Impaired Plasmacytoid Dendritic Cell Innate Immune Responses in Patients with Herpes Virus-Associated Acute Retinal Necrosis This information is current as Nicolai A. Kittan, Antonio Bergua, Sabrina Haupt, Norbert of October 1, 2021. Donhauser, Philipp Schuster, Klaus Korn, Thomas Harrer and Barbara Schmidt J Immunol 2007; 179:4219-4230; ; doi: 10.4049/jimmunol.179.6.4219 http://www.jimmunol.org/content/179/6/4219 Downloaded from References This article cites 57 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/179/6/4219.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 1, 2021 *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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Impaired Plasmacytoid Dendritic Cell Innate Immune Responses in Patients with Herpes Virus-Associated Acute Retinal Necrosis1 Nicolai A. Kittan,2* Antonio Bergua,2† Sabrina Haupt,* Norbert Donhauser,* Philipp Schuster,* Klaus Korn,* Thomas Harrer,‡ and Barbara Schmidt3* Plasmacytoid dendritic cells (PDC), the main producers of type I IFNs in the blood, are important for the recognition and control of viral and bacterial infections. Because several viruses induce IFN-␣ production, severe courses of herpes virus infections in nonimmunocompromised patients may be related to numerical or functional PDC deficits. To evaluate this hypothesis, PBMC and PDC were repeatedly isolated from nine patients with acute retinal necrosis (ARN), caused by herpes ؍ simplex or varicella zoster virus. The patients experienced meningitis/encephalitis and frequent infections in childhood (n and stress Downloaded from ,(4 ؍ infections (n ,(1 ؍ ocular surgery (n ,(2 ؍ recurrent herpes virus infections at unusual localizations (n ,(2 -The median percentage of isolated PDC was significantly lower in patients compared with 18 age .(6 ؍ around ARN (n matched healthy controls (p < 0.001), confirmed by FACS analysis using peripheral blood, and was extremely low during acute disease. PDC counts dropped in five controls suffering from respiratory infections or diarrhea. IFN-␣ production in PDC and PBMC exposed to different stimuli was significantly lower in patients than in controls (p < 0.05). Anergy to these stimuli was observed on four occasions, in particular during acute disease. PDC of patients showed up-regulated IFN /regulatory factor-7 mRNA levels and evidence of in vivo activation (CD80) and maturation (CD83) (p < 0.05). CD8؉ cell http://www.jimmunol.org These data support a risk factor model in which .(0.04 ؍ responses were significantly lower in patients vs controls (p numerical and functional deficits in PDC-mediated innate immune responses contribute to an impaired control of latent herpes virus infections and subsequent development of ARN. The Journal of Immunology, 2007, 179: 4219–4230. cute retinal necrosis (ARN),4 first described in 1971 (1), despite antiviral therapy and vitrectomy with silicon oil instilla- is a rare inflammatory necrotic process affecting one or, tion. The most frequent causes are varicella zoster virus (VZV), A in some cases, both retinas in immunocompetent as well predominantly occurring in elderly individuals, and HSV 1 and 2, as immunocompromised patients (2). The patients present with associated with a history of encephalitis and meningitis in patients by guest on October 1, 2021 unspecific inflammatory symptoms such as a red eye and ocular older and younger than 25 years, respectively (4, 5). Triggering pain accompanied by blurred vision. Clinical signs are focal, well- events such as periocular trauma, neurosurgery, and high-dose cor- demarcated areas of necrosis in the peripheral retina, rapid cen- ticoids have been reported (6). tripetal progression, occlusive vasculopathy, and inflammatory re- A pioneering insight into the pathogenesis of ARN was pro- sponses in the vitreous body and anterior chamber (3). The vided by an early animal model in which HSV inoculation into the sequelae are irreversible retinal damage and severely reduced vi- anterior chamber of rabbits was followed by retinal necrosis of the sion or blindness due to necrosis of the retina, which often occurs uninoculated eye (7), later confirmed in mice (8). The virus spreads through synaptically connected nuclei and neurons to the contralateral, but not ipsilateral, optical nerve and retina. In T cell- *Institute of Clinical and Molecular Virology, German National Reference Centre for and NK-cell depleted mice, however, the virus spreads to both Retroviruses, †Department of Ophthalmology, and ‡Department of Internal Medicine III with Institute for Clinical Immunology, University Hospital Erlangen, University retinas and from the anterior chamber to the ipsilateral retina, re- of Erlangen-Nu¨rnberg, Erlangen, Germany spectively, confirming a role for both cells types in the control of Received for publication October 2, 2006. Accepted for publication June 29, 2007. virus infection (9–11). Notably, T lymphocyte infiltration of the The costs of publication of this article were defrayed in part by the payment of page brain and cytokine production cannot be detected until 1–2 days charges. This article must therefore be hereby marked advertisement in accordance after virus infection (12). The necrotic process seems to be driven with 18 U.S.C. Section 1734 solely to indicate this fact. by CD4ϩ cells, macrophages, polymorphonuclear cells, B cells, 1 This work was supported by the German Research Foundation (Grant SCHM 1702/ and the inflammatory cytokines TNF-␣ and IFN-␥ (13, 14). HSV-1 1-1; SFB466, Project A12; Grant SCHM1702/2-1) (to B.S.), the Graduate College GRK1071 (“Viruses of the Immune System”) (to N.A.K. and S.H.), and the “Akad- tegument proteins have been characterized as major targets for emie der Wissenschaften und Literatur zu Mainz.” T cells within the vitreous fluid (15). In addition, VZV-specific 2 N.A.K. and A.B. contributed equally to the work. delayed hypersensitivity was absent in a subset of patients with 3 Address correspondence and reprint requests to Dr. Barbara Schmidt, Institute of ARN (16). Clinical and Molecular Virology, German National Reference Centre for Retrovi- ruses, Schlossgarten 4, D-91054 Erlangen, Germany. E-mail address: baschmid@viro. Recently, plasmacytoid dendritic cells (PDC) have been identified med.uni-erlangen.de as major producers of type I IFNs in the blood (17, 18). Together with 4 Abbreviations used in this paper: ARN, acute retinal necrosis; VZV, varicella zoster myeloid dendritic cells (MDC), they play a crucial role in innate im- virus; PDC, plasmacytoid dendritic cell; MDC, myeloid dendritic cell; lin, lineage; mune defenses against microbial pathogens (19), including viruses IRF, IFN regulatory factor; IQR, interquartile range. such as HSV (20, 21). Besides a broad antiviral activity, type I IFNs Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 regulate early immune activation toward a cellular-based response, www.jimmunol.org staining. Aliquots (100 blocking reagent recommendations. In general, 10 ELISA module set (Bender Medsystems) according to the manufacturer’s 3M Pharmaceuticals), and LPS (1 (10 lowing day, using UV-irradiated supernatantstimulated from immediately a after clinical isolation HSV-1 and isolate PBMC were stimulated the fol- alyzed unless values above the linear range required further dilution. 4220 EDTA (Sigma-Aldrich), followedwashed by with incubation Dulbecco’s with PBSmined supplemented 100 as with described 1% previously FCSblood (32). and within 0.5 In mM 4 brief,All 2 h ml after FACS of collection. whole determinations PDC blood were was andFlow MDC performed cytometry counts on were EDTA-anticoagulated deter- PMBC and PDC supernatants wereCytokine analyzed assays for IFN- cells/500 tems). PDC and PBMC were200 plated U/ml at a penicillin, density 90 of U/ml(Invitrogen 10 streptomycin, Life and Technologies), 20 ng/mlRPMI supplemented IL-3 1640 with (R&D medium 50 Sys- containing 10%as mg/ml heat-inactivated revealed glutamine, (56°C, by 60 min)CD4-PE trypan FCS (BD blue Biosciences). staining. Theagainst viability PBMC of the and isolated PDC-specific PDC PDCisolated lectin were was PDC BDCA2 above cultivated was 85% (31) in checkedcell (Miltenyi in isolation selected Biotec) kit donors and (Miltenyi usingtwo-step anti- Biotec) FITC-conjugated LS/MS Abs as column isolation described proceduregradient previously using (30). centrifugation the Purity (Biochrom). BDCA4 of ( PDCPBMC were were obtained purified from from EDTA-containing PBMC blood inIsolation using a standard and Ficoll stimulation of PBMC andsent PDC was obtained fromFaculty, all University participants. of (No. Erlangen-Nu¨rnberg death. 3299), This and study informed wasviral con- approved infections, by