Targeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis.

Primary biliary cholangitis (PBC) is a cholestatic autoimmune liver disease characterized by autoreactive T cell response against intrahepatic small bile ducts. Here, we use Il12b-/-Il2ra-/- mice (DKO mice) as a model of autoimmune cholangitis and demonstrate that Cd8a knockout or treatment with an anti-CD8α antibody prevents/reduces biliary immunopathology. Using single-cell RNA sequencing analysis, we identified CD8+ tissue-resident memory T (Trm) cells in the livers of DKO mice, which highly express activation- and cytotoxicity-associated markers and induce apoptosis of bile duct epithelial cells. Liver CD8+ Trm cells also upregulate the expression of several immune checkpoint molecules, including PD-1. We describe the development of a chimeric antigen receptor to target PD-1-expressing CD8+ Trm cells. Treatment of DKO mice with PD-1-targeting CAR-T cells selectively depleted liver CD8+ Trm cells and alleviated autoimmune cholangitis. Our work highlights the pathogenic role of CD8+ Trm cells and the potential therapeutic usage of PD-1-targeting CAR-T cells.

[Superior colliculus-pulvinar-amygdala subcortical visual pathway and its biological significance].

Superior colliculus-pulvinar-amygdala pathway is one of the subcortical visual pathways in mammalian brain. Some recent studies suggest that this pathway is involved in processing emotion-related visual information. This review discusses the possibility that this pathway is more related to visual alert rather than simply the early visual information processing. The biological significance of this pathway is also discussed. Instead of detecting "where" or "what" the visual target is, the task of this early visual stage is to send out a warning signal, i.e., "something appears", so that the brain can be set up in a state of alert, which is important for the survival of animals. Thus, in the early visual information process, detection of new object "emerging" or "disappearing" takes priority over the acquisition of its feature information of "texture" and "shape", etc. The subcortical pathway may provide the neural basis of early visual warning in topological perception, a biological significance critical for animal survival.

MicroRNA-34a promoting apoptosis of human lens epithelial cells through down-regulation of B-cell lymphoma-2 and silent information regulator.

AIM: To investigate the role of microRNA-34a (miR-34a) in the induction of apoptosis of human lens epithelial (HLE-B3) cells. METHODS: The apoptosis of HLE-B3 cells was detected by Annexin V-PE apoptosis detection kit after the treatment with 200 µmol/L H2O2 for 24h and lentiviral miR-34a vector transfection. The expression of miR-34a in the cells was quantified by quantitative real time polymerase chain reaction (qRT-PCR) in response to H2O2 exposure and the vector transfection. The effects of overexpression of miR-34a on the expression of B-cell lymphoma-2 (Bcl-2) and silent information regulator 1 (SIRT1) was determined by qRT-PCR and Western blot. RESULTS: The expression of miR-34a was up-regulated by the treatment of H2O2 in HLE-B3 cells. The increased expression of miR-34a is accompanied with the cell apoptosis. Consistence with the H2O2 exposure, ectopic overexpression of miR-34a in HLE-B3 cells promoted cells apoptosis. Importantly the anti-apoptosis factors Bcl-2 and SIRT1 were reduced significantly by up-regulation of miR-34a in HLE-B3 cells. CONCLUSION: MiR-34a promotes the apoptosis of HLE-B3 cells by down-regulating Bcl-2 and SIRT1, suggesting that miR-34a may involve in the pathogenesis of cataract formation and targeting miR-34a may be a potentially therapeutic approach for treatment of cataract.

Sub-threshold micro-pulse diode laser treatment in diabetic macular edema: A Meta-analysis of randomized controlled trials.

AIM: To examine possible differences in clinical outcomes between sub-threshold micro-pulse diode laser photocoagulation (SDM) and traditional modified Early Treatment Diabetic Retinopathy Study (mETDRS) treatment protocol in diabetic macular edema (DME). METHODS: A comprehensive literature search using the Cochrane Collaboration methodology to identify RCTs comparing SDM with mETDRS for DME. The participants were type I or type II diabetes mellitus with clinically significant macular edema treated by SDM from previously reported randomized controlled trials (RCTs). The primary outcome measures were the changes in the best corrected visual acuity (BCVA) and the central macular thickness (CMT) as measured by optical coherence tomography (OCT). The secondary outcomes were the contrast sensitivity and the damages of the retina. RESULTS: Seven studies were identified and analyzed for comparing SDM (215 eyes) with mETDRS (210 eyes) for DME. There were no statistical differences in the BCVA after treatment between the SDM and mETDRS based on the follow-up: 3mo (MD, -0.02; 95% CI, -0.12 to 0.09; P=0.77), 6mo (MD, -0.02; 95% CI, -0.12 to 0.09; P=0.75), 12mo (MD, -0.05; 95% CI, -0.17 to 0.07; P=0.40). Likewise, there were no statistical differences in the CMT after treatment between the SDM and mETDRS in 3mo (MD, -9.92; 95% CI, -28.69 to 8.85; P=0.30), 6mo (MD, -11.37; 95% CI, -29.65 to 6.91; P=0.22), 12mo (MD, 8.44; 95% CI, -29.89 to 46.77; P=0.67). Three RCTs suggested that SDM laser results in good preservation of contrast sensitivity as mETDRS, in two different follow-up evaluations: 3mo (MD, 0.05; 95% CI, 0 to 0.09; P=0.04) and 6mo (MD, 0.02; 95% CI, -0.10 to 0.14; P=0.78). Two RCTs showed that the SDM laser treatment did less retinal damage than that mETDRS did (OR, 0.05; 95% CI, 0.02 to 0.13; P<0.01). CONCLUSION: SDM laser photocoagulation shows an equally good effect on visual acuity, contrast sensitivity, and reduction of DME as compared to conventional mETDRS protocol with less retinal damage.

Clinical patterns and characteristics of uveitis in a secondary hospital in southern China.

AIM: To investigate the characteristics of uveitis in a secondary hospital in southern China. METHODS: We reviewed all records of patients with uveitis at Hengli Hospital from January 2008 to December 2011. Demographic data, past history, ophthalmic examinations and other laboratory tests were analyzed. RESULTS: One hundred and ninety-nine uveitis patients were enrolled in this study, including 134 (67.3%) males and 65 females (32.7%) with an average age of 41.0±15.1y. The anatomical distribution included 103 (51.8%) cases of anterior uveitis, followed by panuveitis (65, 32.7%), posterior uveitis (29, 14.6%) and intermediate uveitis (2, 1.0%). Of the 98 (49.2%) non-idiopathic cases, there were 10.1% Behcet's disease, 9.5% Vogt-Koyanagi-Harada (VKH) syndrome, 7.5%infectious uveitis, 7.5% traumatic uveitis and 3.5% postoperative uveitis. CONCLUSION: Idiopathic anterior and posterior uveitis, Behcet's disease, VKH syndrome, infectious uveitis and traumatic uveitis are the most common uveitis entities in a secondary hospital in southern China. Additional measures should be taken to prevent infectious and traumatic uveitis.

[Comparative assessment of individualized multifocal intraocular lens implantation].

OBJECTIVE: To evaluate the visual quality after combined implantation of refractive and diffractive multifocal intraocular lens (MIOLs) in both eyes (CustomMatch pattern). METHODS: Prospective, nonrandomized study. Zhongshan Ophthalmic Center, Sun yat-sen university, P.R. China. Age-related cataract patients, selected according to the inclusion criteria and divided into MIOL group and monofocal intraocular lens (SIOL) group, received phacoemulsification and were implanted with combined a ReZoom NXG1 IOL in the dominant eye and a Tecnis ZM900 IOL in the fellow eye or bilateral Sensar AR40e IOLs. Monocular and binocular testing one month after surgery included uncorrected and best-spectacle corrected visual acuity at far, intermediate and near distances under 100 cd/m(2) and 6 cd/m(2), reading visual acuity and reading speed, defocus curve, and subjective vision-related quality of life using questionnaire. RESULTS: Under 100 cd/m(2) and 6 cd/m(2), binocular mean uncorrected visual acuity at 500 cm in MIOL group was logMAR 0.013 +/- 0.149 and logMAR 0.163 +/- 0.220 and binocular mean best-spectacle corrected visual acuity was logMAR -0.027 +/- 0.092 and logMAR 0.109 +/- 0.175 respectively. The mean refraction spherical equivalent for best distance corrected visual acuity was (-0.18 +/- 0.85) D and (-0.32 +/- 0.90) D respectively. Under 100 cd/m(2), better uncorrected visual acuity (decimal 0.63) at 40 cm, 63 cm and 100 cm was achieved in MIOL group. Under 6 cd/m(2), the uncorrected visual acuities in MIOL group at 40 cm and 63 cm distance were significantly higher than those in SIOL group although there were no statistically difference at 100 cm. Uncorrected reading visual acuity and reading speed in MIOL group were better than those in SIOL group, while the results in reading ability were similar when MIOL group without correction compared with SIOL group with correction. The depth of focus was 5.5 diopter in MIOL group. No patient in both groups wore glasses for distance and 70% patients in MIOL group did not need to wear glasses for intermediate and near distances after surgery. CONCLUSION: CustomMatch pattern could provide a satisfactory vision at a full range of near, intermediate and far distance and improve the life quality to a certain extent.

[Comparative assessment of visual quality after combined implantation of multifocal intraocular lens].

OBJECTIVE: To evaluate the visual quality after combined implantation of refractive and diffractive multifocal intraocular lenses (IOL) in both eyes. METHODS: Prospective, nonrandomized study. Age-related cataract patients were divided into multifocal IOL group (MIOL group) and monofocal IOL group (SIOL group) and received phacoemulsification. In MIOL group, a ReZoom NXG1 IOL and a Tecnis Z M900 IOL were implanted into the dominant eye and the fellow eye, respectively. In SIOL group, Sensar AR40e IOLs were implanted into both eyes. Monocular or binocular test was performed one month after surgery, including wavefront aberration, contrast sensitivity with or without glare and near stereoacuity. RESULTS: The root mean square of spherical aberration at pupil diameter of 5 mm was 0.058 +/- 0.159 microm in NXG1 eyes and 0.005 +/- 0.169 microm in ZM900 eyes, both of them were significantly lower than 0.408 +/- 0.160 microm achieved in AR40e eyes (F = 11.734; P = 0.001, 0.000). There was no significant difference in the total ocular aberration, contrast sensitivity and high-order aberration among eyes with these different IOLs. The uncorrected near stereoacuity in MIOL group was (45.60 +/- 35.04) seconds of arc, which was significantly better than (110.00 +/- 41.23) seconds of arc achieved in SIOL group (F = 2.923; P = 0.010). CONCLUSION: Combined implantation of multifocal ReZoom NXG1 IOL and Tecnis ZM900 IOL provides a good visual quality with reduced spherical aberration and satisfactory near stereoacuity.

[Expression of programmed death 1 and its ligands in iris-ciliary body from mice with anterior chamber-associated immune deviation].

OBJECTIVE: To study the expression and possible implication of programmed death 1 (PD-1) and its ligands in the iris-ciliary body from mice with anterior chamber-associated immune deviation (ACAID). METHODS: This was an experimental study. Twenty-four BALB/c mice were divided into ACAID group, negative controls, positive controls and phosphate-buffer saline controls. ACAID was evaluated by delayed-type hypersensitivity response. Expressions of PD-1 and its ligands (PD-L1, PD-L2) in the iris-ciliary body from ACAID mice were determined by real-time polymerase chain reaction and immunohistochemical studies. RESULTS: Delayed-type hypersensitivity was not detected in ACAID group, indicating that ACAID was induced successfully. The expression of PD-1 mRNA in ACAID group was higher than that in all other groups (F = 248. 109, P < 0.05). The positive controls showed a high expression of PD-L1 mRNA (F = 179. 033, P < 0.05). PD-1 and PD-L1 positive cells with round or oval shapes were found in whole iris-ciliary body, especially in the iris base and pupil margin. Expression of PD-1 and PD-L1 proteins were similar to their expression at mRNA levels. Neither mRNA nor protein of PD-L2 was detected in the iris-ciliary body in all groups. CONCLUSION: An increased expression of PD-1 in the iris-ciliary body of ACAID mice indicates that this is involved in the induction of ACAID.