Immunmechanismen bei Netzhautdegeneration

Zusammenfassung

Die progrediente Zelldegeneration in der Retina ist die gemeinsame Endstrecke aller erblich bedingten Netzhautdystrophien. Komplex genetische und metabolisch begünstigte Netzhautdegenerationen wie die altersabhängige Makuladegeneration werden ebenfalls maßgeblich durch apoptotische Prozesse bestimmt. Umfangreiche Untersuchungen an verschiedensten Tiermodellen dieser Erkrankungen weisen auf die frühzeitige und meist chronische Aktivierung des angeborenen Immunsystems als gemeinsamen Effektormechanismus hin. Die Komplementkaskade als humorale Säule und Mikrogliazellen als Phagozyten stellen dabei besonders sensible Sensoren und potente Effektoren der retinalen Immunantwort dar. Neben der genetischen Prädisposition beeinflussen verschiedenste individuelle Faktoren wie das Alter oder die Ernährung die Immunhomöostase der Netzhaut. Aufgrund der effektiven Funktionsweise des innaten Immunsystems kann eine lokale chronische Entzündung die Netzhautdegeneration auf verschiedenste Weise perpetuieren. Dieser Artikel fasst den Stand der aktuellen Literatur zur Rolle des angeborenen Immunsystems bei Netzhautdegenerationen zusammen. Er fokussiert dabei besonders auf Hinweise aus Humanstudien und stellt einen Zusammenhang zwischen der Aktivierung des Komplementsystems und der Funktion von Mikroglia in der degenerierenden Netzhaut dar. Daraus abgeleitete Konzepte beschreiben die Immunpathologie der Netzhaut als neues therapeutisches Ziel für eine Neuroprotektion.

Abstract

Hereditary retinal dystrophies are characterised by a common apoptotic pathway leading to progressive retinal degeneration. Similar degenerative processes are evident in multifactorial and complex retinal disorders including age-related macular degeneration. To understand early triggers of these mechanisms, genetic and experimental mouse models have been developed that mimic various forms of human retinal degeneration. In most of these models, early chronic activation of the innate immune system has been documented. This process mainly involves the complement cascade as humoral component and microglial cells as sensors and effectors of the retinal immune response. Current evidence suggests that the genetic predisposition and individual factors like age or diet critically influence the immune homeostasis in the retina. Based on their effectiveness, innate immune mechanisms are thought to support or even provoke retinal degeneration. This review article summarises recent progress in understanding the role of innate immunity in retinal degenerative diseases. We especially focus on human studies and attempt to provide a link between activation of the complement system and microglial function. Moreover, concepts are presented that highlight the retinal immunopathology as potential therapeutic target to prevent vision loss.

Schlüsselwörter

Genetik - Retina - Mikroglia - Komplementsystem - Netzhautdegeneration

Key words

genetics - retina - microglia - complement system - retinal degeneration

• Literatur

• 1 Wright AF, Chakarova CF, Abd El-Aziz MM et al. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nature reviews Genetics 2010; 11: 273-284
• 2 Cottet S, Schorderet DF. Mechanisms of apoptosis in retinitis pigmentosa. Current molecular medicine 2009; 9: 375-383
• 3 Dunaief JL, Dentchev T, Ying GS et al. The role of apoptosis in age-related macular degeneration. Archives of ophthalmology 2002; 120: 1435-1442
• 4 Barber AJ, Gardner TW, Abcouwer SF. The significance of vascular and neural apoptosis to the pathology of diabetic retinopathy. Investigative ophthalmology & visual science 2011; 52: 1156-1163
• 5 Chang GQ, Hao Y, Wong F. Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice. Neuron 1993; 11: 595-605
• 6 Langmann T. Microglia activation in retinal degeneration. JLeukocBiol 2007; 81: 1345-1351
• 7 Xu H, Chen M, Forrester JV. Para-inflammation in the aging retina. Progress in retinal and eye research 2009; 28: 348-368
• 8 Karlstetter M, Ebert S, Langmann T. Microglia in the healthy and degenerating retina: insights from novel mouse models. Immunobiology 2010; 215: 685-691
• 9 Perry VH, Hume DA, Gordon S. Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 1985; 15: 313-326
• 10 Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 2010; 58: 253-263
• 11 Damani MR, Zhao L, Fontainhas AM et al. Age-related alterations in the dynamic behavior of microglia. Aging cell 2011; 10: 263-276
• 12 Dowling JE, Sidman RL. Inherited retinal dystrophy in the rat. The Journal of cell biology 1962; 14: 73-109
• 13 Essner E, Gorrin G. An electron microscopic study of macrophages in rats with inherited retinal dystrophy. Investigative ophthalmology & visual science 1979; 18: 11-25
• 14 D’Cruz PM, Yasumura D, Weir J et al. Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Human molecular genetics 2000; 9: 645-651
• 15 Gal A, Li Y, Thompson DA et al. Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa. Nature genetics 2000; 26: 270-271
• 16 Thanos S. Sick photoreceptors attract activated microglia from the ganglion cell layer: a model to study the inflammatory cascades in rats with inherited retinal dystrophy. Brain Res 1992; 588: 21-28
• 17 Penfold PL, Killingsworth MC, Sarks SH. Senile macular degeneration: the involvement of immunocompetent cells. Graefe’s archive for clinical and experimental ophthalmology 1985; 223: 69-76
• 18 Garcia-Calderon PA, Engel P, Cols N et al. Immune complexes in retinitis pigmentosa. Ophthalmic paediatrics and genetics 1984; 4: 199-202
• 19 Penfold P, Killingsworth M, Sarks S. An ultrastructural study of the role of leucocytes and fibroblasts in the breakdown of Bruch’s membrane. Australian journal of ophthalmology 1984; 12: 23-31
• 20 Hooks JJ, Detrick-Hooks B, Geis S et al. Retinitis pigmentosa associated with a defect in the production of interferon-gamma. American journal of ophthalmology 1983; 96: 755-758
• 21 Gupta N, Brown KE, Milam AH. Activated microglia in human retinitis pigmentosa, late-onset retinal degeneration, and age-related macular degeneration. ExpEye Res 2003; 76: 463-471
• 22 Newsome DA, Quinn TC, Hess AD et al. Cellular immune status in retinitis pigmentosa. Ophthalmology 1988; 95: 1696-1703
• 23 Grus F, Sun D. Immunological mechanisms in glaucoma. Seminars in immunopathology 2008; 30: 121-126
• 24 Tezel G, Wax MB. Glial modulation of retinal ganglion cell death in glaucoma. Journal of glaucoma 2003; 12: 63-68
• 25 Tezel G, Wax MB. The immune system and glaucoma. Current opinion in ophthalmology 2004; 15: 80-84
• 26 Tezel G, Chauhan BC, LeBlanc RP et al. Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma. Investigative ophthalmology & visual science 2003; 44: 3025-3033
• 27 Yuan L, Neufeld AH. Activated microglia in the human glaucomatous optic nerve head. Journal of neuroscience research 2001; 64: 523-532
• 28 Howell GR, Macalinao DG, Sousa GL et al. Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. The Journal of clinical investigation 2011; 121: 1429-1444
• 29 Fan W, Li X, Wang W et al. Early Involvement of Immune/Inflammatory Response Genes in Retinal Degeneration in DBA/2J Mice. Ophthalmology and eye diseases 2010; 1: 23-41
• 30 Anderson DH, Radeke MJ, Gallo NB et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Progress in retinal and eye research 2010; 29: 95-112
• 31 Mullins RF, Russell SR, Anderson DH et al. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. Faseb J 2000; 14: 835-846
• 32 Johnson LV, Leitner WP, Staples MK et al. Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Experimental eye research 2001; 73: 887-896
• 33 Klein RJ, Zeiss C, Chew EY et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385-389
• 34 Edwards AO, Ritter III R et al. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421-424
• 35 Hageman GS, Anderson DH, Johnson LV 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
• 36 Haines JL, Hauser MA, Schmidt S et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419-421
• 37 Bradley DT, Zipfel PF, Hughes AE. Complement in age-related macular degeneration: a focus on function. Eye 2011; 25: 683-693
• 38 Skerka C, Lauer N, Weinberger AA et al. Defective complement control of factor H (Y402H) and FHL-1 in age-related macular degeneration. Molecular immunology 2007; 44: 3398-3406
• 39 Zipfel PF. Complement and immune defense: from innate immunity to human diseases. Immunology letters 2009; 126: 1-7
• 40 Luo C, Chen M, Xu H. Complement gene expression and regulation in mouse retina and retinal pigment epithelium/choroid. Molecular vision 2011; 17: 1588-1597
• 41 Zamiri P, Sugita S, Streilein JW. Immunosuppressive properties of the pigmented epithelial cells and the subretinal space. Chemical immunology and allergy 2007; 92: 86-93
• 42 Ma W, Zhao L, Fontainhas AM et al. Microglia in the mouse retina alter the structure and function of retinal pigmented epithelial cells: a potential cellular interaction relevant to AMD. PloS one 2009; 4: e7945
• 43 Collier RJ, Wang Y, Smith SS et al. Complement Deposition and Microglial Activation in the Outer Retina in Light-Induced Retinopathy: Inhibition by a 5-HT1A Agonist. Investigative ophthalmology & visual science 2011; 52: 8108-8116
• 44 Weismann D, Hartvigsen K, Lauer N et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 2011; 478: 76-81
• 45 Takizawa F, Tsuji S, Nagasawa S. Enhancement of macrophage phagocytosis upon iC3b deposition on apoptotic cells. FEBS letters 1996; 397: 269-272
• 46 Amarilyo G, Verbovetski I, Atallah M et al. iC3b-opsonized apoptotic cells mediate a distinct anti-inflammatory response and transcriptional NF-kappaB-dependent blockade. European journal of immunology 2010; 40: 699-709
• 47 Lauer N, Mihlan M, Hartmann A et al. Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-h his402 risk variant. J Immunol 2011; 187: 4374-4383
• 48 Scholl HP, Charbel IssaP, Walier M et al. Systemic complement activation in age-related macular degeneration. PloS one 2008; 3: e2593
• 49 Hecker LA, Edwards AO, Ryu E et al. Genetic control of the alternative pathway of complement in humans and age-related macular degeneration. Human molecular genetics 2010; 19: 209-215
• 50 Telander DG. Inflammation and age-related macular degeneration (AMD). Seminars in ophthalmology 2011; 26: 192-197
• 51 Ebert S, Weigelt K, Walczak Y et al. Docosahexaenoic acid attenuates microglial activation and delays early retinal degeneration. Journal of neurochemistry 2009; 110: 1863-1875
• 52 Zhao L, Ma W, Fariss RN et al. Minocycline attenuates photoreceptor degeneration in a mouse model of subretinal hemorrhage microglial: inhibition as a potential therapeutic strategy. The American journal of pathology 2011; 179: 1265-1277