Yuya Kii

B Cell-Derived Vascular Endothelial Growth Factor A Promotes Lymphangiogenesis and High Endothelial Venule Expansion in Lymph Nodes

Vascular endothelial growth factor A (VEGF-A) is a prominent growth factor for both angiogenesis and lymphangiogenesis. Recent studies have shown the importance of VEGF-A in enhancing the growth of lymphatic endothelial cells in lymph nodes (LNs) and the migration of dendritic cells into LNs. VEGF-A is produced in inflamed tissues and/or in draining LNs, where B cells are a possible source of this growth factor. To study the effect of B cell-derived VEGF-A, we created transgenic mice (CD19Cre/hVEGF-Afl) that express human VEGF-A specifically in B cells. We found that the human VEGF-A produced by B cells not only induced lymphangiogenesis in LNs, but also induced the expansion of LNs and the development of high endothelial venules. Contrary to our expectation, we observed a significant decrease in the Ag-specific Ab production postimmunization with OVA and in the proinflammatory cytokine production postinoculation with LPS in these mice. Our findings suggest immunomodulatory effects of VEGF-A: B cell-derived VEGF-A promotes both lymphangiogenesis and angiogenesis within LNs, but then suppresses certain aspects of the ensuing immune responses.

Intraocular expression and release of high-mobility group box 1 protein in retinal detachment

High-mobility group box 1 (HMGB1) protein is a multifunctional protein, which is mainly present in the nucleus and is released extracellularly by dying cells and/or activated immune cells. Although extracellular HMGB1 is thought to be a typical danger signal of tissue damage and is implicated in diverse diseases, its relevance to ocular diseases is mostly unknown. To determine whether HMGB1 contributes to the pathogenesis of retinal detachment (RD), which involves photoreceptor degeneration, we investigated the expression and release of HMGB1 both in a retinal cell death induced by excessive oxidative stress in vitro and in a rat model of RD-induced photoreceptor degeneration in vivo. In addition, we assessed the vitreous concentrations of HMGB1 and monocyte chemoattractant protein 1 (MCP-1) in human eyes with RD. We also explored the chemotactic activity of recombinant HMGB1 in a human retinal pigment epithelial (RPE) cell line. The results show that the nuclear HMGB1 in the retinal cell is augmented by death stress and upregulation appears to be required for cell survival, whereas extracellular release of HMGB1 is evident not only in retinal cell death in vitro but also in the rat model of RD in vivo. Furthermore, the vitreous level of HMGB1 is significantly increased and is correlated with that of MCP-1 in human eyes with RD. Recombinant HMGB1 induced RPE cell migration through an extracellular signal-regulated kinase-dependent mechanism in vitro. Our findings suggest that HMGB1 is a crucial nuclear protein and is released as a danger signal of retinal tissue damage. Extracellular HMGB1 might be an important mediator in RD, potentially acting as a chemotactic factor for RPE cell migration that would lead to an ocular pathological wound-healing response.

Relationship between position of peak retinal nerve fiber layer thickness and retinal arteries on sectoral retinal nerve fiber layer thickness.

PURPOSE We determined the relationship between the position of the peak of the retinal nerve fiber layer (RNFL) thickness, and the retinal arteries, axial length (AL), and sectoral RNFL thickness in healthy eyes. METHODS A prospective, observational cross-sectional study (registration number, UMIN000006040) of 50 healthy right eyes (mean age 25.8 ± 3.7 years) was performed. The RNFL thickness was measured by optical coherence tomography in twelve 30° sectors (clock hours) around the optic disc. The RNFL nasal-superior-temporal-inferior-nasal curves and fundus photographs were used to measure the angles between the supratemporal and infratemporal peak RNFL positions (peak angle), and the retinal artery angle (artery angle), respectively. The relationships between the peak angle, artery angle, AL, and sectoral RNFL thickness were investigated by linear regression analyses. RESULTS The peak angles were highly correlated with the artery angle (r = 0.92, P < 0.001) and correlated negatively with the AL (r = -0.49, -0.38; P < 0.01). After excluding the effect of the AL, the peak and artery angles were correlated significantly with the sectoral RNFL thickness in 8 sectors. After excluding the effect of the peak angle, the AL was correlated significantly with the sectoral RNFL thicknesses in only one sector. CONCLUSIONS The temporal RNFL thickness increased as the superior and inferior RNFL peaks, and retinal arteries shifted toward the fovea, whereas an inverse relationship was observed for the inferior and supranasal areas. The sectoral RNFL thickness is correlated better with the peak and artery angles than the axial length. (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary &recptno=R000007154&language=J number, UMIN000006040.).

Responsiveness of eyes with polypoidal choroidal vasculopathy with choroidal hyperpermeability to intravitreal ranibizumab

BackgroundTo determine the role played by vascular endothelial growth factor (VEGF) in polypoidal choroidal vasculopathy (PCV) based on an interventional immunology theory.MethodsEyes with PCV were divided in a masked fashion into those with choroidal hyperpermeability (HP group) and those with normal choroidal permeability (NP group) based on the indocyanine green angiograms. The inter-rater agreement rate was evaluated using Fleiss’ kappa. Patients were treated by intravitreal ranibizumab (IVB). The central choroidal thickness and central foveal thickness (CFT) at the baseline and 7 days after the treatment were measured by optical coherence tomography.ResultsAmong the 57 consecutive eyes diagnosed with PCV, 42 eyes of 42 patients met the inclusion criteria (21 eyes/HP group vs 21 eyes /NP group). Central choroidal thickness in HP group was significantly thicker than that in the NP group (P < .001, Mann–Whitney U test). The inter-rater agreement was high with a Fleiss’ kappa = 0.95, P < .0001. The percentage reduction in the CFT in HP group (14.0%) was significantly less than that in NP group (20.4%; P = .013, Mann–Whitney U test).ConclusionsEyes with PCV that are associated with choroidal hyper-permeability may not be strongly associated with VEGF-related pathology, and may not respond favorably to anti-VEGF monotherapy.

Stromal-Derived Factor-1 and Inflammatory Cytokines in Retinal Vein Occlusion

Purpose: To identify the roles of stromal-derived factor (SDF-1) and inflammatory cytokines in retinal vein occlusion (RVO). Methods: Samples were collected by vitrectomy and the levels of SDF-1, vascular endothelial growth factor, and inflammatory cytokines (interleukins [IL-1β, IL-6, IL-8, IL-10, IL-12p70]; tumor necrosis factor-α) were measured in 20 eyes with RVO, and 9 eyes with epiretinal membrane served as negative controls. Four eyes with inflammatory diseases were also investigated. Results: SDF-1 levels in active RVO (A-RVO; 4 eyes with iris neovascularization) were significantly higher than those in quiescent RVO (Q-RVO; 16 eyes without iris neovascularization) and the negative controls (p <. 01), whereas there were no significant difference between the Q-RVO and the negative controls. There were no significant correlations between the concentrations of SDF-1 and other cytokines. Conclusions: Elevation of intravitreous SDF-1 levels in A-RVO but not Q-RVO suggested a pivotal role of SDF-1 in angiogenic changes during RVO.

Relationship between supernormal sectors of retinal nerve fibre layer and axial length in normal eyes

To determine the effect of the axial length on the supernormal and false‐positive sectors of the peripapillary retinal nerve fibre layer (RNFL) in healthy eyes using the normative database embedded in a spectral domain optical coherence tomographic (SD‐OCT) instrument.

Posterior Pole Asymmetry Analyses of Retinal Thickness of Upper and Lower Sectors and Their Association With Peak Retinal Nerve Fiber Layer Thickness in Healthy Young Eyes

PURPOSE To determine the symmetry of the retinal thicknesses (RT) between the 32 pairs of superior and inferior sectors by posterior pole asymmetrical analysis (PPAA) of the spectral-domain optical coherence tomographic (SD-OCT) images in healthy eyes. In addition, to determine their association with the position of the peak retinal nerve fiber layer (RNFL) thickness. METHODS A prospective, observational, cross-sectional study of 64 right eyes. The Spectralis SD-OCT was used to obtain the images, and the PPAA determined the RT of the 64 cells within the central 24° area. The program also compared the thicknesses of corresponding cells across the fovea-disc axis. Circular scans were used to measure the supra- and infratemporal RNFL peak angle differences (PADs). The relationships between the RT of the corresponding cells and the relationship between the differences of the RT of the corresponding cells and PAD were investigated by linear regression analysis. RESULTS The mean differences between the RT of corresponding cells ranged from 3.1 to 23.2 μm. The RT of all upper cells were significantly correlated with the RT of the corresponding lower cells (R = 0.45-0.97, P < 0.001). The coefficients of correlation between the corresponding pairs of central- and temporal-macular cells were higher than that of the peripheral and nasal-macular cells. The differences of the pairs of nasal-macular cells RT were significantly correlated with the PAD. CONCLUSIONS The symmetry of the RT between the upper and lower cells was high in the central and temporal-macular areas but not in the peripheral and nasal-macular areas. (www.umin.ac.jp/ctr number, UMIN000006040.).

Association between retinal thickness of 64 sectors in posterior pole determined by optical coherence tomography and axial length and body height.

PURPOSE We determined a significant correlation between the retinal thickness (RT) in 64 cells or sectors of the posterior pole, and the axial length (AL) and the body height (BH). METHODS A prospective, observational cross-sectional study of 64 right eyes of 64 healthy volunteers (mean age, 26.0 ± 4.5 years; range, 22-39 years). The RT within the central 24° area was measured in the Spectralis spectral domain-optical coherence tomographic (SD-OCT) images. The correlations between the RT and the AL or the BH were determined by linear regression analyses. RESULTS The mean ± SD of the AL was 25.04 ± 1.30 mm, and that of the BH was 167.2 ± 8.5 cm. The RTs of the central four cells around the fovea were not significantly correlated with the AL. The RTs of 54 cells were significantly and negatively associated with the AL (r = -0.25 to -0.56, P < 0.05). In contrast, the RTs of the central to temporal eight cells were significantly and positively correlated with the BH (r = 0.26-0.37, P < 0.05). The RTs of 56 cells were not significantly correlated with the BH. CONCLUSIONS The RT of the posterior retina, except in the fovea, decreased as AL elongated, and those of the central temporal areas were significantly correlated with the BH. Thus, the AL and BH must be considered when the RT is evaluated. The 64-sector analysis on OCT is useful to assess the detailed changes of RT affected by them. (http://www.umin.ac.jp/ctr/index.htm number, UMIN000007154.).

Retinopathy associated with Machado–Joseph disease (spinocerebellar ataxia 3) with CAG trinucleotide repeat expansion☆

PURPOSE To report characteristic atrophic maculopathy in a patient with Machado--Joseph disease (spinocerebellar ataxia 3) caused by trinucleotide repeat expansion of the relevant gene. METHODS Case report. RESULTS A 64-year-old Japanese man had suffered from slurred speech and gait disturbance since 57 years of age. Cerebellar ataxia, extensor plantar response, and other neurological signs were compatible with features of Machado--Joseph disease. Magnetic resonance imaging showed atrophies of cerebellum and cerebral cortex. Family history suggested an autosomal dominant inheritance of the disease. The patient presented with gaze-evoked nystagmus and limitations of eye movement in all directions. Ophthalmoscopy and fluorescein angiogram revealed symmetric changes in the posterior fundi, which consisted of patchy atrophies at the level of the retinal pigment epithelium. Scotopic electroretinogram showed no abnormalities with normal oscillatory potentials. Polymerase chain reaction analysis of the Machado--Joseph disease gene identified a heterozygous trinucleotide (CAG) repeat expansion. CONCLUSION This case illustrates a rare association of atrophic maculopathy and external ophthalmoplegia in Machado--Joseph disease, contrasted with the common occurrence of retinal degeneration in spinocerebellar ataxia 7. Dystrophic changes in the retinal pigment epithelium have rarely been described but may be one of the characteristic complications of Machado--Joseph disease.

Circumpapillary course of retinal pigment epithelium can be fit to sine wave and amplitude of sine wave is significantly correlated with ovality ratio of optic disc.

The purpose of this study was to develop a method of quantifying the degree of optic disc tilt in normal eyes. This was a prospective, observational cross sectional study of 126 right eyes of 126 healthy volunteers. The optic disc tilt was determined from the circular peripapillary optical coherence tomographic (OCT) scan images. The course of the retinal pigment epithelium (RPE) layer in the peripapillary cross sectional scan images was fit to a sine wave curve, and the amplitude of the sine curve was used to reflect the degree of the optic disc tilt in the optical axis. The repeatability of the amplitude determinations was calculated. The correlation between the amplitude and the ovality ratio of the optic disc was determined. The correlation between the amplitude and the body height was also calculated. The mean amplitudewas 36.6 ± 17.5 pixels, which was significantly and inversely correlated with the ovality ratio of the optic disc (R = -0.59, P<0.001). The intra-rater and inter-rater correlation coefficients of the amplitude were significant high (P<0.001, both). The amplitude was significantly and inversely correlated with the body height (R = -0.38, P<0.001), but not with the axial length. In conclusion, a sine wave function can be used to describe the course of the RPE in the circumpapillary OCT images. The results indicate that the amplitude of the sine wave can be used to represent the degree of optic disc tilt. Thus, the sine wave analyses can be used as a quantifiable and repeatable method to determine the optic disc tilt.