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Klin Monbl Augenheilkd 2011; 228(5): 439-445
DOI: 10.1055/s-0031-1273355
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Immunreaktionen beim Glaukom

Autoimmunity and GlaucomaF. H. Grus1 , O. W. Gramlich2
  • 1Universitäts-Augenklinik, Experimentelle Ophthalmologie
  • 2Augenheilkunde, Augenklinik der Universitätsmedizin
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Publikationsverlauf

Eingegangen: 14.3.2011

Angenommen: 7.4.2011

Publikationsdatum:
29. April 2011 (online)

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Zusammenfassung

Das Glaukom ist eine der häufigsten Ursache der Erblindung weltweit. Nach geltender Definition beschreibt der Begriff Glaukom eine Gruppe okulärer Erkrankungen, die zu einem fortschreitenden Verlust retinaler Ganglienzellen mit nachfolgenden typischen glaukomatösen Gesichtsfeldausfällen führen. Der intraokuläre Druck (IOD) wird zwar weiter als wichtigster Risikofaktor gewertet, seine Senkung halbiert das Risiko der Krankheitsprogression, stoppt sie aber nicht vollständig. Allerdings entwickelt eine Vielzahl von Patienten ein Glaukom, ohne dass ein erhöhter IOD bei ihnen vorliegt. Dies sind Hinweise darauf, dass der erhöhte IOD nicht die einzige Ursache der glaukomatösen Schädigung sein kann. Aktuell werden insbesondere der Mangel neurotropher Faktoren, eine vaskuläre Schädigung, Glutamattoxizität und Gliaaktivierung als Faktoren der Krankheitsentstehung diskutiert. Neben den bereits genannten Theorien rückt auch eine Beteiligung des Immunsystems immer mehr in den Mittelpunkt der Diskussion. Unsere Arbeitsgruppe konnte in vielen Untersuchungen des Serums und Kammerwassers von Glaukompatienten veränderte Immunreaktionen von Autoantikörpern gegen verschiedene Proteine nachweisen, so etwa gegen Hitzeschockproteine (HSP), α-Fodrin, saures Gliafaserprotein (GFAP) und Myelin-basisches Protein (MBP) und gegen Vimentin. In vitro konnte gezeigt werden, dass Antikörper gegen kleine Hitzeschockproteine die Apoptose retinaler Ganglienzellen (RGZ) auslösen können. Im experimentellen Autoimmun-Glaukomtiermodell kam es nach Immunisierung mit dem Hitzeschockprotein27 zu einem apoptotischen Untergang retinaler Ganglienzellen. Unklar ist, ob diese immunologischen Veränderungen Ursache oder Folge der Erkrankung sind. Unabhängig davon kann eine Veränderung in den Antikörperprofilen gegen okuläre Antigene als Grundlage einer diagnostischen Analyse verwendet werden, bevor sich die ersten klinischen Zeichen einer Glaukomerkrankung zeigen.

Abstract

Glaucoma is one of the most common causes of irreversible blindness worldwide. The pathogenesis of the disease is not fully understood. Elevated intraocular pressure is still considered to be one of the most important risk factors, but cannot explain all cases of glaucoma disease. The involvement of autoimmune mechanisms may play an important role in the pathogenesis of glaucoma. Evidence to support this theory has been shown by our group in previous studies: glaucoma patients were found to develop antibody alterations against specific retina and optic nerve proteins. In the experimental autoimmune glaucoma model, we demonstrated that an immunisation with these proteins causes retinal ganglion cell loss in an autoimmune context. In spite of these results, it is still unclear whether the changes in antibody patterns have a causal connection with glaucoma development or are merely an epiphenomena of the disease. However, these changes in the natural autoimmunity offer a new approach to gain deeper insight into glaucoma pathophysiology and to develop a diagnostic approach for early diagnosis.

Schlüsselwörter

Glaukom - Autoimmunität - Proteomics - natürliche Autoimmunität - Autoantikörper

Key words

glaucoma - autoimmunity - proteomics - natural autoimmunity - autoantibodies

Literatur

  • 1 Pfeiffer N, Krieglstein G K, Wellek S. Knowledge about glaucoma in the unselected population: a German survey.  J Glaucoma. 2002;  11 (5) 458-463
    Google Scholar
  • 2 Sommer A et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey.  Arch Ophthalmol. 1991;  109 (8) 1090-1095
    Google Scholar
  • 3 Quigley H A. Open-angle glaucoma.  N Engl J Med. 1993;  328 (15) 1097-1106
    Google Scholar
  • 4 Pfeiffer N. Glaukom und okuläre Hypertension: Grundlagen – Diagnostik – Therapie; 23 Tabellen. 2. ed. Stuttgart: Thieme; 2005. 2. ed.: 86
    Google Scholar
  • 5 EUGS .Terminology and Guidelines for Glaucoma, European Glaucoma Society. 2003 . : Introduction chapter.
    Google Scholar
  • 6 Quigley H A, Broman A T. The number of people with glaucoma worldwide in 2010 and 2020.  Br J Ophthalmol. 2006;  90 (3) 262-267
    Google Scholar
  • 7 World Health Organization .Blindness and Visual Disability Fact Sheet N° 282. Genf: World Health Organization; 2004
    Google Scholar
  • 8 Guo L, Cordeiro M F. Assessment of neuroprotection in the retina with DARC.  Prog Brain Res. 2008;  173 437-450
    Google Scholar
  • 9 Flammer J, Orgul S. Optic nerve blood-flow abnormalities in glaucoma.  Prog Retin Eye Res. 1998;  17 (2) 267-289
    Google Scholar
  • 10 Flammer J et al. The impact of ocular blood flow in glaucoma.  Prog Retin Eye Res. 2002;  21 (4) 359-393
    Google Scholar
  • 11 Galang N, Sasaki H, Maulik N. Apoptotic cell death during ischemia/reperfusion and its attenuation by antioxidant therapy.  Toxicology. 2000;  148 (2 – 3) 111-118
    Google Scholar
  • 12 Vrabec J P, Levin L A. The neurobiology of cell death in glaucoma.  Eye. 2007;  21 (Suppl 1) S11-S14
    Google Scholar
  • 13 Inman D M, Horner P J. Reactive nonproliferative gliosis predominates in a chronic mouse model of glaucoma.  Glia. 2007;  55 (9) 942-953
    Google Scholar
  • 14 Tanihara H et al. Up-regulation of glial fibrillary acidic protein in the retina of primate eyes with experimental glaucoma.  Arch Ophthalmol. 1997;  115 (6) 752-756
    Google Scholar
  • 15 Tezel G et al. Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma.  Invest Ophthalmol Vis Sci. 2003;  44 (7) 3025-3033
    Google Scholar
  • 16 Lipton S A, Rosenberg P A. Excitatory amino acids as a final common pathway for neurologic disorders.  N Engl J Med. 1994;  330 (9) 613-622
    Google Scholar
  • 17 Dreyer E B et al. Elevated glutamate levels in the vitreous body of humans and monkeys with glaucoma.  Arch Ophthalmol. 1996;  114 (3) 299-305
    Google Scholar
  • 18 Grus F H et al. Autoimmunity and glaucoma.  J Glaucoma. 2008;  17 (1) 79-84
    Google Scholar
  • 19 Wax M B. The case for autoimmunity in glaucoma.  Exp Eye Res. 2010; [Epub ahead of print]
    Google Scholar
  • 20 Grus F, Sun D. Immunological mechanisms in glaucoma.  Semin Immunopathol. 2008;  30 (2) 121-126
    Google Scholar
  • 21 Wax M B, Barrett D A, Pestronk A. Increased incidence of paraproteinemia and autoantibodies in patients with normal-pressure glaucoma.  Am J Ophthalmol. 1994;  117 (5) 561-568
    Google Scholar
  • 22 Wax M B et al. Anti-Ro/SS-A positivity and heat shock protein antibodies in patients with normal-pressure glaucoma.  Am J Ophthalmol. 1998;  125 (2) 145-157
    Google Scholar
  • 23 Joachim S C et al. IgG antibody patterns in aqueous humor of patients with primary open angle glaucoma and pseudoexfoliation glaucoma.  Mol Vis. 2007;  13 1573-1579
    Google Scholar
  • 24 Grus F H et al. Serum autoantibodies to alpha-fodrin are present in glaucoma patients from Germany and the United States.  Invest Ophthalmol Vis Sci. 2006;  47 (3) 968-976
    Google Scholar
  • 25 Li W H et al. Proteomics-based identification of autoantibodies in the sera of healthy Chinese individuals from Beijing.  Proteomics. 2006;  6 (17) 4781-4789
    Google Scholar
  • 26 Avrameas S. Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi seauton’.  Immunol Today. 1991;  12 (5) 154-159
    Google Scholar
  • 27 Grus F H et al. Complex autoantibody repertoires in patients with glaucoma.  Mol Vis. 2004;  10 132-137
    Google Scholar
  • 28 Joachim S C et al. 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. 2007;  32 (6) 501-509
    Google Scholar
  • 29 Joachim S C et al. Sera of glaucoma patients show autoantibodies against myelin basic protein and complex autoantibody profiles against human optic nerve antigens.  Graefes Arch Clin Exp Ophthalmol. 2008;  246 (4) 573-580
    Google Scholar
  • 30 Tezel G, Edward D P, Wax M B. Serum autoantibodies to optic nerve head glycosaminoglycans in patients with glaucoma.  Arch Ophthalmol. 1999;  117 (7) 917-924
    Google Scholar
  • 31 Maruyama I, Ohguro H, Ikeda Y. Retinal ganglion cells recognized by serum autoantibody against gamma-enolase found in glaucoma patients.  Invest Ophthalmol Vis Sci. 2000;  41 (7) 1657-1665
    Google Scholar
  • 32 Ikeda Y et al. Clinical significance of serum antibody against neuron-specific enolase in glaucoma patients.  Jpn J Ophthalmol. 2002;  46 (1) 13-17
    Google Scholar
  • 33 Yang J et al. Serum autoantibody against glutathione S-transferase in patients with glaucoma.  Invest Ophthalmol Vis Sci. 2001;  42 (6) 1273-1276
    Google Scholar
  • 34 Paterson P Y et al. Endogenous myelin basic protein-serum factors (MBP-SFs) and anti-MBP antibodies in humans. Occurrence in sera of clinically well subjects and patients with multiple sclerosis.  J Neurol Sci. 1981;  52 (1) 37-51
    Google Scholar
  • 35 Warren K G, Catz I. Relative frequency of autoantibodies to myelin basic protein and proteolipid protein in optic neuritis and multiple sclerosis cerebrospinal fluid.  J Neurol Sci. 1994;  121 (1) 66-73
    Google Scholar
  • 36 Ponomarenko N A et al. Catalytic activity of autoantibodies toward myelin basic protein correlates with the scores on the multiple sclerosis expanded disability status scale.  Immunol Lett. 2006;  103 (1) 45-50
    Google Scholar
  • 37 Poletaev A, Osipenko L. General network of natural autoantibodies as immunological homunculus (Immunculus).  Autoimmun Rev. 2003;  2 (5) 264-271
    Google Scholar
  • 38 Tezel G, Wax M B. The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells.  J Neurosci. 2000;  20 (10) 3552-3562
    Google Scholar
  • 39 Maruyama I et al. Autoantibody against neuron-specific enolase found in glaucoma patients causes retinal dysfunction in vivo.  Jpn J Ophthalmol. 2002;  46 (1) 1-12
    Google Scholar
  • 40 Romano C et al. Epitope mapping of anti-rhodopsin antibodies from patients with normal pressure glaucoma.  Invest Ophthalmol Vis Sci. 1999;  40 (6) 1275-1280
    Google Scholar
  • 41 Wax M B et al. Induced Autoimmunity to Heat Shock Proteins Elicits Glaucomatous Loss of Retinal Ganglion Cell Neurons via activated T-cell-derived fas-ligand.  J Neurosci. 2008;  28 (46) 12085-12096
    Google Scholar
  • 42 Wax M B et al. A Model of Experimental Autoimmune Glaucoma in Rats Elicited by Immunization With Heat Shock Protein27.  Invest Ophthalmol Vis Sci. 2002;  43 (12) 2884
    Google Scholar
  • 43 Joachim S C et al. Complex Antibody Profile Changes in an Experimental Autoimmune Glaucoma Animal Model.  Invest Ophthalmol Vis Sci. 2009;  50 (10) 4734-4742
    Google Scholar
  • 44 Joachim S C et al. Enhanced characterization of serum autoantibody reactivity following HSP 60 immunization in a rat model of experimental autoimmune glaucoma.  Curr Eye Res. 2010;  35 (10) 900-908
    Google Scholar
  • 45 Gramlich O W et al. Ophthalmopathology in rats with MBP-induced experimental autoimmune encephalomyelitis.  Graefes Arch Clin Exp Ophthalmol. 2011;  [Epub ahead of print]
    Google Scholar
  • 46 Acarin L et al. Glial expression of small heat shock proteins following an excitotoxic lesion in the immature rat brain.  Glia. 2002;  38 (1) 1-14
    Google Scholar
  • 47 Sanz O et al. Expression of 27 kDa heat shock protein (Hsp27) in immature rat brain after a cortical aspiration lesion.  Glia. 2001;  36 (3) 259-270
    Google Scholar
  • 48 Jeon G S et al. Glial expression of the 90-kDa heat shock protein (HSP90) and the 94-kDa glucose-regulated protein (GRP94) following an excitotoxic lesion in the mouse hippocampus.  Glia. 2004;  48 (3) 250-258
    Google Scholar
  • 49 Villapol S et al. Survivin and heat shock protein 25 / 27 colocalize with cleaved caspase-3 in surviving reactive astrocytes following excitotoxicity to the immature brain.  Neuroscience. 2008;  153 (1) 108-119
    Google Scholar
  • 50 Pandey P et al. Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3.  Oncogene. 2000;  19 (16) 1975-1981
    Google Scholar
  • 51 Paul C et al. Dynamic processes that reflect anti-apoptotic strategies set up by HspB1 (Hsp27).  Exp Cell Res. 2010;  316 (9) 1535-1552
    Google Scholar
  • 52 Boltz-Nitulescu G, Bazin H, Spiegelberg H L. Specificity of fc receptors for IgG2a, IgG1 /IgG2b, and IgE on rat macrophages.  J Exp Med. 1981;  154 (2) 374-384
    Google Scholar
  • 53 Marta C B, Bansal R, Pfeiffer S E. Microglial Fc receptors mediate physiological changes resulting from antibody cross-linking of myelin oligodendrocyte glycoprotein.  J Neuroimmunol. 2008;  196 (1 – 2) 35-40
    Google Scholar
  • 54 Sutter A, Hekmat A, Luckenbach G A. Antibody-mediated tumor cytotoxicity of microglia.  Pathobiology. 1991;  59 (4) 254-258
    Google Scholar
  • 55 Ulvestad E et al. Fc receptors for IgG on cultured human microglia mediate cytotoxicity and phagocytosis of antibody-coated targets.  J Neuropathol Exp Neurol. 1994;  53 (1) 27-36
    Google Scholar
  • 56 Kim S U, Vellis de J. Microglia in health and disease.  J Neurosci Res. 2005;  81 (3) 302-313
    Google Scholar
  • 57 Badie B et al. Expression of Fas ligand by microglia: possible role in glioma immune evasion.  J Neuroimmunol. 2001;  120 (1 – 2) 19-24
    Google Scholar
  • 58 Salvesen G S. Caspases and apoptosis.  Essays Biochem. 2002;  38 9-19
    Google Scholar
  • 59 Hughes W F. Quantitation of ischemic damage in the rat retina.  Exp Eye Res. 1991;  53 (5) 573-582
    Google Scholar
  • 60 Adachi M et al. High intraocular pressure-induced ischemia and reperfusion injury in the optic nerve and retina in rats.  Graefes Arch Clin Exp Ophthalmol. 1996;  234 (7) 445-451
    Google Scholar
  • 61 Grozdanic S D et al. Functional characterization of retina and optic nerve after acute ocular ischemia in rats.  Invest Ophthalmol Vis Sci. 2003;  44 (6) 2597-2605
    Google Scholar
  • 62 Prasad S S et al. Retinal gene expression after central retinal artery ligation: effects of ischemia and reperfusion.  Invest Ophthalmol Vis Sci. 2010;  51 (12) 6207-6219
    Google Scholar
  • 63 Joachim S et al. Up-regulation of antibody response to heat shock proteins and tissue antigens in an ocular ischemia model.  Invest Ophthalmol Vis Sci. 2011;  [Epub ahead of print]
    Google Scholar
  • 64 Scofield R H. Autoantibodies as predictors of disease.  Lancet. 2004;  363 (9420) 1544-1546
    Google Scholar
  • 65 Shmerling R H. Autoantibodies in systemic lupus erythematosus – there before you know it.  N Engl J Med. 2003;  349 (16) 1499-1500
    Google Scholar

PD Dr. Franz H. Grus

Universitäts-Augenklinik, Experimentelle Ophthalmologie

55101 Mainz

Telefon: ++ 49/61 31/17 33 28

eMail: grus@eye-research.org