Vitreous proteomics, a gateway to improved understanding and stratification of diverse uveitis aetiologies

Abstract

Purpose The vitreous proteome might provide an attractive gateway to discriminate between various uveitis aetiologies and gain novel insights into the underlying pathophysiological processes. Here, we investigated 180 vitreous proteins to discover novel biomarkers and broaden disease insights by comparing (1). primary vitreoretinal lymphoma ((P)VRL) versus other aetiologies, (2). sarcoid uveitis versus tuberculosis (TB)‐associated uveitis and (3). granulomatous (sarcoid and TB) uveitis versus other aetiologies. Methods Vitreous protein levels were determined by proximity extension assay in 47 patients with intraocular inflammation and a prestudy diagnosis (cohort 1; training) and 22 patients with a blinded diagnosis (cohort 2; validation). Differentially expressed proteins identified by t‐tests on cohort 1 were used to calculate Youden’s indices. Pathway and network analysis was performed by ingenuity pathway analysis. A random forest classifier was trained to predict the diagnosis of blinded patients. Results For (P)VRL stratification, the previously reported combined diagnostic value of IL‐10 and IL‐6 was confirmed. Additionally, CD70 was identified as potential novel marker for (P)VRL. However, the classifier trained on the entire cohort (cohort 1 and 2) relied primarily on the interleukin score for intraocular lymphoma diagnosis (ISOLD) or IL‐10/IL‐6 ratio and only showed a supportive role for CD70. Furthermore, sarcoid uveitis displayed increased levels of vitreous CCL17 as compared to TB‐associated uveitis. Conclusion We underline the previously reported value of the ISOLD and the IL‐10/IL‐6 ratio for (P)VRL identification and present CD70 as a potentially valuable target for (P)VRL stratification. Finally, we also show that increased CCL17 levels might help to distinguish sarcoid uveitis from TB‐associated uveitis.

Serum CCL17 distinguishes sarcoid uveitis from TB‐uveitis and QFT‐negative uveitis

“…Recently, we reported that vitreous from sarcoid uveitis contained significantly higher CCL17 levels than vitreous from TB-uveitis (Schrijver et al 2021). This finding underscores immunopathobiological differences between sarcoid uveitis and TB-uveitis despite the high level of clinical similarity.…”

“…This finding underscores immunopathobiological differences between sarcoid uveitis and TB-uveitis despite the high level of clinical similarity. Moreover, we proposed vitreous CCL17 as a potential biomarker to discriminate sarcoid uveitis from TBuveitis (Youden's index 0.45, sensitivity 67% and specificity 78%) (Schrijver et al 2021).…”

Update in Molecular Testing for Intraocular Lymphoma

“…Genomic analysis of IOL is actively being pursued and has already revealed novel therapeutic targets towards the goal of personalized management of patients with IOL [ 91 , 92 , 93 ]. Ongoing proteomic analysis can identify novel diagnostic biomarkers for IOL [ 94 ]. Further advancements in this area have the potential to improve timely diagnoses of IOL, improving patient outcomes.…”

Value of Combined Diagnosis for Choroidal Lymphoma: A Case Report

“…Presently, the diagnosis of IOL depends on intraocular biopsy, followed by a combination of cytologic evaluation, immunohistochemistry, and flow cytometry [ 16 , 17 ]. Moreover, molecular testing and proteomic analysis can identify novel diagnostic biomarkers for IOL, which have the potential to improve timely diagnoses of IOL and patient outcomes [ 18 ]. Hernández-Pons et al [ 19 ] used the IgH Rearrangements Molecular Analysis Kit and monoclonal amplification with three primer mixes (FR1-JH, FR2-JH, and FR3-JH) and diagnosed approximately 90% of all mature B-cell lymphoproliferative processes.…”