Proteomic Profile of Tears for the Diagnosis of Uveitis Associated with Juvenile Idiopathic Arthritis: Setting Targets to Achieve Results

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The paper presents epidemiologic and pathophysiological aspects of the problem statement for early recognition of Uveitis (Uv) associated with Juvenile Idiopathic Arthritis (JIA) in terms of the proteomic profile of tears as well as the results of an attempt to solve this problem by means of the Tandem Mass-Spectrometry (TMS). The solution of this problem is of the highest relevance due to revolutionary changes in treatment strategies after introducing highly effective biologics. Content analysis of literature reviews reveals the following: 1. the incidence of JIA-Uv in the Northwest Federal District of Russian Federation averages 0.5-0.7 per 100 000 of children with the prevalence being ten-fold higher than incidence, 2. without Methotrexate treatment 4-7 years after the diagnosis of JIA-Uv cataract is revealed in 35-40% of children and in 5% – glaucoma as well, 3. even with Methotrexate in 28-40% of children the complications of JIA-Uv inevitably will be revealed with blurred vision in 10-36% of children, 4. timely diagnosis of JIA-Uv and adequate treatment reduce the risk of complications by 4% per year, 5. current medical care system reveals in one third of children already the complications of JIA-Uv. Revelation in tears of the motif mode for protein interaction network, triggering mobilization/inhibition of cells which moderate Uv would contradict the traditional point of view on existing natural anatomic and physiologic barriers, isolating the intraocular space, but however seems to be possible since JIA is a systemic disease and Uv leads to damage of the blood-retinal barriers. To reveal protein biomarkers of JIA-Uv tears of 31 children aged 2-17 years were studied: 17 – chronic JIA-Uv, 4 – JIA without Uv, 4 – idiopathic Uv, 3 – systemic vasculitis, 3 – healthy children. We used the current clinical guidelines and standards to diagnose the pathology and TMS with hierarchical clustering methodology for protein identification: nano C18 column attached to Shimadzu nano LC coupled in-line to LTQ Orbitrap XL tandem mass spectrometer, data-dependent 4-event scan method, a survey FT-MS parent scan followed by sequential data dependent FT-MS/MS scans on the three most abundant peptide ions. Proteins were identified from the mass spectra results with Proteome Discoverer 1.2 software for protein database search using the International Protein Index (IPI) and Human Protein Database. Quantification was conducted using SIEVE 2.0 after normalization to albumin keeping in mind the validity of proportional change of its concentration after stimulation of lacri-mation. Data from SIEVE were exported to IPA (Ingenuity Pathway Analysis) for filtering. The extracellular proteins selected in Ingenuity were further analyzed for disease relation and networks formation. TMS revealed more than 3000 proteins in tears and 300 of them have been considered to be the first row candidates to be biomarkers of JIA-Uv. The top two proteins, lactoferrin and lipocalin were upregulated over ten-fold in children with Uv. Pathway analysis placed these proteins into the inflammation-related IL-1 and TNF-α related networks which also included proteins involved in the development of endothelial dysfunction, inflammation and retinopathy. In addition, IL-23, which was previously linked to Uveitis, was found to be upregulated. Taken together, our proof-of-principle study presents a novel and yet untested approach for detection of early biomarkers of Uveitis and identified several candidate proteins.

Vyacheslav G Chasnyk

Author for correspondence.
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, PhD, Dr Med Sci, Professor, Head of the Department of Hospital Pediatrics

Ekaterina V Gaidar
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, Research Fellow, Chair of Hospital Pediatrics

Anatolii Viktorovich Kononov
North-Western State Medical University named after I.I. Mechnikov
Russian Federation

MD, Research Fellow, Chair of ophthalmology

Tatyana Ammosova
Howard University
Russian Federation

PhD, Assistant Professor, Department of Medicine

Alla Hynes
Eye Care Physicians and Surgeons
Russian Federation

MD, Ophthalmologist, Director

Margarita F Dubko
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, PhD, Associate Professor, Chair of Hospital Pediatrics

Mikhail M Kostik
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, PhD, Associate Professor, Chair of Hospital Pediatrics

Tatiana N Nikitina
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, PhD, Assistant Professor, Chair of Ophthalmology

Elena D Serogodskaia
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, PhD, Assistant Professor, Chair of Ophthalmology

Olga V Kalashnikova
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, PhD, Associate Professor, Chair of Hospital Pediatrics

Vera V Masalova
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, PhD, Associate Professor, Chair of Hospital Pediatrics

Ludmila S Snegireva
St Petersburg State Pediatric Medical University, Ministry of Healthcare of the Russian Federation
Russian Federation

MD, Department of Pediatrics No 3

Vladimir A Keltsev
Togliatti Municipal Clinical Hospital No 5
Russian Federation

MD, PhD, Consulting professor

Liudmila I Grebenkina
Togliatti Municipal Clinical Hospital No 5
Russian Federation

MD, PhD, Pediatric cardiologist

Yuri Obukhov
Howard University
Russian Federation

PhD, Research Scientist

Xionghao Lin
Howard University
Russian Federation

PhD, Research Scientist

Sergei Nekhai
Howard University
Russian Federation

PhD, Professor, Department of Medicine

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Copyright (c) 2017 Chasnyk V.G., Gaidar E.V., Kononov A.V., Ammosova T., Hynes A., Dubko M.F., Kostik M.M., Nikitina T.N., Serogodskaia E.D., Kalashnikova O.V., Masalova V.V., Snegireva L.S., Keltsev V.A., Grebenkina L.I., Obukhov Y., Lin X., Nekhai S.

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