Biomarkers for PVR in rhegmatogenous retinal detachment

Abstract

Purpose Various profibrotic and proinflammatory cytokines have been found upregulated in uncomplicated primary retinal detachment (pRD), but without providing a uniform picture. Here, we compare the cyto- and chemokine profiles in pRD with and without proliferative vitreoretinopathy (PVR) in an attempt to unravel relevant differences not in single cytokines, but in the cytokine profiles at diagnosis. Methods Undiluted vitreous fluid (VF) was obtained at the beginning of surgery from 174 eyes with pRD without relevant PVR (maximally grade B; group 1; n = 81) and with moderate or advanced PVR requiring a gas tamponade (group 2; n = 49) or silicon oil filling (group 3; n = 44). VF of eyes undergoing macular hole (MH) surgery served as controls (group 4; n = 26). Forty-three cytokines were quantified in parallel using a multiplex cytokine analysis system (Bioplex). For all comparisons we applied Holm’s correction to control for multiple comparisons. Results 44.9% of group 2 eyes presented grade C1 and 55.1% C2-C3, whereas 86.4% of group 3 eyes exhibited a PVR grade of C2-D. CCL19 was the only cytokine that displayed higher concentrations in the vitreous of eyes with PVR C1 compared to lower PVR grades. Eyes with PVR C2-D showed higher levels of CCL27, CXCL6, IL4, IL16, CXCL10, CCL8, CCL22, MIG/CXCL9, CCL15, CCL19, CCL 23 and CXCL12 compared to controls. Interestingly, no difference of cytokine levels was detected between C1 and C2-D PVR. Conclusions CCL19 may represent a potential biomarker for early PVR progression that holds promise for future diagnostic and therapeutic applications.

Inflammatory and Fibrogenic Factors in Proliferative Vitreoretinopathy Development

“…89 An early response to retinal detachment is the infiltration into the subretinal space of IL-1β-secreting macrophages which may contribute to photoreceptor death through the (nucleotide-binding oligomerization domain) NOD-like receptor family and pyrin-domaincontaining-3 protein inflammasome, 90 as well as stimulating RPE cells to upregulate inflammatory cytokines, including IL-6. 91 IL-1α and IL-1β are present in subretinal and vitreal fluid in cases of RRD and established PVR and are variably reported to be raised in PVR, 38,80,86 whereas other studies suggest that elevated IL-1α, but not IL-1β levels are associated with subsequent PVR risk. 9,92 Generic inflammatory cytokines are likely to be present in all eyes with retinal detachment irrespective of whether they subsequently develop PVR, and in the report suggesting IL-1α associated with subsequent PVR risk, there was extensive overlap between levels in patients who did and did not subsequently develop PVR, 9 suggesting limited utility as a biomarker.…”

“…[78][79][80][81][82][83] IL-6 can also stimulate corneal epithelial cells and stromal fibroblasts (and macrophages) to produce profibrotic VEGF. 78 Like most inflammatory cytokines, IL-6 is present in subretinal fluid in high titers during retinal detachment and RRD repair, 84,85 and their presence is correlated with the subsequent, development of postoperative PVR, 9 as well as being elevated in the vitreous of patients with early PVR, 38,86 and correlating with PVR severity when found in sub silicone-oil fluid, 87 but, because subretinal and vitreous IL-6 levels significantly overlap between patients with uncomplicated retinal detachment and severe or future PVR, they have limited biomarker potential.…”

“…73 RPE cells secrete CTLA-2α, differentiating T cells into TGFβproducing T reg cells. 104 In patients with RRD caused by PVR, variably elevated levels of TGF-β 2 are recorded in aqueous and vitreous samples and excised PVR fibrous membranes, 43,86,93,105,106 and single nucleotide polymorphisms in TGFβ 1&2 associate with PVR risk. 45 Because TGFβ isoforms regulate the synthesis and degradation of ECM proteins both in vitro and in vivo, causing increased collagen accumulation and fibrosis, they are obvious candidates as PVR predicative biomarkers.…”

“…114 Most chemokines tested for are elevated in the subretinal fluid of patients with primary RRD compared to vitreous from patients with macular hole. 86,[115][116][117] One study finds higher CCL2 levels in established PVR than in primary RRD, suggesting a late role in the disease process. 118 Zandi et al 86 record elevated levels of a multiplicity of chemokines (CCL8, 15,19,22,23,26,27 and CXCL6,9,10,12) in cases of PVR compared to primary RRD without PVR but find that only levels of CCL19 are associated with the grade of PVR.…”

“…86,[115][116][117] One study finds higher CCL2 levels in established PVR than in primary RRD, suggesting a late role in the disease process. 118 Zandi et al 86 record elevated levels of a multiplicity of chemokines (CCL8, 15,19,22,23,26,27 and CXCL6,9,10,12) in cases of PVR compared to primary RRD without PVR but find that only levels of CCL19 are associated with the grade of PVR. 86 Ricker et al [115][116][117]119 find that CCL17, 19,22, and CXCL9 to predict the development of postoperative PVR and CCL19 also correlated with postoperative visual acuity, and Hoerster et al 108 find that aqueous CCL2 predicts the development of PVR.…”