- Research article
- Open Access
- Open Peer Review
Prevalence of anti-retinal autoantibodies in different stages of Age-related macular degeneration
© Adamus et al.; licensee BioMed Central Ltd. 2014
- Received: 27 June 2014
- Accepted: 18 November 2014
- Published: 8 December 2014
Age-related macular degeneration (AMD) is the leading cause of central vision loss in older adults. Anti-retinal autoantibodies (AAbs) have been found in individuals with AMD. The goal of the study was to determine the AAb specificity in different stages of AMD, and determine whether there is a prevalent AAb signature.
Sera of 134 participants in the Age-related Eye Disease Study were analyzed for anti-retinal AAbs by western blotting. The subjects were classified by diagnostic subgroups based upon their clinical classification: No AMD, Intermediate AMD, and Late AMD - geographic atrophy (GA) and Late AMD - neovascular (NV).
The presence of anti-retinal AAb was detected in 58% patients with Intermediate and Late AMD, and 54% of those with no AMD. AAbs bound to fifteen different retinal antigens. Most individuals had 1 specific AAbs (67%), with the remainder having 2 to 4 different AAbs. Over 40% of patients with Intermediate AMD, and 46% of those with GA had anti-enolase AAbs, compared with 29% of individuals with NV and 29% with no AMD. Different AAbs signatures related to NV as compared to GA and/or Intermediate AMD were distinguished. Anti-40-kDa (10%) and 42-kDa (16%) autoantibodies were associated with Intermediate AMD, while anti-30-kDa AAbs (23%) were primarily present in GA. Anti-32-kDa (12%), 35-kDa (21%), and 60-kDa (8%) AAbs were more frequent in NV AMD.
A unique AAb pattern for each of the disease subgroups was present when AMD progressed from the intermediate to the late forms of severity. Differences in the frequency of specific AAbs between AMD subgroups suggested that they may participate in pathogenicity of AMD. Further studies are necessary to confirm these observations in the larger cohort and individual AMD patients over time.
- Age-related macular degeneration
- Antibody signature
Age-related macular degeneration (AMD) is the leading cause of central vision loss in older adults [1, 2]. The etiology of AMD appears to be diverse, including age, genetic predisposition, diet, smoking, and other environmental risk factors [3, 4]. Considerable evidence supports a strong role for local inflammation including the accumulation of macrophages, lymphocytes, and mast cells found in association with both forms of late AMD: geographic atrophy (GA) and neovascular AMD [5–9]. Large drusen deposits in the macula (intermediate AMD) generally precede development of the late stages of AMD. The composition of these immunologically active drusen deposits includes proteins, lipids, complement, and other substances that may act as triggers for immune responses in the eye [7, 10]. In addition, the activation of complement factors and secondary mediators of inflammation such as cytokines and chemokines has been demonstrated in serum from AMD patients [3, 11–13]. These findings suggest the possible involvement of IL-22 and IL-17 in the inflammation that contributes to pathogenicity of AMD, and C5a may be one of the factors contributing to the elevated serum levels in AMD patients [14, 15].
There is increasing evidence for the presence of anti-retinal autoantibodies (AAbs) in association with AMD, although it is unclear whether such AAbs play an active role in the etiology of disease or if they are generated in a response to retinal injury from the underlying disease processes [16–21]. It is possible that both the generation of AAbs as well as the activation of complement could be responses to retinal damage/degradation [21–23]. Nevertheless, recent studies have demonstrated the presence of various AAbs in individuals with AMD, including anti-aldolase C, anti-pyruvate kinase isoform M2, anti-retinaldehyde binding protein 1, and anti-retinol binding protein 3 [16, 17, 20, 24]. The detection of AAbs could conceivably be important in subtyping the disease with specific antibody signatures (multiple antibody arrays), eventually helping define pathogenesis and optimum therapy. The goal of our study was to determine the AAb specificity in different stages of AMD, and prevalence of AAb signatures in relation to AMD severity.
Sera of 134 participants in the Age-related Eye Disease Study (AREDS) were selected for analysis. Detailed demographic and clinical information was obtained before blood samples were collected. Informed consent to participate in the Age-related Eye Disease Study was obtained from all participants. The study was approved by the Oregon Health and Science University Institutional Review Board (IRB#2421) and was conformed to the provisions of the Declaration of Helsinki.
Association of autoantibodies against retinal proteins with different stages of AMD
Stage of AMD
Number of subjects
Presence of AAbs seropositive/group
No AMD (Control group) None or small drusen
Intermediate AMD Large drusen in one or both eyes (drusen 125 μm or greater)
Late AMD Total (NV, GA, and Both)
Both: neovascular and geographic atrophy
Testing for anti-retinal autoantibodies
Western blotting was performed using retinal proteins extracted from a donor human retina with 1% octyl glucoside in phosphate/saline buffer (PBS), pH 7.2, and separated by gel electrophoresis as described previously . Briefly, after separation by SDS-gel electrophoresis on a 10% gel (Bio-Rad) the proteins were transferred to an Immobilon membrane (Millipore). Next, individual strips containing retinal proteins were blocked with a buffer containing 10% normal goat serum and 1% bovine serum albumin in PBS for one hour followed by the incubation with 1:100 diluted serum for 1 hour. Secondary anti-human IgG (H and L chain) antibodies conjugated to alkaline phosphatase (Invitrogen) were added for another hour. Then color reaction was developed by adding the phosphatase substrate until dark bands appeared in positive controls (anti-recoverin and anti-enolase antibodies). A negative control strip was not incubated with primary antibodies.
GraphPad Prism software (San Diego, CA) was used for statistical analysis. Statistical analyses were performed using one-way analysis of variance or Student’s t test. P <0.05 was considered as statistically significant. Fisher’s exact test was employed to evaluate differences in autoantibody frequency between groups. Differences between groups were evaluated using one-way ANOVA.
Prevalence of autoantibodies in AMD subgroups
Seropositivity associated with different stages of AMD and control group
Patients seropositive for a single antigen
35 k (12%)
68 k (16%)
46 k (28%)
40 k (10%)
42 k (16%)
46 k (41%)
Late AMD - Geographic Atrophy
30 k (23%)
46 k (46%)
Late AMD - Neovascular AMD
32 k (13%)
35 k (21%)
46 k (29%)
60 k (8%)
Late AMD - Both GA + NV
Association of autoantibodies with smoking and arthritis in AMD
The etiology of AMD is complex and includes genetic risk factors, environmental factors, age, and immune and autoimmune causes . Several potential immune mediators are known to play a role in the pathogenic process of AMD, such as infiltration of macrophages, presence of cytokines/chemokines, T-lymphocytes, as well as formation of autoantibodies [1, 5]. Our studies demonstrated a complex pattern of AAbs against several retinal proteins in individuals with AMD with fairly constant presence over the severity spectrum of the disease. We also identified AAbs that could be markers of disease activity (Figures 3 and 4). We believe that early generation of anti-retinal AAbs may create an environment that promotes cell loss, angiogenesis, and progression to late stages of AMD . Since in autoimmune diseases, the immune response is itself part of the disease process, it is possible that the consistent presence of AAbs suggests their contribution to pathogenic processes through the availability of the antigens from degenerating retina.
Previously published studies showed the association of AAbs with AMD, suggesting a contribution of the immune system to pathogenicity of the disease [7, 17, 19, 32, 33]. Several autoantibodies to retinal antigens have been identified, including anti-glial fibrillary acidic protein (GFAP), anti-α-enolase, and anti-carboxyethylpyrrole (CEP), an oxidized component of drusen [17, 32, 34, 35]. GFAP is a 52-kDa antigen, the main intermediate filament protein in mature astrocytes, that was targeted in 44% of the AMD patients’ population studied ; however, we have not found AAbs against 52-kDa antigen in a measurable level in our cohort. The study examined approximately the same number of patients as our study reported anti-enolase AAbs in 67% of the AMD patients, which are similar to our findings . Other studies showed that AAbs in individuals with neovascular AMD recognized retinol-binding protein 3 (RBP3, 120-kDa), retinol-binding protein 1 (RLBP1, 36-kDa) and aldolase C (39-kDa) . RBP3 is an essential protein for the exchange of retinoid between the RPE and photoreceptors and their survival because it prevents the potentially cytotoxic effects of retinoids. Autoantibodies against RBP3 were detected in 33% (6 of 18) of patients with AMD and also in 24% (11 of 45) of patients with Macular Telangiectasia Type 2 . The authors suggested that the existence of mutual AAbs in MacTel-2 and AMD shared some common etiologic or pathogenic mechanisms for both conditions. RBP3, also known as interphotoreceptor retinoid binding protein (IRBP), is a unique protein to the photoreceptor cells in the retina, which has been found to be highly pathogenic in animals. Immunization of animals with IRBP induced an intraocular inflammatory disease that is primarily mediated by T cells but anti-IRBP antibodies are also present, suggesting their role in inflammation. Moreover, anti-IRBP autoantibodies and T cell have been also found in patients with uveitis, retinitis pigmentosa, and progressive rod-cone degeneration [37–41]. Cellular retinaldehyde-binding protein (CRALBP), transcribed from the RLBP1 gene, is a 36-kDa protein found in the RPE and in retinal Müller cells . Both elevated seroreactivity to RBP3 and RLBP1 in AMD patients suggests that the inflammation, in particular, autoimmunity, is strongly associated with the pathogenesis of the disease . In our cohort, a 35-kDa antigen is likely to be CRALBP although its identity wasn’t confirmed (due to insufficient quantity of samples) if confirmed, these AAbs would be found to be 2 times more frequent in individuals with AMD than in controls. Nonetheless, anti-CRALBP AAbs have been found in uveitis, showing 54% seropositivity in patients with uveitis compared to 17% in normal subjects , they were also detected in patients with cancer-associated retinopathy, CAR (Adamus, unpublished information). Altogether, these findings indicated that anti-IRBP and anti-CRALBP AAbs are not highly specific for AMD individuals.
It is not surprising to find autoantibodies against α-enolase (46-kDa), aldolase C (40-kDa), and pyruvate kinase M2 (60-62-kDa) that previously were found in both neovascular and geographic atrophy AMD [17, 20]. These key enzymes of the glycolytic pathway may promote autoimmunity by acting as autoantigens. α-Enolase, also called non-neuronal enolase, belongs to a family of glycolytic enzymes but also has other cellular functions related to its subcellular localizations that are distinct from its well-established activity in glycolysis [44–46]. Furthermore, differential expression of α-enolase and presence of specific AAbs have been related to several pathologies, such as cancer, Alzheimer’s disease, autoimmune diseases, and rheumatoid arthritis, among others. Antibodies against α-enolase have been strongly associated with CAR [25, 47–49]. Recently, we showed that AAbs against anti-glycolytic enzymes were highly associated with CAR and gynecological cancers . In vitro and in vivo studies showed that anti-enolase AAbs have pathogenic potential in killing retinal cells [51–53]. Generation of AAbs against enolase and other anti-glycolytic enzymes may be a normal process since they can be found in healthy individuals. However, it is possible that excessive production of such autoantibodies can be generated as a consequence of enolase uptake by antigen-presenting cells and subsequent B cell activation, can potentially initiate a tissue injury as a result of immune complex deposition, or an induction of apoptosis leading to the death of retinal cells.
Autoantibodies against CEP, an adduct that develops from an oxidation fragment of docosahexaenoic acid (DHA), are present in plasma and are more abundant in AMD than in controls, suggesting their potential as a biomarker for AMD . Animal studies showed that mice immunized with CEP-modified mouse serum albumin generated anti-CEP antibodies that consequently induced AMD-like lesions in the outer retina, suggesting that autoimmunity was associated with the initiation or progression of AMD . CEP is typically present in photoreceptor rod outer segments, and RPE in the mouse retina, and its reactivity is more intense in photoreceptors of human AMD retina than healthy retina .
In AREDS, persons with either intermediate drusen, extensive small drusen, or the pigment abnormalities associated with AMD were more likely to be female, and more likely to have a history of arthritis . This might suggest an association with chronic inflammatory disease. We found that women with arthritis and intermediate AMD had significantly greater incidence of AAbs than men, suggesting possible sex hormone effects. Changes in sex hormones mainly influence onset of rheumatoid arthritis in older individuals of both sexes . Lower levels of testosterone in men, and early menopause in women, may be signs of premature aging, putting them at greater risk of developing diseases and thus antibodies.
Epidemiologic evidence indicates that smoking cigarettes results in an increased risk of AMD [27, 55]. Smokers of both sexes have an increased risk of developing seropositive rheumatoid arthritis (RA) . For example, in RA, the presence of anti-citrullinated protein antibodies has been described to be specifically associated with smoking. Also, smoking has also been shown to be associated with AAbs in various other autoimmune diseases, such as anti-dsDNA in systemic lupus erythematosus, and anti-Jo1 in idiopathic inflammatory myopathy. There is evidence that citrullinated α-enolase is present in the lungs of smokers . However, the precise mechanisms whereby smoking may trigger immunity to citrullinated α-enolase remain to be elucidated. Gender differences in our cohort were evident in AAb frequencies in never, current, and ever smokers with somewhat surprising results. Women who had never smoked presented with a higher prevalence of anti-retinal AAbs than women who were former smokers, which suggests a possible influence of sex hormones (e.g., estrogens). Estrogen strongly stimulate the immune response  and also can induce AAb levels in persons after quitting smoking . Never-smoking men with AMD were protected from developing anti-retinal AAbs, in contrast to ex-smokers who had higher prevalence of AAbs. Testosterone plays an important role in the modulation of inflammatory processes and may neutralize the adverse changes of immune response . Testosterone is known to promote apoptosis of Th2 cells and development of the Th1 phenotype of cytokine production, which results in suppression of humoral immune response. A fall of testosterone concentration in aging men can influence oxidative modification and the immune response, which is important in the pathogenesis of atherosclerosis.
The role of AAbs in the induction or acceleration of retinal deterioration is uncertain. Our studies showed that AAbs against retinal proteins are apparently different in various AMD severity subgroups. However, the differences in frequency of specific AAbs between AMD subgroups may suggest that they participate in pathogenicity of AMD. Also, different AAbs co-exist in individual patients, possibly creating antibody signatures specific to each stage of AMD. If confirmed by other studies, these elevated levels of specific antibodies may be a useful predictor or biomarker of AMD progression from intermediate to late AMD. On the other hand, it is reasonable to suggest that the high frequency of AAbs in persons with AMD as well as healthy individuals is a consequence of this progressive ‘aging’ of the immune system. However, pathogenic AAbs that can be detected in peripheral blood years before the destruction of retinal cells may lead to obvious clinical symptoms. Regardless of their role, AAbs may be useful as biomarkers and we presented a few possible candidates for each stage of AMD progression even though we could not provide the identity of the targeted antigens (except enolase). This was a limitation of this research because insufficient serum amounts did not allow for full identification of these retinal antigens. Further studies are necessary to confirm our results in the larger cohort of patients with AMD, and also to examine individual patients over the progression of their macular disease, and to identify the targeted antigens.
This work was supported in part by the National Eye Institute grants EY13053 (GA) and EY021532 (MK), the Macular Degeneration Center Research Fund (MK), core grant P30EY010572 and unrestricted grant to Casey Eye Institute from the Foundation to Prevent Blindness.
- Whitcup SM, Sodhi A, Atkinson JP, Holers VM, Sinha D, Rohrer B, Dick AD: The role of the immune response in Age-related macular degeneration. Inter J Inflamm. 2013, 2013: 10-Google Scholar
- Kokotas H, Grigoriadou M, Petersen MB: Age-related macular degeneration: genetic and clinical findings. Clin Chem Lab Med. 2010, 49 (4): 601-616.PubMedGoogle Scholar
- Telender D: Inflammation and Age-related macular degeneration (AMD). Sem Ophthalmol. 2011, 26 (3): 192-197. 10.3109/08820538.2011.570849.View ArticleGoogle Scholar
- AREDS G: Risk factors associated with age-related macular degeneration: a case–control study in the age-related eye disease study: age-related eye disease study report number 3. Ophthalmol. 2000, 107 (12): 2224-2232.View ArticleGoogle Scholar
- Nussenblatt RB, Ferris F: Age-related macular degeneration and the immune response: implications for therapy. Amer J Ophthalmol. 2007, 144 (4): 618-626. 10.1016/j.ajo.2007.06.025. e612View ArticlePubMedPubMed CentralGoogle Scholar
- Donoso LA, Kim D, Frost A, Callahan A, Hageman G: The role of inflammation in the pathogenesis of Age-related macular degeneration. Surv Ophthalmol. 2006, 51 (2): 137-152. 10.1016/j.survophthal.2005.12.001.View ArticlePubMedPubMed CentralGoogle Scholar
- Buschini E, Piras A, Nuzzi R, Vercelli A: Age related macular degeneration and drusen: neuroinflammation in the retina. Prog Neurobiol. 2011, 95 (1): 14-25. 10.1016/j.pneurobio.2011.05.011.View ArticlePubMedGoogle Scholar
- Cherepanoff S, McMenamin P, Gillies MC, Kettle E, Sarks SH: Bruch’s membrane and choroidal macrophages in early and advanced age-related macular degeneration. Br J Ophthalmol. 2010, 94 (7): 918-925. 10.1136/bjo.2009.165563.View ArticlePubMedGoogle Scholar
- Klein R, Myers CE, Cruickshanks KJ, Gangnon RE, Danforth LG, Sivakumaran TA, Iyengar SK, Tsai MY, Klein BEK: Markers of inflammation, oxidative stress, and endothelial dysfunction and the 20-year cumulative incidence of early age-related macular degeneration: The beaver dam eye study. JAMA Ophthalmol. 2014, 132 (4): 446-455. 10.1001/jamaophthalmol.2013.7671.View ArticlePubMedPubMed CentralGoogle Scholar
- Mullins RF, Russell SR, Anderson DH, Hageman GS: 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 (7): 835-846.PubMedGoogle Scholar
- Morohoshi K, Goodwin AM, Ohbayashi M, Ono SJ: Autoimmunity in retinal degeneration: autoimmune retinopathy and age-related macular degeneration. J Autoimmun. 2009, 33 (3–4): 247-254.View ArticlePubMedGoogle Scholar
- Raoul W, Auvynet C, Camelo S, Guillonneau X, Feumi C, Combadière C, Sennlaub F: CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axes and their possible involvement in age-related macular degeneration. J Neuroinflamm. 2010, 7: 87-10.1186/1742-2094-7-87.View ArticleGoogle Scholar
- Grunin M, Burstyn-Cohen T, Hagbi-Levi S, Peled A, Chowers I: Chemokine receptor expression in peripheral blood monocytes from patients with neovascular Age-related macular degeneration. Inves Ophthalmol Vis Sci. 2012, 53 (9): 5292-5300. 10.1167/iovs.11-9165.View ArticleGoogle Scholar
- Liu B, Wei L, Meyerle C, Tuo J, Sen HN, Li Z, Chakrabarty S, Agron E, Chan CC, Klein ML, Chew E, Ferris F, Nussenblatt RB: Complement component C5a promotes expression of IL-22 and IL-17 from human T cells and its implication in age-related macular degeneration. J Transl Med. 2011, 9: 1-12. 10.1186/1479-5876-9-1.View ArticlePubMedGoogle Scholar
- Bradley DT, Zipfel PF, Hughes AE: Complement in age-related macular degeneration: a focus on function. Eye. 2011, 25 (6): 683-693. 10.1038/eye.2011.37.View ArticlePubMedPubMed CentralGoogle Scholar
- Cherepanoff S, Mitchell P, Wang JJ, Gillies MC: Retinal autoantibody profile in early age-related macular degeneration: preliminary findings from the blue mountains Eye study. Clin Exp Ophthalmol. 2006, 34 (6): 590-595. 10.1111/j.1442-9071.2006.01281.x.View ArticleGoogle Scholar
- Joachim SC, Bruns K, Lackner KJ, Pfeiffer N, Grus FH: 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. 2007, 245 (5): 619-626. 10.1007/s00417-006-0429-9.View ArticlePubMedGoogle Scholar
- Gu J, Pauer GJT, Yue X, Narendra U, Sturgill GM, Bena J, Gu X, Peachey NS, Salomon RG, Hagstrom SA, Crabb JW, Genomic C, Group PAS: Assessing susceptibility to Age-related macular degeneration with proteomic and genomic biomarkers. Mol Cell Proteomics. 2009, 8 (6): 1338-1349. 10.1074/mcp.M800453-MCP200.View ArticlePubMedPubMed CentralGoogle Scholar
- Morohoshi K, Patel N, Ohbayashi M, Chong V, Grossniklaus HE, Bird AC, Ono SJ: Serum autoantibody biomarkers for age-related macular degeneration and possible regulators of neovascularization. Exp Mol Pathol. 2012, 92 (1): 64-73. 10.1016/j.yexmp.2011.09.017.View ArticlePubMedGoogle Scholar
- Morohoshi K, Ohbayashi M, Patel N, Chong V, Bird AC, Ono SJ: Identification of anti-retinal antibodies in patients with age-related macular degeneration. Exp Mol Pathol. 2012, 93 (2): 193-199. 10.1016/j.yexmp.2012.03.007.View ArticlePubMedGoogle Scholar
- Dhillon B, Wright AF, Tufail A, Pappworth I, Hayward C, Moore I, Strain L, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Armbrecht A-M, Laude A, Deary IJ, Staniforth SJ, Holmes LV, Goodship THJ, Marchbank KJ: Complement factor H autoantibodies and Age-related macular degeneration. Inves Ophthalmol Vis Sci. 2010, 51 (11): 5858-5863. 10.1167/iovs.09-5124.View ArticleGoogle Scholar
- Penfold PL, Madigan MC, Gillies MC, Provis JM: Immunological and aetiological aspects of macular degeneration. Prog Ret Eye Res. 2001, 20 (3): 385-414. 10.1016/S1350-9462(00)00025-2.View ArticleGoogle Scholar
- Chen M, Forrester JV, Xu H: Synthesis of complement factor H by retinal pigment epithelial cells is down-regulated by oxidized photoreceptor outer segments. Exp Eye Res. 2007, 84 (4): 635-645. 10.1016/j.exer.2006.11.015.View ArticlePubMedGoogle Scholar
- Patel N, Ohbayashi M, Nugent AK, Ramchand K, Toda M, Chau KY, Bunce C, Webster A, Bird AC, Ono SJ, Chong V: Circulating anti-retinal antibodies as immune markers in age-related macular degeneration. Immunol. 2005, 115 (3): 422-430. 10.1111/j.1365-2567.2005.02173.x.View ArticleGoogle Scholar
- Adamus G, Ren G, Weleber RG: Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmol. 2004, 4 (1): 5-10.1186/1471-2415-4-5.View ArticlePubMedPubMed CentralGoogle Scholar
- Menzel EJ, Zlabinger GJ, Dunky A, Steffen C: Autoimmunity and T-cell subpopulations in old age. Arch Gerontol Geriatr. 1988, 7 (4): 249-260. 10.1016/0167-4943(88)90008-8.View ArticlePubMedGoogle Scholar
- Evans JR: Risk factors for Age-related macular degeneration. Prog Ret Eye Res. 2001, 20 (2): 227-253. 10.1016/S1350-9462(00)00023-9.View ArticleGoogle Scholar
- Lee J, Taneja V, Vassallo R: Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dental Res. 2012, 91 (2): 142-149. 10.1177/0022034511421200.View ArticleGoogle Scholar
- Arnson Y, Shoenfeld Y, Amital H: Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun. 2010, 34 (3): J258-J265. 10.1016/j.jaut.2009.12.003.View ArticlePubMedGoogle Scholar
- Ardeljan D, Chan C-C: Aging is not a disease: distinguishing age-related macular degeneration from aging. Prog Ret Eye Res. 2013, 37: 68-89.View ArticleGoogle Scholar
- Kyger M, Worley A, Adamus G: Autoimmune responses against photoreceptor antigens during retinal degeneration and their role in macrophage recruitment into retinas of RCS rats. J Neuroimmunol. 2013, 254 (1–2): 91-100.View ArticlePubMedGoogle Scholar
- Gu X, Meer SG, Miyagi M, Rayborn ME, Hollyfield JG, Crabb JW, Salomon RG: Carboxyethylpyrrole protein adducts and autoantibodies, biomarkers for Age-related macular degeneration. J Biol Chem. 2003, 278 (43): 42027-42035. 10.1074/jbc.M305460200.View ArticlePubMedGoogle Scholar
- Kubicka-Trząska A, Wilańska J, Romanowska-Dixon B, Sanak M: Circulating antiretinal antibodies predict the outcome of anti-VEGF therapy in patients with exudative age-related macular degeneration. Acta Ophthalmol. 2012, 90 (1): e21-e24. 10.1111/j.1755-3768.2011.02237.x.View ArticlePubMedGoogle Scholar
- Hollyfield JG, Bonilha VL, Rayborn ME, Yang X, Shadrach KG, Lu L, Ufret RL, Salomon RG, Perez VL: Oxidative damage-induced inflammation initiates age-related macular degeneration. Nat Med. 2008, 14 (2): 194-198. 10.1038/nm1709.View ArticlePubMedPubMed CentralGoogle Scholar
- Renganathan K, Gu J, Rayborn ME, Crabb JS, Salomon RG, Collier RJ, Kapin MA, Romano C, Hollyfield JG, Crabb JW: CEP biomarkers as potential tools for monitoring therapeutics. PLoS One. 2013, 8 (10): e76325-10.1371/journal.pone.0076325.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhu L, Shen W, Zhu M, Coorey NJ, Nguyen AP, Barthelmes D, Gillies MC: Anti-retinal antibodies in patients with macular telangiectasia type 2. Invest Ophthalmol Vis Sci. 2013, 54 (8): 5675-5683. 10.1167/iovs.13-12050.View ArticlePubMedGoogle Scholar
- Solomon A, Banin E, Anteby I, Benezra D: Retinitis pigmentosa, coats disease and Uveitis. Eur J Ophthalmol. 1999, 9 (3): 202-205.PubMedGoogle Scholar
- Wiggert B, Kutty G, Long KO, Inouye L, Gery I, Chader GJ, Aguirre GD: Interphotoreceptor retinoid-binding protein (IRBP) in progressive rod- cone degeneration (prcd)–biochemical, immunocytochemical and immunologic studies. Exp Eye Res. 1991, 53 (3): 389-398. 10.1016/0014-4835(91)90245-A.View ArticlePubMedGoogle Scholar
- Adamus G, Chan CC: Experimental autoimmune uveitides: multiple antigens, diverse diseases. Int Rev Immunol. 2002, 21 (2–3): 209-229.View ArticlePubMedGoogle Scholar
- Caspi RR: A look at autoimmunity and inflammation in the eye. J Clin Invest. 2010, 120 (9): 3073-3083. 10.1172/JCI42440.View ArticlePubMedPubMed CentralGoogle Scholar
- Heckenlively J, Ferreyra H: Autoimmune retinopathy: a review and summary. Semin Immunopathol. 2008, 30 (2): 127-134. 10.1007/s00281-008-0114-7.View ArticlePubMedGoogle Scholar
- Kennedy BN, Li C, Ortego J, Coca-Prados M, Sarthy VP, Crabb JW: CRALBP transcriptional regulation in ciliary epithelial, retinal Müller and retinal pigment epithelial cells. Exp Eye Res. 2003, 76 (2): 257-260. 10.1016/S0014-4835(02)00308-1.View ArticlePubMedGoogle Scholar
- Deeg CA, Raith AJ, Amann B, Crabb JW, Thurau SR, Hauck SM, Ueffing M, Wildner G, Stangassinger M: CRALBP is a highly prevalent autoantigen for human autoimmune Uveitis. Clin Develop Immunol. 2007, 2007: 39245-View ArticleGoogle Scholar
- Diaz-Ramos A, Roig-Borrellas A, Garcia-Melero A, Lopez-Alemany R: Alpha-enolase, a multifunctional protein: its role on pathophysiological situations. J Biomed Biotechnol. 2012, 2012: 12-View ArticleGoogle Scholar
- J-w K, Dang CV: Multifaceted roles of glycolytic enzymes. Tre Biochem Sci. 2005, 30 (3): 142-150. 10.1016/j.tibs.2005.01.005.View ArticleGoogle Scholar
- Butterfield DA, Lange MLB: Multifunctional roles of enolase in Alzheimer’s disease brain: beyond altered glucose metabolism. J Neurochem. 2009, 111 (4): 915-933. 10.1111/j.1471-4159.2009.06397.x.View ArticlePubMedPubMed CentralGoogle Scholar
- Adamus G, Aptsiauri N, Guy J, Heckenlively J, Flannery J, Hargrave PA: The occurrence of serum autoantibodies against enolase in cancer-associated retinopathy. Cli Immunol Immunopath. 1996, 78: 120-129. 10.1006/clin.1996.0021.View ArticleGoogle Scholar
- Adamus G, Amundson D, Seigel GM, Machnicki M: Anti-enolase alpha autoantibodies in cancer-associated retinopathy: epitope mapping and cytotoxicity on retinal cells. J Autoimmun. 1998, 11: 671-677. 10.1006/jaut.1998.0239.View ArticlePubMedGoogle Scholar
- Adamus G: Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev. 2009, 8 (5): 410-414. 10.1016/j.autrev.2009.01.002.View ArticlePubMedPubMed CentralGoogle Scholar
- Adamus G, Choi D, Raghunath A, Schiffman J: Significance of anti-retinal autoantibodies in cancer-associated retinopathy with gynecological cancers. J Clin Exp Ophthalmol. 2013, 4: 304-View ArticleGoogle Scholar
- Adamus G, Machnicki M: Cytotoxic effect of anti-recoverin and anti-enolase autoantibodies on retinal cells. J Allerg Clin Immunol. 1997, 99: S20-Google Scholar
- Terrier B, Degand N, Guilpain P, Servettaz A, Guillevin L, Mouthon L: Alpha-enolase: a target of antibodies in infectious and autoimmune diseases. Autoimmun Rev. 2007, 6 (3): 176-182. 10.1016/j.autrev.2006.10.004.View ArticlePubMedGoogle Scholar
- Ren G, Adamus G: Cellular targets of anti-alpha-enolase autoantibodies of patients with autoimmune retinopathy. J Autoimmun. 2004, 23 (2): 161-167. 10.1016/j.jaut.2004.06.003.View ArticlePubMedGoogle Scholar
- Pikwer M, Giwercman A, Bergström U, Nilsson J-Å, Jacobsson LTH, Turesson C: Association between testosterone levels and risk of future rheumatoid arthritis in men: a population-based case–control study. Ann Rheum Dis. 2014, 73 (3): 573-579. 10.1136/annrheumdis-2012-202781.View ArticlePubMedGoogle Scholar
- Smith W, Assink J, Klein R, Mitchell P, Klaver CCW, Klein BEK, Hofman A, Jensen S, Wang JJ, de Jong PTVM: Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmol. 2001, 108 (4): 697-704. 10.1016/S0161-6420(00)00580-7.View ArticleGoogle Scholar
- Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, Alfredsson L: Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case–control study, using incident cases. Ann Rheum Dis. 2003, 62 (9): 835-841. 10.1136/ard.62.9.835.View ArticlePubMedPubMed CentralGoogle Scholar
- Mahdi H, Fisher BA, Kallberg H, Plant D, Malmstrom V, Ronnelid J, Charles P, Ding B, Alfredsson L, Padyukov L, Symmons DP, Venables PJ, Klareskog L, Lundberg K: Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet. 2009, 41 (12): 1319-1324. 10.1038/ng.480.View ArticlePubMedGoogle Scholar
- Cutolo M, Straub R: Insights into endocrine-immunological disturbances in autoimmunity and their impact on treatment. ArthrRes Ther. 2009, 11 (2): 218-10.1186/ar2630.View ArticleGoogle Scholar
- Mooney LA, Perera FP, Van Bennekum AM, Blaner WS, Karkoszka J, Covey L, Hsu Y, Cooper TB, Frenkel K: Gender differences in autoantibodies to oxidative DNA base damage in cigarette smokers. Can Epidemiol Biomark Preven. 2001, 10 (6): 641-648.Google Scholar
- Barud W, Palusiński R, Bełtowski J, Wójcicka G: Inverse relationship between total testosterone and anti-oxidized low density lipoprotein antibody levels in ageing males. Atherosclerosis. 2002, 164 (2): 283-288. 10.1016/S0021-9150(02)00069-2.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2415/14/154/prepub
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