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1.  Significance of Anti-retinal Autoantibodies in Cancer-associated Retinopathy with Gynecological Cancers 
Background
The presence of autoantibodies (AAbs) is the primary serological indicator of autoimmunity. Cancer-associated retinopathy (CAR) is associated with AAbs and different types of cancer. The goal of the study was to examine the profile of serum autoantibodies in women with gynecological cancers with and without paraneoplastic visual manifestation.
Methods
Retrospective studies of a cohort of 46 women with symptoms of CAR and gynecological tumors, including endometrial, cervical, ovarian, and fallopian tubes, 111 women with similar tumors without symptoms of CAR, and 60 age-matched healthy controls. Presence of serum AAbs and the identity of targeted antigens were performed by western blotting and their significance was evaluated using an Fisher’s exact test.
Results
The patients with gynecological CAR had the highest proportion of seropositivity (80%), followed by patients with gynecological cancers without CAR (61%) and healthy controls (58%). Differences in recognition frequencies were found for 17 antigens and 5 retinal antigens were frequently targeted: enolase, aldolase C, carbonic anhydrase II, recoverin and GAPDH. The occurrence of anti-glycolytic enzymes was 2-3 times more frequent in CAR and cancer patients than healthy controls. Anti-recoverin AAbs were prevalent in endometrial CAR. Anti-CAII antibodies were not significantly different between groups of women. In this cohort, cancer was diagnosed before the onset of retinopathy with latency from 2 months to 30 years. The discovery of the ovarian and endometrial cancers and manifestation of visual problems often coincided but Fallopian tube carcinoma was found after visual onset.
Conclusion
New retinal targets were identified for gynecological CAR. Each gynecological-CAR has its own autoantibody profile different from non-CAR profile, implying that a complex autoantibody signature may be more predictable for diagnosis than a singular AAb. Specific anti-retinal AAbs were most prevalent in women with CAR but their profiles were not fully distinguished from cancer controls.
doi:10.4172/2155-9570.1000307
PMCID: PMC3963281  PMID: 24672741
Autoantibodies; Autoimmune retinopathy; Cancer; Autoantigen; Antibody profiling; Retina; Paraneoplastic
2.  Autoimmune Responses against Photoreceptor Antigens during Retinal Degeneration and their Role in Macrophage Recruitment into Retinas of RCS Rats 
Journal of neuroimmunology  2012;254(1-2):91-100.
Autoimmunity may contribute to retinal degeneration. The studies examined the evolution of autoimmune responses against retina in naïve dystrophic RCS rats over the course of retinal degeneration. We showed that anti-retinal autoantibodies and T cells are generated in response to the availability of antigenic material released from dying photoreceptor cells during retinal degeneration but with distinctive activation trends. Passive transfer of anti-retinal antibodies enhanced disease progression by disrupting the BRB, upregulating MCP-1, attracting blood macrophages into retina, and augmenting apoptotic photoreceptor cell death. Our findings directly link anti-retinal autoantibodies to activated macrophage entry and their possible role in neurodegeneration.
doi:10.1016/j.jneuroim.2012.10.007
PMCID: PMC3534925  PMID: 23110938
retinal degeneration; passive transfer; autoimmunity; autoantibody; RCS rat; macrophages
3.  Paraneoplastic Vitelliform Retinopathy: Clinicopathologic Correlation and Review of the Literature 
Survey of ophthalmology  2012;57(6):558-564.
Traditionally the paraneoplastic retinopathies have been classified into two groups: melanoma-associated retinopathy (MAR) and cancer-associated retinopathy (CAR). MAR occurs in individuals with metastatic cutaneous or uveal melanoma and is characterized by nyctalopia, photopsias, and variable vision loss. In most cases, the fundus is essentially normal in appearance. More recently, there have been multiple reports of a MAR-like retinopathy with associated detachments of the retinal pigment epithelium (RPE) and neurosensory retina. Such a clinical presentation has been termed paraneoplastic vitelliform retinopathy. In the present report, we describe an 80-year-old male with metastatic cutaneous melanoma who developed paraneoplastic vitelliform retinopathy. For the first time, histopathology from enucleation specimens provides a clinicopathologic disease correlation with focal abnormalities in the inner nuclear and outer plexiform layers.
doi:10.1016/j.survophthal.2012.02.004
PMCID: PMC3470815  PMID: 22784677
paraneoplastic vitelliform retinopathy; melanoma; uveal; cutaneous; MAR; CAR; autoantibodies; retina; autoimmune; retinopathy
4.  Detection of autoantibodies against heat shock proteins and collapsin response mediator proteins in autoimmune retinopathy 
BMC Ophthalmology  2013;13:48.
Background
Autoimmune retinopathy (AR) and Cancer-Associated Retinopathy (CAR) are associated with a diverse repertoire of anti-retinal autoantibodies (AAbs) but not all antigenic targets have been characterized. Identification of new AAbs may help with clinical diagnosis and prognosis of retinal dysfunction in AR. The goal was to identify frequently targeted retinal autoantigens within the 60-70-kDa molecular weight range.
Methods
Human retinal proteins were separated by SDS-PAGE and 2D gel electrophoresis (2-DE) and sera from AR patients with and without cancer were used to identify immunoreactive proteins by Western blotting. Proteins were identified following separation by electrophoresis, Coomassie staining using in-gel trypsin digestion and mass spectrometric analysis. Circulating serum hsp60 and anti-hsp60 antibody levels were determined by quantitative ELISA.
Results
Retrospective evaluation of 819 patients with anti-retinal AAbs showed that 29% patients had AAbs targeted proteins between 60-70-kDa. Shotgun mass spectrometry of human retinal proteins present in 1D-gel found 66 species within this range. To identify the immunoreactive proteins, we performed Western blots of 2-DE gels and showed a group of heat shock proteins (hsps), including hsp60 and CRMP proteins that were frequently recognized by AR patient AAbs, irrespective of cancer status. These results were validated by immunostaining of purified hsp60 and CRMP2 proteins. ELISA results revealed that patients with AR and CAR had significantly increased levels of serum anti-hsp60 antibodies compared to control healthy subjects (p < 0.0001). However, circulating hsp60 protein was not significantly elevated in sera of either patient group.
Conclusions
Different anti-retinal antibodies frequently co-exist in a single patient, creating antibody-arrays related to the syndrome. Hsps and CRMP-2 are newly identified autoantigens in AR. A frequent co-association of anti-hsp antibodies with other anti-retinal AAbs may augment pathogenic processes, leading to retinal degeneration.
doi:10.1186/1471-2415-13-48
PMCID: PMC3851198  PMID: 24066722
Autoantibody; Autoimmune retinopathy; CAR; Retina; Autoantigen; Heat shock proteins; CRMP-2
5.  Serum TRPM1 Autoantibodies from Melanoma Associated Retinopathy Patients Enter Retinal ON-Bipolar Cells and Attenuate the Electroretinogram in Mice 
PLoS ONE  2013;8(8):e69506.
Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous malignant melanoma and the presence of autoantibodies that label neurons in the inner retina. The visual symptoms and electroretinogram (ERG) phenotype characteristic of MAR resemble the congenital visual disease caused by mutations in TRPM1, a cation channel expressed by both melanocytes and retinal bipolar cells. Four serum samples from MAR patients were identified as TRPM1 immunoreactive by 1. Labeling of ON-bipolar cells in TRPM1+/+ but not TRPM1−/− mouse retina, 2. Labeling of TRPM1-transfected CHO cells; and 3. Attenuation of the ERG b-wave following intravitreal injection of TRPM1-positive MAR IgG into wild-type mouse eyes, and the appearance of the IgG in the retinal bipolar cells at the conclusion of the experiment. Furthermore, the epitope targeted by the MAR autoantibodies was localized within the amino-terminal cytoplasmic domain of TRPM1. Incubation of live retinal neurons with TRPM1-positive MAR serum resulted in the selective accumulation of IgG in ON-bipolar cells from TRPM1+/+ mice, but not TRPM1−/− mice, suggesting that the visual deficits in MAR are caused by the uptake of TRPM1 autoantibodies into ON-bipolar cells, where they bind to an intracellular epitope of the channel and reduce the ON-bipolar cell response to light.
doi:10.1371/journal.pone.0069506
PMCID: PMC3731326  PMID: 23936334
6.  Effective Arrestin–Specific Immunotherapy of Experimental Autoimmune Uveitis with RTL: A Prospect for Treatment of Human Uveitis 
Purpose:
To evaluate the immunotherapeutic efficacy of recombinant T cell receptor ligands (RTLs) specific for arrestin immunity in treatment of experimental autoimmune uveitis (EAU) in humanized leukocyte antigen (HLA-DR3) transgenic (Tg) mice.
Methods:
We generated de novo recombinant human DR3-derived RTLs bearing covalently tethered arrestin peptides 291–310 (RTL351) or 305–324 (RTL352). EAU was induced by immunization of HLA-DR3 mice with arrestin or arrestin peptide and treated with RTLs by subcutaneous delivery. T cell proliferation and cytokine expression was measured in RTL-treated and control mice.
Results:
RTL351 prevented the migration of cells outside of the spleen and the recruitment of inflammatory cells into the eye, and provided full protection against inflammation from EAU induced with arrestin or arrestin peptides. RTL351 significantly inhibited T cell proliferation and secretion of inflammatory cytokines interleukin 2 (IL-2), interferon γ (IFN-γ), IL-6, and IL-17 and chemokines (macrophage inflammatory proteins [MIP-1a] and regulated and normal T cell expressed and secreted [RANTES]), which is in agreement with the suppression of intraocular inflammation. RTL350 (“empty,” no peptide) and RTL352 were not effective.
Conclusions:
Immunotherapy with a single RTL351 successfully prevented and treated arrestin-induced EAU in HLA-DR3 mice and provided proof of concept for therapy of autoimmune uveitis in human patients. The beneficial effects of RTL351 should be attributed to a significant decrease in Th1/Th17 mediated inflammation.
Translational Relevance:
Successful therapies for autoimmune uveitis must specifically inhibit pathogenic inflammation without inducing generalized immunosuppression. RTLs can offer such an option. The single retina-specific RTLs may have a value as potential immunotherapeutic drug for human autoimmune uveitis because they effectively prevent disease induced by multiple T cell specificities.
doi:10.1167/tvst.2.2.1
PMCID: PMC3763891  PMID: 24049712
experimental autoimmune uveitis; immunotherapy; inflammation
8.  Optical Coherence Tomography Findings in Autoimmune Retinopathy 
American journal of ophthalmology  2012;153(4):750-756.e1.
PURPOSE
To report optical coherence tomography (OCT) features of patients with autoimmune retinopathy.
DESIGN
Consecutive case series.
METHOD
Eight patients who presented with unexplained loss of central vision, visual field defects, and/or photopsia were diagnosed with autoimmune retinopathy based on clinical features, electroretinogram (ERG) findings, and serum antiretinal antibody analysis. All patients underwent OCT testing of the macula and nerve fiber layer (NFL).
RESULTS
Outer retinal abnormalities and/or decreased macular thickness on OCT were seen in all patients. Macular OCT showed reduced central macular and foveal thicknesses in 6 patients (mean thickness 143 ± 30 μm and 131 ± 29 μm respectively). In all but 1 patient, loss of the photoreceptor layer or disruption of the photoreceptor outer and inner segment junction was noted. Three patients showed only mild to moderate focal NFL loss.
CONCLUSIONS
Retinal atrophy and reduced macular thickness on OCT are predominant features in patients with autoimmune retinopathy. OCT provides objective measures of retinal damage and may offer clues toward understanding the mechanism of visual dysfunction and the diagnosis of autoimmune retinopathy.
doi:10.1016/j.ajo.2011.09.012
PMCID: PMC3495560  PMID: 22245461
9.  Bilateral paraneoplastic optic neuropathy and unilateral retinal compromise in association with prostate cancer: a differential diagnostic challenge in a patient with unexplained visual loss 
We report a 77-year-old Caucasian man with a 1-year complaint of unexplained visual loss and a 4-year history of prostate cancer. A complete ophthalmologic exam, Goldmann visual fields (GVFs), intravenous fluorescein angiography (IVFA), macular and disc optical coherence tomography (OCT), pattern-reversal visual evoked potentials (PVEPs), and flash electroretinograms (ERGs) were performed. On examination, visual acuity was reduced bilaterally. Fundus exam showed juxtapapillary changes (OS > OD) and, in OS, disc pallor, peripheral RPE dropout and whitish retinal discoloration along the arcades. OCTs were normal OU. Cancer-associated retinopathy (CAR) was suspected. A flash ERG was normal OD and markedly reduced and electronegative OS. An IVFA showed bilateral juxtapapillary staining and changes highly suggestive of sequelae of central retinal artery occlusion (CRAO) OS, in which a cilioretinal artery existed along the papillomacular bundle. GVFs showed bilateral blind spot enlargement and centrocecal scotomas, and PVEPs were delayed. These findings suggested cancer-associated optic neuropathy (CAON), confirmed by presence of anti-optic nerve autoantibodies (auto-Abs). No anti-retinal auto-Abs were found. CAON is a less common paraneoplastic manifestation than CAR and it is rarely observed in association with prostate cancer. A combination of visual function testing methods permitted the recognition, in this highly unusual case, of the concurrent presence of unilateral ERG changes most likely attributable to CRAO complications in OS, in all likelihood unrelated to CAON, and not to be confused with unilateral CAR. Auto-Ab testing in combination with visual function tests helps achieve a better understanding of the pathophysiology of vision loss in paraneoplastic visual syndromes.
doi:10.1007/s10633-012-9327-0
PMCID: PMC3491897  PMID: 22569848
Electroretinogram; Visual evoked potentials; Visual field; Central retinal artery occlusion; Paraneoplastic optic neuropathy; Autoimmunity
10.  Cancer-Associated Retinopathy in Neuroendocrine Carcinoma of the Fallopian Tube 
A 70-year-old woman developed progressive visual loss with compromised visual acuity and visual fields, cells in the anterior chamber and vitreous, attenuated retinal arterioles, and macular edema. She had undergone right oophorectomy and partial salpingectomy nearly 50 years earlier. Full-field and multifocal electroretinography showed waveforms of markedly attenuated amplitudes, findings consistent with cancer-associated retinopathy (CAR). Positron emission tomography revealed a nodule in the anterior wall of a right hydrosalpinx. Total laparoscopic hysterectomy yielded a neuroendocrine fallopian tube malignancy. She underwent partial treatment with paclitaxel and carboplatin that was aborted because of the development of herpes zoster infection. At 15 months following diagnosis, her ophthalmic status was stable. This is the first report of CAR in neuroendocrine carcinoma of the fallopian tube.
doi:10.1097/WNO.0b013e3181e22ef0
PMCID: PMC3491900  PMID: 20724944
11.  Cancer-associated retinopathy caused by benign thymoma 
doi:10.1136/bjo.2008.151563
PMCID: PMC3487380  PMID: 20424218
12.  Neuroprotective Effects of Recombinant T-cell Receptor Ligand in Autoimmune Optic Neuritis in HLA-DR2 Mice 
This study examined the neuroprotective effects of T-cell receptor ligand (RTL) on autoimmune optic neuritis in humanized HLA-DR3 mice. Such immunotherapy significantly suppressed inflammation, inhibited demyelination with signs of myelin recovery, and prevented axonal loss in the optic nerves.
Purpose.
Optic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve and leads to apoptotic retinal ganglion cell (RGC) death, which contributes to the persistence of visual loss. Currently, ON has no effective treatment. The goal was to determine the effectiveness of immunotherapy with recombinant T-cell receptor ligand (RTL) in preventing ON in humanized HLA-DR2 transgenic mice.
Methods.
Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein in humanized HLA-DR2 (DRβ1*1501) transgenic mice. Five consecutive doses of RTL342M were administrated at the onset of ON. The development of autoimmune ON was assessed by histopathology at different time points. The levels of myelin loss, axonal loss, and RGC damage were examined by immunofluorescence.
Results.
HLA-DR2 mice developed chronic ON 2 days before EAE characterized by progressive neurodegeneration in both organs. RTL342M significantly suppressed inflammation in the optic nerve and spinal cord and provided protection for at least 30 days. Examination of myelin loss showed a marked suppression of demyelination and an increase in myelin recovery in the optic nerve. Moreover, RTL342M treatment revealed a neuroprotective effect on optic nerve axons and RGCs in retinas at postimmunization (PI) day 62.
Conclusions.
RTL342M suppressed clinical and histologic signs of EAE/ON by preventing the recruitment of inflammatory cells into the optic nerve and showed neuroprotective effects against ON. However, to achieve full therapeutic benefit, more doses may be needed. These findings suggest a possible clinical application of this novel class of T-cell-tolerizing drugs for patients with optic neuritis.
doi:10.1167/iovs.11-8419
PMCID: PMC3292374  PMID: 22167100
13.  Activation of OX40 Prolongs and Exacerbates Autoimmune Experimental Uveitis 
This study reveals an important role for OX40-mediated T-cell costimulation in the development of uveitis.
Purpose.
T cells are essential for the development of autoimmune uveitis. Although the costimulatory molecule OX40 promotes T-cell function and expansion, it is unclear whether OX40 is implicated in ocular inflammation. The purpose of this study was to examine the role of OX40 in uveitis.
Methods.
Experimental autoimmune uveitis (EAU) was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein peptide 161–180 (IRBP161–180). Some mice received an intravenous administration of OX40-activating antibody on days 0 and 4 after IRBP161–180 sensitization or on days 10 and 14 of uveitis onset. The severity of EAU was evaluated by histology at different time points. In addition, ocular inflammatory cytokine expression was determined by real time-PCR, and peripheral activated CD4+CD44+CD62L− T cells and IL-7Rα expression were analyzed by flow cytometry. The activated CD4+CD44+ lymphocytes were rechallenged with IRBP161–180 in vitro to assess their antigen recall response.
Results.
The authors demonstrated a marked OX40 expression by infiltrating lymphocytes in enucleated human eyes with end-stage inflammation. In addition, the administration of OX40-activating antibody prolonged and exacerbated the disease course of EAU. Moreover, activation of OX40 not only increased CD4+CD44+CD62L− lymphocyte number, it upregulated IL-7Rα expression in the activated T-cell population. Lastly, these cells exhibited a stronger interferon-γ response to IRBP161–180 restimulation in vitro.
Conclusions.
The results reveal a pathogenic role of OX40 in uveitis. Furthermore, the upregulation of IL-7R in CD4+CD44+ lymphocytes suggests that the activation of OX40 promotes the generation or expansion of uveitogenic memory T cells.
doi:10.1167/iovs.11-7664
PMCID: PMC3208192  PMID: 21948545
14.  Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy 
Purpose
Autoimmune retinopathies and optic neuropathies are complex disorders of the retina and the optic nerve, in which patients develop autoantibodies (AAbs) against retinal and optic nerve proteins. Autoimmunity might significantly influence the outcome of retinal and optic nerve degenerative process but the pathogenic process is not fully elucidated. To better understand the role of AAbs in pathogenicity of these suspected autoimmune visual disorders, we focused on unique AAbs specificities associated with the syndrome to identify their antigenic targets in the optic nerve and retina.
Methods
Serum samples were obtained from patients, whose visual disorders were potentially autoimmune in nature, including patients with cancer with possible paraneoplastic syndrome. Autoantibodies were tested against human optic nerve and retinal antigens for specificity by Western blotting and immunofluorescence.
Results
Out of 209 tested for anti-optic nerve autoantibodies, 55% showed specific neuronal autoantibodies. The repertoire of anti-optic nerve autoantibodies often differed from anti-retinal antibodies. The major antigenic targets for these antibodies could be divided into four groups. Autoantibodies specific to classical glycolytic enzymes involved in energy production (α and γ enolases, glyceraldehyde 3-phosphate dehydrogenase) also reacted with retinal antigens. Autoantibodies targeted neuronal-specific myelin proteins (MBP, MOG), aquaporin 4, and collapsing response mediator protein 5 reacted with optic nerve antigens. They showed immunostaining of axons and myelin in the optic nerve as determined by double immunofluorescence.
Conclusion
We identified novel neuronal autoantigens not previously known to be associated with acquired autoimmune retinopathy and optic neuropathy. Knowledge of the full autoantibody repertoire perpetuating this syndrome is an important first requirement in increasing our understanding of the autoimmune process to facilitate better diagnosis, prognosis, and treatment.
doi:10.1007/s12348-011-0028-8
PMCID: PMC3168374  PMID: 21744285
Autoimmunity; Retinopathy; Optic nerve; Neuropathy; Autoantibodies; Retina; Immunofluorescence; Western blotting; Retinal degeneration
15.  Diversity in autoimmunity against retinal, neuronal, and axonal antigens in acquired neuro-retinopathy 
Purpose
Autoimmune retinopathies and optic neuropathies are complex disorders of the retina and the optic nerve, in which patients develop autoantibodies (AAbs) against retinal and optic nerve proteins. Autoimmunity might significantly influence the outcome of retinal and optic nerve degenerative process but the pathogenic process is not fully elucidated. To better understand the role of AAbs in pathogenicity of these suspected autoimmune visual disorders, we focused on unique AAbs specificities associated with the syndrome to identify their antigenic targets in the optic nerve and retina.
Methods
Serum samples were obtained from patients, whose visual disorders were potentially autoimmune in nature, including patients with cancer with possible paraneoplastic syndrome. Autoantibodies were tested against human optic nerve and retinal antigens for specificity by Western blotting and immunofluorescence.
Results
Out of 209 tested for anti-optic nerve autoantibodies, 55% showed specific neuronal autoantibodies. The repertoire of anti-optic nerve autoantibodies often differed from anti-retinal antibodies. The major antigenic targets for these antibodies could be divided into four groups. Autoantibodies specific to classical glycolytic enzymes involved in energy production (α and γ enolases, glyceraldehyde 3-phosphate dehydrogenase) also reacted with retinal antigens. Autoantibodies targeted neuronal-specific myelin proteins (MBP, MOG), aquaporin 4, and collapsing response mediator protein 5 reacted with optic nerve antigens. They showed immunostaining of axons and myelin in the optic nerve as determined by double immunofluorescence.
Conclusion
We identified novel neuronal autoantigens not previously known to be associated with acquired autoimmune retinopathy and optic neuropathy. Knowledge of the full autoantibody repertoire perpetuating this syndrome is an important first requirement in increasing our understanding of the autoimmune process to facilitate better diagnosis, prognosis, and treatment.
doi:10.1007/s12348-011-0028-8
PMCID: PMC3168374  PMID: 21744285
Autoimmunity; Retinopathy; Optic nerve; Neuropathy; Autoantibodies; Retina; Immunofluorescence; Western blotting; Retinal degeneration
16.  A Promising Therapeutic Approach for Treatment of Posterior Uveitis: Recombinant T Cell Receptor Ligand Protects Lewis Rats from Acute and Recurrent Experimental Autoimmune Uveitis 
Ophthalmic Research  2010;44(1):24-33.
Introduction
Chronic autoimmune uveitis is a major cause of vision loss from intraocular inflammation in humans. In this study we report that a recombinant TCR ligand (RTL220) composed of the α1 and β1 domains of MHC class II molecules linked to the uveitogenic interphotoreceptor retinoid-binding protein (IRBP) 1177–1191 peptide is effective in the suppression of acute and recurrent experimental autoimmune uveitis (EAU). Material and Methods: EAU was induced with IRBP1177–1191 peptide or by adoptive transfer of specific T cells in Lewis rats. The rats received 5 doses of RTL220 subcutaneously every other day starting at the onset of clinic signs of EAU.
Results
The administration of RTL220 resulted in a delayed onset and a significant amelioration of the disease severity at clinical levels and showed protection of the retina from inflammatory damage at histological levels. In treatment of recurrent EAU, RTL220 administrated at the first or second onset of clinical disease significantly inhibited EAU, modulated immune responses and provided protection from relapses of uveitis. The systemic and local proinflammatory cytokines were significantly reduced, including IL-17. There was local and systemic increase in IL-10 and reduction in the expression of the proinflammatory chemokines CCL2, CCL3 and CCL5.
Conclusions
Our studies demonstrate a successful treatment of acute and recurrent EAU with RTL220, which effectively suppressed the recurrence of inflammation and reversed clinical and histological EAU by altering cytokine and chemokine expression. These findings strongly support a possible clinical application of this novel class of peptide/MHC class II drugs for patients with autoimmune uveitis.
doi:10.1159/000281815
PMCID: PMC2889253  PMID: 20145422
Experimental autoimmune uveitis, rat; RTL, treatment; Cytokine; Chemokine
17.  Identification of Autoantibodies against TRPM1 in Patients with Paraneoplastic Retinopathy Associated with ON Bipolar Cell Dysfunction 
PLoS ONE  2011;6(5):e19911.
Background
Paraneoplastic retinopathy (PR), including cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), is a progressive retinal disease caused by antibodies generated against neoplasms not associated with the eye. While several autoantibodies against retinal antigens have been identified, there has been no known autoantibody reacting specifically against bipolar cell antigens in the sera of patients with PR. We previously reported that the transient receptor potential cation channel, subfamily M, member 1 (TRPM1) is specifically expressed in retinal ON bipolar cells and functions as a component of ON bipolar cell transduction channels. In addition, this and other groups have reported that human TRPM1 mutations are associated with the complete form of congenital stationary night blindness. The purpose of the current study is to investigate whether there are autoantibodies against TRPM1 in the sera of PR patients exhibiting ON bipolar cell dysfunction.
Methodology/Principal Findings
We performed Western blot analysis to identify an autoantibody against TRPM1 in the serum of a patient with lung CAR. The electroretinograms of this patient showed a severely reduced ON response with normal OFF response, indicating that the defect is in the signal transmission between photoreceptors and ON bipolar cells. We also investigated the sera of 26 patients with MAR for autoantibodies against TRPM1 because MAR patients are known to exhibit retinal ON bipolar cell dysfunction. Two of the patients were found to have autoantibodies against TRPM1 in their sera.
Conclusion/Significance
Our study reveals TRPM1 to be one of the autoantigens targeted by autoantibodies in at least some patients with CAR or MAR associated with retinal ON bipolar cell dysfunction.
doi:10.1371/journal.pone.0019911
PMCID: PMC3096646  PMID: 21611200
18.  Molecular Biomarkers for Autoimmune Retinopathies: Significance of Anti-Transducin-Alpha Autoantibodies 
Autoimmune retinopathies (AR) are uncommon retinal degenerations with vision loss associated with unique clinical symptoms and findings and with serum anti-retinal autoantibodies. The experimental and clinical studies corroborate that autoantibodies in high titers can penetrate into the retina affecting function of the target antigens, which leads to retinal dysfunction and degeneration. Anti-recoverin and anti-enolase α-enolase autoantibodies were more frequently recognized in AR but autoantibodies with other specificities have also been documented, indicating immunological heterogeneity. Our goal was to examine the associations of anti-retinal autoantibodies with retinopathy in order to identify molecular biomarkers for better diagnosis and prognosis of retinopathies. In these studies we examined 39 patients (10 with cancers) of average age of ∼57 years old with sudden onset of unexplained progressive vision loss and the presence of circulating serum autoantibodies against 40-kDa retinal protein. The patients presented the retinal phenotype characterized by defects in visual fields and reduced scotopic ERG responses. Anti-40-kDa autoantibodies had specificity to the amino terminus of transducin-α. None of the normal subjects' sera had anti-40-kDa autoantibodies. In conclusion, clinical phenotype of patients with anti-transducin-α autoantibodies differed from other phenotypes of AR. These patients, often women at a ratio ∼2:1, had defects in rod (scotopic) photoreceptor function and typically did not have cancers, whereas anti-recoverin phenotype is associated with cancer and severe loss of rod and cones function, and anti-enolase retinopathy typically presents with cone dysfunction and is equal in cancer and non-cancer patients. Our studies suggest that anti-transducin autoantibodies can serve as molecular biomarkers for retinal phenotypes and could be used for progression of retinal dysfunction and degeneration.
doi:10.1016/j.yexmp.2009.08.003
PMCID: PMC2783245  PMID: 19744478
biomarker; retinopathy; autoantibody; autoimmunity; transducin
19.  Electroretinographic findings in transplant chorioretinopathy 
Aim:
Transplant chorioretinopathy is a rare complication following solid organ or bone marrow transplantation and can result in severe vision loss. This series presents electroretinogram (ERG) results in patients with this condition.
Methods:
Patients who presented with bilateral vision loss following bone marrow or solid organ transplantation were identified. A complete ophthalmologic examination, fundus photography, and fluorescein angiography (FA) were performed. Full-field ERG was obtained in all patients and a multifocal ERG (mfERG) was obtained in two patients.
Results:
Four patients were identified. All patients had bilateral vision loss and displayed a characteristic pattern of mottled hyperfluorescence on FA. Three patients developed progressive vision loss ranging from 20/60 to hand motions whereas one retained 20/40 vision. All patients exhibited moderate to severe cone dysfunction, while the degree of rod abnormalities was varied. Two patients with severe cone dysfunction showed mild clinical changes initially, but later developed progressive vision loss and chorioretinal atrophy.
Conclusion:
Transplant chorioretinopathy patients undergoing ERG testing show cone dysfunction with a variable degree of rod dysfunction. ERG abnormalities preceded the visual acuity and clinical changes in two patients, suggesting that ERG may be a helpful predictor of the clinical course in this rare disease.
PMCID: PMC2915864  PMID: 20689794
transplant; chorioretinopathy; electroretinogram; ERG; mfERG
21.  Autoimmunity against Carbonic Anhydrase II Affects Retinal Cell Functions in Autoimmune Retinopathy 
Journal of autoimmunity  2009;32(2):133-139.
Autoantibodies against various retinal proteins, including anti-carbonic anhydrase II (CAII) autoantibodies, have been found in patients with cancer-associated retinopathy and autoimmune retinopathy without diagnosed cancer. We studied sera from retinopathy patients that showed reactivity with a 30-kDa retinal protein, which was identified as carbonic anhydrase II (CAII), and immunolabeled cells in human retina. The goal of the study was to examine whether patients’ autoantibodies induce pathogenic effects on the catalytic function of CAII, which may have metabolic consequences on cell survival. Our findings revealed that anti-CAII autoantibodies have the capacity to induce cellular damage by impairing CAII cellular function through inhibiting the catalytic activity of CAII in a dose dependent manner, decreasing intracellular pH, increasing intracellular calcium, which in effect decreases retinal cell viability. The destabilized catalytic function of CAII and alterations in cytosolic pH were found very early, suggesting that autoantibodies are the inducers of apoptosis. In summary, our study showed that anti-CAII autoantibodies provoke pathogenic effects on retinal cells by decreasing cell survival by blocking the CAII cellular functions. The current experiments may facilitate better understanding the role of the immune system in retinal degeneration and help to develop better strategies for therapy of autoimmune retinopathy.
doi:10.1016/j.jaut.2009.02.001
PMCID: PMC2692195  PMID: 19269136
autoimmune retinopathy; autoantibody; carbonic anhydrase II; calcium; pH; retina
22.  Autoantibody Targets and their Cancer Relationship in the Pathogenicity of Paraneoplastic Retinopathy 
Autoimmunity reviews  2009;8(5):410-414.
Paraneoplastic retinopathies (PR), including cancer-associated retinopathy (CAR) or the closely related melanoma-associated retinopathy (MAR) occur in a small subset of patients with retinal degeneration and systemic cancer. This autoimmune syndrome is characterized by sudden, progressive loss of vision in association with circulating anti-retinal autoantibodies. The PR syndromes are heterogeneous, may produce a number of ocular symptoms, and may be associated with several different neoplasms, including lung, breast, prostate, gynecological, and colon cancer, melanoma, and hematologic malignancies. We examined the onset of retinopathy in correlation to the diagnosis of cancer and the presence of specific anti-retinal autoantibodies in PR patients. In some patients without diagnosed malignant tumors, the onset of ocular symptoms and the presence of autoantibodies preceded the diagnosis of cancer by months to years, including anti-recoverin, anti-transducin-α, and anti-carbonic anhydrase II antibodies. Although anti-retinal autoantibodies may not be a good predictor of a specific neoplasm, they can be used as biomarkers for different subtypes of retinopathy. Identification of autoantibodies involved in autoimmune-mediated PR will help elucidate the mechanisms underlying the PR syndromes and develop targeted therapies for these sight-threatening disorders.
doi:10.1016/j.autrev.2009.01.002
PMCID: PMC2680817  PMID: 19168157
Cancer-associated retinopathy; anti-retinal autoantibodies; recoverin; enolase; autoimmune retinopathy
23.  Non-Invasive Stem Cell Therapy in a Rat Model for Retinal Degeneration and Vascular Pathology 
PLoS ONE  2010;5(2):e9200.
Background
Retinitis pigmentosa (RP) is characterized by progressive night blindness, visual field loss, altered vascular permeability and loss of central vision. Currently there is no effective treatment available except gene replacement therapy has shown promise in a few patients with specific gene defects. There is an urgent need to develop therapies that offer generic neuro-and vascular-protective effects with non-invasive intervention. Here we explored the potential of systemic administration of pluripotent bone marrow-derived mesenchymal stem cells (MSCs) to rescue vision and associated vascular pathology in the Royal College Surgeons (RCS) rat, a well-established animal model for RP.
Methodology/Principal Findings
Animals received syngeneic MSCs (1×106 cells) by tail vein at an age before major photoreceptor loss. Principal results: both rod and cone photoreceptors were preserved (5–6 cells thick) at the time when control animal has a single layer of photoreceptors remained; Visual function was significantly preserved compared with controls as determined by visual acuity and luminance threshold recording from the superior colliculus; The number of pathological vascular complexes (abnormal vessels associated with migrating pigment epithelium cells) and area of vascular leakage that would ordinarily develop were dramatically reduced; Semi-quantitative RT-PCR analysis indicated there was upregulation of growth factors and immunohistochemistry revealed that there was an increase in neurotrophic factors within eyes of animals that received MSCs.
Conclusions/Significance
These results underscore the potential application of MSCs in treating retinal degeneration. The advantages of this non-invasive cell-based therapy are: cells are easily isolated and can be expanded in large quantity for autologous graft; hypoimmunogenic nature as allogeneic donors; less controversial in nature than other stem cells; can be readministered with minor discomfort. Therefore, MSCs may prove to be the ideal cell source for auto-cell therapy for retinal degeneration and other ocular vascular diseases.
doi:10.1371/journal.pone.0009200
PMCID: PMC2821411  PMID: 20169166
24.  Neuroinflammation in advanced canine glaucoma 
Molecular Vision  2010;16:2092-2108.
Purpose
The pathophysiological events that occur in advanced glaucoma are not well characterized. The principal purpose of this study is to characterize the gene expression changes that occur in advanced glaucoma.
Methods
Retinal RNA was obtained from canine eyes with advanced glaucoma as well as from healthy eyes. Global gene expression patterns were determined using oligonucleotide microarrays and confirmed by real-time PCR. The presence of tumor necrosis factor (TNF) and its receptors was evaluated by immunolabeling. Finally, we evaluated the presence of serum autoantibodies directed against retinal epitopes using western blot analyses.
Results
We identified over 500 genes with statistically significant changes in expression level in the glaucomatous retina. Decreased expression levels were detected for large number of functional groups, including synapse and synaptic transmission, cell adhesion, and calcium metabolism. Many of the molecules with decreased expression levels have been previously shown to be components of retinal ganglion cells. Genes with elevated expression in glaucoma are largely associated with inflammation, such as antigen presentation, protein degradation, and innate immunity. In contrast, expression of many other pro-inflammatory genes, such as interferons or interleukins, was not detected at abnormal levels.
Conclusions
This study characterizes the molecular events that occur in the canine retina with advanced glaucoma. Our data suggest that in the dog this stage of the disease is accompanied by pronounced retinal neuroinflammation.
PMCID: PMC2965571  PMID: 21042562
25.  Resveratrol prevents antibody-induced apoptotic death of retinal cells through upregulation of Sirt1 and Ku70 
BMC Research Notes  2008;1:122.
Background
To determine whether resveratrol, a natural plant-derived drug, has protective effects against antibody-induced apoptosis of retinal cells in vitro and to provide insights on the mechanism of resveratrol protection.
Findings
E1A.NR3 retinal cells pretreated with 40 μM resveratrol were grown in the presence of anti-recoverin (Rec-1), anti-enolase (Enol-1) antibodies, and normal purified immunoglobulins. When the cells were exposed to resveratrol before treatment with Enol-1 or Rec-1 antibodies, 30–55% more cells survived compared to the resveratrol-untreated cells. Western blotting showed a reduction in proapoptotic protein Bax in the cytoplasm and mitochondria of resveratrol-treated cells. Resveratrol-pretreated cells also showed a significant decrease in intracellular calcium and an inhibition of caspase-3 activity as compared to the untreated cells. Sirt1 expression was greatly reduced in the cells grown in the presence of Rec-1 and Enol-1, but it increased about five times in the resveratrol-pretreated cells. Immunocytochemistry revealed that Sirt1 expression in the cytoplasm and nucleus was colocalized with Ku70 expression in resveratrol-treated cells, suggesting possible interaction with each other in the cell. The pattern of the Ku70 cellular localization also overlapped with the Bax cellular localization in treated and untreated cells.
Conclusion
In vitro protection of retinal cells from apoptosis by resveratrol occurred through multiple early molecular events, such as reduction of intracellular calcium levels, down-regulation of Bax, up-regulation of Sirt1 and Ku70 activities, and inhibition of caspase-3 activity. These findings will help designing future in vivo and pre-clinical treatments for autoimmune retinopathies.
doi:10.1186/1756-0500-1-122
PMCID: PMC2633309  PMID: 19046449

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