apoptosis pathway. Bmc Ophthalmol 15:64CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wilding C et al (2015) GFAP antibodies show protective effect on oxidatively stressed neuroretinal cells via interaction with ERP57. J Pharmacol Sci 127(3):298–304CrossRefPubMedGoogle Scholar
  26. 26.
    Bell K et al (2016) Neuroprotective effects of antibodies on retinal ganglion cells in an adolescent retina organ culture. J Neurochem 139(2):256–269CrossRefPubMedGoogle Scholar
  27. 27.
    de Hoz R et al (2016) Retinal macroglial responses in health and disease. Biomed Res Int 2016:2954721PubMedPubMedCentralGoogle Scholar
  28. 28.
    Gramlich OW et al (2016) Immune response after intermittent minimally invasive intraocular pressure elevations in an experimental animal model of glaucoma. J Neuroinflammation 13(1):82CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Gramlich OW et al (2013) Enhanced insight into the autoimmune component of glaucoma: IgG autoantibody accumulation and pro-inflammatory conditions in human glaucomatous retina. PLoS ONE 8(2):e57557CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Joachim SC et al (2009) Complex antibody profile changes in an experimental autoimmune glaucoma animal model. Invest Ophthalmol Vis Sci 50(10):4734–4742CrossRefPubMedGoogle Scholar
  31. 31.
    Laspas P et al (2011) Autoreactive antibodies and loss of retinal ganglion cells in rats induced by immunization with ocular antigens. Invest Ophthalmol Vis Sci 52(12):8835–8848CrossRefPubMedGoogle Scholar
  32. 32.
    Joachim SC et al (2013) Immune response against ocular tissues after immunization with optic nerve antigens in a model of autoimmune glaucoma. Mol Vis 19:1804–1814PubMedPubMedCentralGoogle Scholar
  33. 33.
    Joachim SC et al (2012) Retinal ganglion cell loss is accompanied by antibody depositions and increased levels of microglia after immunization with retinal antigens. PLoS ONE 7(7):e40616CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Teister J et al (2017) Decelerated neurodegeneration after intravitreal injection of alpha-synuclein antibodies in a glaucoma animal model. Sci Rep 7(1):6260CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Grus FH, Joachim SC, Pfeiffer N (2007) Proteomics in ocular fluids. Proteomics Clin Appl 1(8):876–888CrossRefPubMedGoogle Scholar
  36. 36.
    de Souza GA, Godoy LM, Mann M (2006) Identification of 491 proteins in the tear fluid proteome reveals a large number of proteases and protease inhibitors. Genome Biol 7(8):R72CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zhou L et al (2012) In-depth analysis of the human tear proteome. J Proteomics 75(13):3877–3885CrossRefPubMedGoogle Scholar
  38. 38.
    Funke S et al (2016) Analysis of the effects of preservative-free tafluprost on the tear proteome. Am J Transl Res 8(10):4025–4039PubMedPubMedCentralGoogle Scholar
  39. 39.
    Pieragostino D et al (2013) Shotgun proteomics reveals specific modulated protein patterns in tears of patients with primary open angle glaucoma naive to therapy. Mol Biosyst 9(6):1108–1116CrossRefPubMedGoogle Scholar
  40. 40.
    Pieragostino D et al (2012) Differential protein expression in tears of patients with primary open angle and pseudoexfoliative glaucoma. Mol Biosyst 8(4):1017–1028CrossRefPubMedGoogle Scholar
  41. 41.
    Joachim SC et al (2007) IgG antibody patterns in aqueous humor of patients with primary open angle glaucoma and pseudoexfoliation glaucoma. Mol Vis 13(175):1573–1579PubMedGoogle Scholar
  42. 42.
    Kaeslin MA et al (2016) Changes to the aqueous humor proteome during glaucoma. PLoS ONE 11(10):e165314CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bouhenni RA et al (2011) Identification of differentially expressed proteins in the aqueous humor of primary congenital glaucoma. Exp Eye Res 92(1):67–75CrossRefPubMedGoogle Scholar
  44. 44.
    Duan XM et al (2010) Proteomic analysis of aqueous humor from patients with primary open angle glaucoma. Mol Vis 16(303-05):2839–2846PubMedPubMedCentralGoogle Scholar
  45. 45.
    Grus FH et al (2008) Transthyretin and complex protein pattern in aqueous humor of patients with primary open-angle glaucoma. Mol Vis 14(167–73):1437–1445PubMedPubMedCentralGoogle Scholar
  46. 46.
    Du S et al (2016) Multiplex cytokine levels of aqueous humor in acute primary angle-closure patients: fellow eye comparison. BMC Ophthalmol 16:6CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Kuchtey J et al (2010) Multiplex cytokine analysis reveals elevated concentration of Interleukin-8 in glaucomatous aqueous humor. Investig Ophthalmol Vis Sci 51(12):6441–6447CrossRefGoogle Scholar
  48. 48.
    Alexander JP, Samples JR, Acott TS (1998) Growth factor and cytokine modulation of trabecular meshwork matrix metalloproteinase and TIMP expression. Curr Eye Res 17(3):276–285CrossRefPubMedGoogle Scholar
  49. 49.
    Chen KH et al (1999) Increased interleukin-6 in aqueous humor of neovascular glaucoma. Invest Ophthalmol Vis Sci 40(11):2627–2632PubMedGoogle Scholar
  50. 50.
    Sacca SC, Izzotti A (2014) Focus on molecular events in the anterior chamber leading to glaucoma. Cell Mol Life Sci 71(12):2197–2218CrossRefPubMedGoogle Scholar
  51. 51.
    Funke S et al (2016) Glaucoma related proteomic alterations in human retina samples. Sci Rep 6:29759.  https://doi.org/10.1038/srep29759 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Joachim SC et al (2007) Analysis of IgG antibody patterns against retinal antigens and antibodies to alpha-crystallin, GFAP, and alpha-enolase in sera of patients with “wet” age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 245(5):619–626CrossRefPubMedGoogle Scholar
  53. 53.
    Joachim SC et al (2010) Enhanced characterization of serum autoantibody reactivity following HSP 60 immunization in a rat model of experimental autoimmune glaucoma. Curr Eye Res 35(10):900–908CrossRefPubMedGoogle Scholar
  54. 54.
    Zhao W et al (2017) Autoantibodies associated with glaucoma. Biomed Res 28(11):4913–4921Google Scholar
  55. 55.
    Miyara N et al (2008) Proteomic analysis of rat retina in a steroid-induced ocular hypertension model: potential vulnerability to oxidative stress. Jpn J Ophthalmol 52(2):84–90.  https://doi.org/10.1007/s10384-007-0507-5 CrossRefPubMedGoogle Scholar
  56. 56.
    Crabb JW et al (2010) Preliminary quantitative proteomic characterization of glaucomatous rat retinal ganglion cells. Exp Eye Res 91(1):107–110CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Cao L et al (2015) Alterations in molecular pathways in the retina of early experimental glaucoma eyes. Int J Physiol Pathophysiol Pharmacol 7(1):44–53PubMedPubMedCentralGoogle Scholar
  58. 58.
    Anders F et al (2017) Proteomic profiling reveals crucial retinal protein alterations in the early phase of an experimental glaucoma model. Graefes Arch Clin Exp Ophthalmol 255(7):1395–1407CrossRefPubMedGoogle Scholar
  59. 59.
    Ausio J, de Paz AM, Esteller M (2014) MeCP2: the long trip from a chromatin protein to neurological disorders. Trends Mol Med 20(9):487–498CrossRefPubMedGoogle Scholar
  60. 60.
    Chahrour M et al (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320(5880):1224–1229CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Gonzales ML, LaSalle JM (2010) The role of MeCP2 in brain development and neurodevelopmental disorders. Curr Psychiatry Rep 12(2):127–134CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Guy J et al (2011) The role of MECP2 in the brain. Annu Rev Cell Dev Biol 27:631–652CrossRefPubMedGoogle Scholar
  63. 63.
    Abuhatzira L et al (2007) MeCP2 deficiency in the brain decreases BDNF levels by REST/CoREST-mediated repression and increases TRKB production. Epigenetics 2(4):214–222CrossRefPubMedGoogle Scholar
  64. 64.
    Sampathkumar C et al (2016) Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons. Elife 5:e19374CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ghaffariyeh A et al (2011) Brain-derived neurotrophic factor as a biomarker in primary open-angle glaucoma. Optom Vis Sci 88(1):80–85CrossRefPubMedGoogle Scholar
  66. 66.
    Ahmad TK et al (2016) Transcriptional regulation of brain-derived neurotrophic factor (BDNF) by methyl CpG binding protein 2 (MeCP2): a novel mechanism for re-myelination and/or myelin repair involved in the treatment of multiple sclerosis (MS). Mol Neurobiol 53:1092–1107CrossRefGoogle Scholar
  67. 67.
    Forbes-Lorman RM, Kurian JR, Auger AP (2014) MeCP2 regulates GFAP expression within the developing brain. Brain Res 1543:151–158CrossRefPubMedGoogle Scholar
  68. 68.
    Wilding C et al (2014) γ‑synuclein antibodies have neuroprotective potential on neuroretinal cells via proteins of the mitochondrial apoptosis pathway. PLoS ONE 9(3):e90737CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Surgucheva I, Surguchov A (2008) Gamma-synuclein: cell-type-specific promoter activity and binding to transcription factors. J Mol Neurosci 35(3):267–271CrossRefPubMedGoogle Scholar
  70. 70.
    Tezel G et al (2012) Immunoproteomic analysis of potential serum biomarker candidates in human glaucoma. Investig Ophthalmol Vis Sci 53(13):8222–8231CrossRefGoogle Scholar
  71. 71.
    McFarland K et al (2014) MECP2: a novel huntingtin interactor. Hum Mol Genet 23(4):1036–1044CrossRefPubMedGoogle Scholar
  72. 72.
    Leoh LS et al (2012) The stress oncoprotein LEDGF/p75 interacts with the methyl CpG binding protein and influences its transcriptional activity. Mol Cancer Res 10(3):378–391CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Ganapathy V, Casiano CA (2004) Autoimmunity to the nuclear autoantigen DFS70 (LEDGF): what exactly are the autoantibodies trying to tell us? Arthritis Rheum 50(3):684–688CrossRefPubMedGoogle Scholar
  74. 74.
    Mahler M et al (2016) Towards a better understanding of the clinical association of anti-DFS70 autoantibodies. Autoimmun Rev 15:198–201CrossRefPubMedGoogle Scholar
  75. 75.
    Muro Y et al (2006) HLA-associated production of anti-DFS70/LEDGF autoantibodies and systemic autoimmune disease. J Autoimmun 26:252–257CrossRefPubMedGoogle Scholar
  76. 76.
    Ochs RL et al (2016) The significance of autoantibodies to DFS70/LEDGFp75 in health and disease: integrating basic science with clinical understanding. Clin Exp Med 16:273–293CrossRefPubMedGoogle Scholar
  77. 77.
    Schmelter C et al (2017) Peptides of the variable IgG domain as potential biomarker candidates in primary open-angle glaucoma (POAG). Hum Mol Genet 26(22):4451–4464.  https://doi.org/10.1093/hmg/ddx332 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2018

Authors and Affiliations

  1. 1.Experimentelle OphthalmologieAugenklinik der Universitätsmedizin MainzMainzDeutschland

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