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      Botulinum toxin-induced acute anterior uveitis in a patient with Behçet’s disease under infliximab treatment: a case report

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          Abstract

          Background

          Injections of lipopolysaccharide in animal models generate acute anterior uveitis (also known as endotoxin-induced uveitis), but the effects of lipopolysaccharide injection are unknown in humans. We describe an unusual case in which acute anterior uveitis was dramatically activated subsequent to botulinum toxin injection in a patient with Behçet’s disease but the acute anterior uveitis was satisfactorily attenuated by infliximab.

          Case presentation

          A 53-year-old Japanese man had normal ocular findings at his regularly scheduled appointment. He had been diagnosed as having incomplete-type Behçet’s disease 11 years before. Three years after the diagnosis he was given systemic infusions of 5 mg/kg infliximab every 8 weeks and he had not experienced a uveitis attack for 8 years with no treatment other than infliximab. Two days after the eye examination, he received intracutaneous botulinum toxin injections to treat axillary hyperhidrosis on both sides. Three hours after the injections, he noted rapidly increasing floaters in his right eye. Four days after the injections, his right eye showed severe acute anterior uveitis with deteriorated aqueous flare and anterior vitreous opacity. He received his scheduled infliximab injection, and the right acute anterior uveitis immediately attenuated.

          Conclusions

          Botulinum toxin may have clinical effects similar to those of lipopolysaccharide in endotoxin-induced uveitis models. To the best of our knowledge, this is the first report to suggest that botulinum toxin may trigger acute anterior uveitis, although the precise mechanism is still unclear.

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          Most cited references10

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          Overproduction of monocyte derived tumor necrosis factor alpha, interleukin (IL) 6, IL-8 and increased neutrophil superoxide generation in Behçet's disease. A comparative study with familial Mediterranean fever and healthy subjects.

          The etiopathogenesis of Behçet's disease (BD) has not yet been clarified but might involve immune dysfunction. As cytokines are involved in the regulation of immune responses and inflammatory reactions, we investigated whether they may play a role in the pathogenesis of BD. We investigated spontaneous and lipopolysaccharide (LPS) stimulated production of tumor necrosis factor alpha (TNF alpha), interleukin (IL) 1, IL-6, IL-8 and granulocyte monocyte macrophage colony stimulating factor (GM-CSF) by peripheral blood monocytes from 21 patients with BD, 10 healthy controls and 10 patients with familial Mediterranean fever (FMF), another chronic inflammatory disease. We also studied superoxide generation and surface antigen expression by polymorphonuclear neutrophils (PMN). The spontaneous secretion of TNF alpha, IL-6 and IL-8 by monocytes was significantly increased in patients with active BD. The secretion of TNF alpha, IL-1, IL-6 and IL-8 was found to be in normal range in asymptomatic patients with FMF. The LPS stimulated production of TNF alpha, IL-6, IL-1 and IL-8 was significantly increased in patients with BD, without any correlation with BD activity. In vitro, PMN spontaneously generated significant amounts of superoxide in patients with active BD. Taken together, our results suggest that monocyte and PMN dysfunctions may play a role in the pathogenesis of BD.
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            Contribution of TNF-alpha to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo.

            To investigate the effect of TNF-alpha on leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis (EIU) in the rat. EIU was induced in Long-Evans rats by a single footpad injection of lipopolysaccharide (LPS; 350 microg/kg) from Salmonella typhimurium. A single injection of recombinant TNF receptor P75 (etanercept) was given subcutaneously 24 hours before the administration of LPS. Twenty-four hours after administration of LPS, leukocyte adhesion was evaluated in vivo with SLO-acridine orange angiography and ex vivo with concanavalin A lectin staining of retinal flatmounts. Neutrophil activation was quantified by a myeloperoxidase activity assay. Vascular leakage was assessed by Evans blue extravasation. Retinal cell death was assessed with TUNEL staining and quantified with a modified ELISA protocol. Involvement of caspase-3 and -8 was determined by M30 antibody staining, Western blot analysis, and a test for enzymatic activity. Twenty-four hours after the LPS injection, significant increases in leukocyte rolling, adhesion, and activation were observed. In addition, increased levels of apoptosis in the vascular endothelium and the ganglion cell and inner nuclear layers and activation of caspase-8 and -3 were observed. After administration of the TNF-alpha inhibitor, significant reduction in the leukocyte rolling, adhesion, activation, and apoptosis in all the affected layers was observed. The quantitative analysis of vascular leakage revealed a significant decrease after treatment with etanercept. Retinal cell death quantification showed a significant decrease after treatment with the TNF-alpha inhibitor. Anti-TNF-alpha treatment reduces the LPS-induced increases in leukocyte rolling, adhesion, and vascular leakage in this rat model of inflammatory uveitis. These results suggest the involvement of TNF-alpha in inflammatory uveitis and its potential use as a therapeutic agent in the reduction of ocular inflammation.
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              Expression of toll-like receptor 4 and its associated lipopolysaccharide receptor complex by resident antigen-presenting cells in the human uvea.

              To investigate the in vivo expression of toll-like receptor 4 (TLR4) and its associated lipopolysaccharide (LPS) receptor complex in the human eye. Normal human ocular tissues were evaluated for in vivo TLR4, MD-2, and CD14 mRNA and protein expression by RT-PCR and immunohistochemistry, respectively. The distribution patterns and phenotypes of the cells expressing these proteins were further characterized by confocal microscopy and double-label immunofluorescence studies. Normal human uvea, retina, sclera, and conjunctiva constitutively expressed TLR4, MD-2, and CD14 mRNA. The protein expression of these molecules was restricted, however, to resident antigen-presenting cells (APCs) in the normal human uvea, consisting mainly of HLA-DR(+) dendritic cells (DCs). These APCs endowed with the complete LPS receptor complex appeared to be strategically positioned in perivascular and subepithelial locations for surveying blood-borne or intraocular LPS. In contrast, other cell types of the normal human cornea, conjunctiva, retina, and sclera did not express TLR4/MD-2 protein in vivo as detectable by immunohistochemistry. The present study demonstrates for the first time that resident APCs in the normal human uvea express TLR4 and its associated LPS receptor complex. This has significant implications for the understanding of normal ocular immunity as well as unraveling the potential role of Gram-negative bacteria in the pathogenesis of acute anterior uveitis (AAU).
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                Author and article information

                Contributors
                hiro.sasa1228@icloud.com
                shunsuke_8@hotmail.co.jp
                arche_rarryow@hotmail.co.jp
                +81-56184-3111 , mzako@aol.com
                Journal
                J Med Case Rep
                J Med Case Rep
                Journal of Medical Case Reports
                BioMed Central (London )
                1752-1947
                4 May 2017
                4 May 2017
                2017
                : 11
                : 124
                Affiliations
                [1 ]ISNI 0000 0001 0727 1557, GRID grid.411234.1, Department of Ophthalmology, , Aichi Medical University, ; Nagakute, Aichi Japan
                [2 ]Department of Ophthalmology, Asai Hospital, 178-1 Yakata-cho, Seto, Aichi 489-0866 Japan
                Article
                1288
                10.1186/s13256-017-1288-1
                5415788
                28468639
                dac055d6-d4a6-4564-97fd-354f63c4bb17
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 20 December 2016
                : 9 April 2017
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2017

                Medicine
                behçet’s disease,botulinum toxin,endotoxin-induced uveitis,infliximab,lipopolysaccharide

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