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Brief Report |

Precision Medicine Personalized Proteomics for the Diagnosis and Treatment of Idiopathic Inflammatory Disease

Gabriel Velez, BS1,2,3; C. Nathaniel Roybal, MD, PhD1,2; Diana Colgan, PhD1,2; Stephen H. Tsang, MD, PhD4,5; Alexander G. Bassuk, MD, PhD6; Vinit B. Mahajan, MD, PhD1,2
[+] Author Affiliations
1Omics Laboratory, University of Iowa Carver College of Medicine, Iowa City
2Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City
3Medical Scientist Training Program, University of Iowa Carver College of Medicine, Iowa City
4Barbara and Donald Jonas Laboratory of Stem Cells and Regenerative Medicine and Bernard and Shirlee Brown Glaucoma Laboratory, Edward S. Harkness Eye Institute, Columbia University, New York, New York
5Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, New York
6Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City
JAMA Ophthalmol. 2016;134(4):444-448. doi:10.1001/jamaophthalmol.2015.5934.
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Importance  To better characterize posterior uveitis, vitreous samples from 15 patients were subjected to antibody arrays, and the expression levels of 200 human cytokines were evaluated. Expression was analyzed by 1-way analysis of variance (significance at P < .01), unsupervised cluster algorithm, and pathway analysis.

Observations  Unbiased clustering of patients, based on their cytokine expression profile, suggested that particular protein networks and molecular pathways are altered in various forms of uveitis. Expression of interleukin 23 (IL-23), IL-1 receptor I (IL-1RI), IL-17R, tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2), insulinlike growth factor–binding protein 2 (IGFBP-2), nerve growth factor (b-NGF), platelet-derived growth factor receptor β polypeptide (PDGFRb), bone morphogenic protein 4 (BMP-4), and stem cell factor (SCF) constituted a common cytokine signature in the vitreous of patients with uveitis. In 1 patient with progressive, idiopathic visual loss, this last-line analysis implicated retinal autoimmunity, a diagnosis that was validated when her serum sample was found to contain antibodies to S-arrestin, a retinal protein and potent cause of autoimmune retinal degeneration.

Conclusions and Relevance  The analysis identifies a common cytokine signature for posterior uveitis and guides the diagnosis of a patient with idiopathic uveitis. Personalized treatment reversed the visual loss, illustrating how proteomic tools may individualize therapy.

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Figure 1.
Clinical Course of Idiopathic Inflammatory Eye Disease With Persistent Retinal Edema Before and After Personalized Proteomics

The patient had a visual acuity of 20/70 OD and 20/20 OS. A, Her right eye had an epiretinal membrane at presentation (white arrowhead); the left eye was normal. B, Spectral-domain optical coherence tomography (SD-OCT) confirmed the epiretinal membrane (blue arrowhead) and moderate cystic retinal edema in the right eye with a normal electroretinogram (ERG); the left eye had normal findings. C, The postvitrectomy SD-OCT showed relapsing retinal edema (white arrowhead) with 20/70 visual acuity OD, despite intermittent intravitreal corticosteroid injections, and normal findings in the postvitrectomy left eye. The personalized proteome of vitreous fluid biopsy indicated an antiretinal antibody autoimmune reaction (described in Figure 2). After implantation of a controlled-release fluocinolone acetonide device (Retisert; Bausch & Lomb), retinal edema resolved without any relapse, and her visual acuity stabilized to 20/30 OD. D, The left eye eventually developed retinal edema (white arrowhead) and an epiretinal membrane (blue arrowhead). E, The later ERG showed abnormalities consistent with retinal inflammation. The scotopic rod-specific ERG waveform was within a normal range. However, the transient photopic wave had a more than 3-ms delay in latency. In addition, the 30-Hz flicker was 50% below normal amplitudes with a 2-ms delay in latency. Div indicates division.

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Figure 2.
Common Cytokine Signature in a Vitreous Sample From a Patient With Idiopathic Inflammatory Eye Disease

A, Unbiased hierarchal clustering revealed the idiopathic inflammatory case (patient 9) clustered with cases of autoimmune retinopathy (P < .01). Orange indicates high expression; black to green, low expression, with black representing the lowest. B, Each uveitis type expressed unique protein profiles (described in eFigure 2 in the Supplement) and uveitis with a common cytokine signature consisting of upregulated interleukin 23 (IL-23), IL-1 receptor I (IL-1RI), IL-17R, tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2), insulinlike growth factor–binding protein 2 (IGFBP-2), nerve growth factor (b-NGF), platelet-derived growth factor receptor β polypeptide (PDGFRb), bone morphogenic protein 4 (BMP-4), and stem cell factor (SCF) and downregulated vascular endothelial growth factor C (VEGF-C) and neutrophil-activating protein 2 (NAP-2). C, Hierarchal clustering of differentially expressed proteins (P < .01) show an unmistakable cytokine signature in the idiopathic case and autoimmune retinopathy cases. AIR indicates autoimmune retinopathy; ALCAM, activated leukocyte cell adhesion molecule; AR, androgen receptor; ARN, acute retinal necrosis; 4-1BB, tumor necrosis factor receptor superfamily member 9 (TNFRSF9); BLC, B lymphocyte chemoattractant; BTC, betacellulin; CNV, choroidal neovascularization; CTACK, cutaneous T-cell–attracting chemokine; EGF R, endothelial growth factor receptor; ENA-78, epithelial neutrophil-activating peptide 78; EpCAM, epithelial cell adhesion molecule; FasL, Fas ligand; FcrRIIB/C, fragment crystalizable receptor II; FGF-7, fibroblast growth factor 7; GCP-2, granulocyte chemotactic peptide-2; HCC-1, hemofiltrate CC-chemokine-1; ICAM-3, intracellular adhesion molecule 3; IGF-1, insulinlike growth factor 1; MCF R, mitochondrial substrate carrier family protein; MCP-1, monocyte chemoattractant protein 1; MICA, major HLA-A; MIF, migration inhibitory factor; MIP-1d, macrophage inflammatory protein 1d; MPIF-1, myeloid progenitor inhibitory factor 1; MRC, macrophage mannose receptor 1; NrCAM, neuronal cell adhesion molecule; NRG1-b1, neuregulin-1; PAI-I, plasminogen activator inhibitor I; PARC, C-C motif chemokine 18; PIGF, placental growth factor; TECK, thymus expressed chemokine; TGF-b2, transforming growth factor β2; TIM-1, T-cell Ig mucin I; TNFR1, tumor necrosis factor receptor 1; and TREM-1, triggering receptor expressed on myeloid cells 1.

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