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Immune Cell Infiltration Into the Eye Is Controlled by IL-10 in Recoverin-Induced Autoimmune Retinopathy

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Immune Cell Infiltration Into the Eye Is Controlled by IL-10 in Recoverin-Induced Autoimmune Retinopathy Immune Cell Infiltration into the Eye Is Controlled by IL-10 in Recoverin-Induced Autoimmune Retinopathy This information is current as Enayat Nikoopour, Cheng-mao Lin, Sarah Sheskey, John R. of September 28, 2021. Heckenlively and Steven K. Lundy J Immunol 2019; 202:1057-1068; Prepublished online 11 January 2019; doi: 10.4049/jimmunol.1800574 http://www.jimmunol.org/content/202/4/1057 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/01/10/jimmunol.180057 Material 4.DCSupplemental http://www.jimmunol.org/ References This article cites 39 articles, 4 of which you can access for free at: http://www.jimmunol.org/content/202/4/1057.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Immune Cell Infiltration into the Eye Is Controlled by IL-10 in Recoverin-Induced Autoimmune Retinopathy Enayat Nikoopour,*,†,‡ Cheng-mao Lin,* Sarah Sheskey,* John R. Heckenlively,* and Steven K. Lundy†,‡ Autoimmune retinopathy (AIR) is a treatable condition that manifests in acute and progressive vision loss in patients. It has recently been determined that AIR is associated with an imbalance of TH1 versus regulatory T cell immunity toward the retinal protein, recoverin. This study describes a new murine model to understand the immunopathology of AIR and its association with T cell responses toward recoverin. Immunization of C57BL/6 mice with recoverin resulted in ocular inflammation including infiltration of CD4+ and CD8+ T lymphocytes, B cells, and CD11b+Ly6C+ inflammatory monocytes in the eyes. Production of IFN-g and IL-17 from T cells was exacerbated in IL-10 knockout (KO) mice and kinetics of disease development was accelerated. Infiltration of T cells and inflammatory monocytes into the eyes dramatically increased in recoverin-immunized IL-10 KO mice. Downloaded from An immunodominant peptide of recoverin, AG-16, was capable of inducing disease in IL-10 KO mice and resulted in expansion of AG-16 tetramer-specific CD4+ T cells in lymphoid organs and eyes. Adoptive transfer of recoverin-stimulated cells into naive mice was sufficient to induce AIR, and immunization of B cell–deficient mice led to a milder form of the disease. This model supports the hypothesis that recoverin-specific T cell responses are major drivers of AIR pathogenesis and that IL-10 is an important factor in protection. The Journal of Immunology, 2019, 202: 1057–1068. http://www.jimmunol.org/ utoimmune retinopathy (AIR) is characterized by sudden The diagnosis of AIR is supported by the detection of ARA and progressive loss of vision in association with cir- of the IgG isotype in patients’ serum. Abs against proteins A culating anti-retinal autoantibodies (ARA) (1–3). The involved in the glycolytic pathway, a-Enolase and Aldolase C, condition may occur as a primary autoimmune condition or in have been reported in sera of AIR patients. However, the association with retinitis pigmentosa (RP) or various cancers expression of these proteins is not restricted to retina, and (1–4). The clinical manifestations of AIR and cancer-associated autoantibodies against them have been detected in various retinopathies (CAR) are acute retinal degeneration leading to re- autoimmune diseases (5). One of the ARA most correlated with ductions in the visual field and altered electrical conductance in AIR is anti-recoverin Ab (6). Recoverin, a 23-kDa retina-specific by guest on September 28, 2021 response to light stimulation in electroretinogram (ERG). Visual calcium-binding protein in photoreceptors, was first identified as defects in CAR and AIR patients are similar but more acute than an immune target in patients with CAR (7, 8). Despite association changes observed in patients with RP, but in a subgroup of RP with disease, there is only indirect evidence showing autoanti- patients, an underlying defect in immune regulation may contribute bodies may have a pathogenic role. The presumed direct role of to acceleration of retinal degeneration. AIR is most often dis- the Abs in pathogenesis of AIR is mostly based on induction of tinguished from nonautoimmune RP based on differential clini- apoptosis of retinal cells in vitro and intravitreal injection of Abs cal findings, including lack of pigment deposits, later disease in animal models (9). Anti-recoverin Abs, for example, have been onset, more rapid progression, and unique visual field defects. shown to induce apoptosis of photoreceptor cells in vitro (10). The role of the many different pathways of the immune system in the pathogenesis and progression of AIR is not well *Department of Ophthalmology and Visual Sciences–Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI 48105; †Division of Rheumatology, understood. The strongest evidence that the immune system is Department of Internal Medicine, University of Michigan Medical School, Ann involved in AIR pathogenesis is that modulation of the immune ‡ Arbor, MI 48109; and Graduate Program in Immunology, University of Michigan system with generally immunosuppressive drugs (11) and rit- Medical School, Ann Arbor, MI 48109 uximab (12) have been used successfully for treatment of AIR ORCIDs: 0000-0003-2409-9423 (C.-m.L.); 0000-0002-3655-2216 (S.K.L.). patients. These drugs have broad specificities but primarily Received for publication April 25, 2018. Accepted for publication December 1, 2018. target T cell–based immunity rather than humoral immunity. This work was supported by Laura and Edmond Opler. The fundus imaging and Indeed, we have recently found that new onset AIR patients optical coherence tomography were performed in the Molecular Biology Core Facil- ity of the Kellogg Eye Center, which is supported by National Institutes of Health have a strong TH1-biased immune response toward recoverin National Eye Institute Grant P30 EY007003. (13). Our main objective in the current study was to establish a Address correspondence and reprint requests to Dr. Steven K. Lundy, Division of Rheu- mouse model to discover the specific mechanisms underlying matology, Department of Internal Medicine, University of Michigan Medical School, 4043 the pathogenesis of AIR. We found that breaking peripheral Biomedical Sciences Research Building, Ann Arbor, MI 48109-2200. E-mail address: [email protected] immune tolerance of recoverin resulted in significant infiltra- The online version of this article contains supplemental material. tion of immune cells and inflammation of the retina. Recoverin- Abbreviations used in this article: AIR, autoimmune retinopathy; ARA, anti-retinal specific TH1andTH17 cell responses and disease progression autoantibody; CAR, cancer-associated retinopathy; ERG, electroretinogram; KO, were greatly enhanced in IL-10–deficient mice. Adoptive knockout; MHC II, MHC class II; PTX, pertussis toxin; RP, retinitis pigmentosa; transfer and recoverin-peptide immunization methods were WT, wild-type. also developed to further define the role of T cells in the disease Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 progression. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800574 1058 RECOVERIN-INDUCED RETINAL AUTOIMMUNITY Materials and Methods supernatants were collected for ELISA assays for IFN-g,IL-17,and/or Mice IL-10 cytokines (R&D Systems). C57BL/6 mice were purchased from The Jackson Laboratories. Breeders for Detection of recoverin-specific Abs tm1Cgn B6.129P2-Il10 /J (IL-10 knockout [KO]) mouse strain were kindly pro- Peripheral blood was collected at the time of sacrifice and sera were an- vided by Dr. G. Chen, University of Michigan, and B cell–deficient B6.129S2- alyzed for Ab measurement as follows. EIA plates were coated with 2 mg/ml Ighmtm1Cgn/J (mMT) mice were purchased from The Jackson Laboratories. recombinant mouse recoverin in carbonate buffer (pH 9.5) overnight at 4˚C. Mice were bred and maintained in a specific pathogen-free environment. The Excess protein was removed and plates were blocked with 1% BSA in animal protocols used in this study were approved by the University of Mich- PBS. Sera were diluted to 1:400 or 1:1600, and 100 ml was added into igan Unit for Laboratory Animal Medicine in accordance with the guidelines set wells in triplicate and incubated for 2 h at room temperature. For negative forth by the National Institutes of Health and the State of Michigan. control, sera were added to wells without Ag coating. Plates were washed Recombinant recoverin and peptides three times, and anti-mouse biotinylated IgG (1:500), and streptavidin– horse radish peroxidase (1:500) was added for 30 min. Plates were washed Recombinant mouse recoverin (1) was prepared at the Center for Structural three times and TMB substrate was added, color reaction was stopped with Biology Protein Core Facility of the University of Michigan. A pET11a vector 2N sulfuric acid, and then the absorbance at OD450 was measured. containing full-length transcript of mouse recoverin was transfected into Rosetta 2(DE3)Escherichia coli strain. The protein product was purified using fast Intracellular cytokine staining protein liquid chromatography and screened with ToxinSensor Chromogenic Cells were isolated either directly from draining lymph nodes of immunized LAL Endotoxin Assay Kit (GenScript) to rule out the possibility of en- mice or from cultures of lymph node cells or splenocytes as indicated and treated dotoxin contamination.
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