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Investigation of Cytotoxic T Lymphocyte Function during Allorejection in the Anterior Chamber of the Eye.

ABSTRACT: Cytotoxic T lymphocytes (CTL) are an essential part of our immune system by killing infected and malignant cells. To fully understand this process, it is necessary to study CTL function in the physiological setting of a living organism to account for their interplay with other immune cells like CD4+ T helper cells and macrophages. The anterior chamber of the eye (ACE), originally developed for diabetes research, is ideally suited for non-invasive and longitudinal in vivo imaging. We take advantage of the ACE window to observe immune responses, particularly allorejection of islets of Langerhans cells by CTLs. We follow the onset of the rejection after vascularization on islets until the end of the rejection process for about a month by repetitive two-photon microscopy. We find that CTLs show reduced migration on allogeneic islets in vivo compared to in vitro data, indicating CTL activation. Interestingly, the temporal infiltration pattern of T cells during rejection is precisely regulated, showing enrichment of CD4+ T helper cells on the islets before arrival of CD8+ CTLs. The adaptation of the ACE to immune responses enables the examination of the mechanism and regulation of CTL-mediated killing in vivo and to further investigate the killing in gene-deficient mice that resemble severe human immune diseases.

SUBMITTER: Chang HF

PROVIDER: S-EPMC7369940 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Investigation of Cytotoxic T Lymphocyte Function during Allorejection in the Anterior Chamber of the Eye.

Chang Hsin-Fang HF Wirkner Marie-Louise ML Krause Elmar E Rettig Jens J

International journal of molecular sciences 20200630 13

Cytotoxic T lymphocytes (CTL) are an essential part of our immune system by killing infected and malignant cells. To fully understand this process, it is necessary to study CTL function in the physiological setting of a living organism to account for their interplay with other immune cells like CD4<sup>+</sup> T helper cells and macrophages. The anterior chamber of the eye (ACE), originally developed for diabetes research, is ideally suited for non-invasive and longitudinal in vivo imaging. We t ...[more]

PMID: 32629968

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Project description:ImportanceExfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.ObjectiveTo determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.Design, setting, and participantsA 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.ExposuresRare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.Main outcomes and measuresThe primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.ResultsThe discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.Conclusions and relevanceIn this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.

Project description:PurposeWe sought to investigate anatomic mechanisms of angle narrowing by assessing ocular biometric determinants of anterior chamber angle width.DesignPopulation-based cross-sectional study.MethodsSubjects ≥50 years of age from the Chinese American Eye Study underwent a comprehensive ocular examination, including anterior segment optical coherence tomography imaging and ultrasound A-scan. Independent variables, including anterior chamber depth (ACD), lens vault (LV), iris curvature (IC), anterior chamber width, lens thickness, vitreous cavity depth, and axial length, and dependent variables, including angle opening distance, were measured in 1 randomly selected eye per subject. Univariable and multivariable regression models with standardized regression coefficients (SRCs) and semipartial correlation coefficients squares (SPCC2) were used to assess relative and unique contributions by independent variables to angle width.ResultsTwo thousand two hundred twenty-five subjects (1433 women and 834 men) were included in the analysis. All biometric parameters except lens thickness differed between men and women (age-adjusted P < .001). In model 1A (R2 = 0.66), which included ACD, lens thickness, and vitreous cavity depth, ACD (SRC = 0.64, SPCC2 = 0.19) and IC (SRC = -0.26, SPCC2 = 0.041) were the strongest determinants of angle opening distance. In model 1B (R2 = 0.58), which included LV and axial length, LV (SRC = -0.46, SPCC2 = 0.1) and IC (SRC = -0.3, SPCC2 = 0.047) were the strongest determinants of angle opening distance. Determinants of angle width were similar in separate multivariable models for men and women.ConclusionsACD, LV, and IC are the strongest determinants of angle width in Chinese Americans. Sex-related differences in angle width are explained by differences among biometric measurements. These results provide insights into anatomic mechanisms of angle narrowing and have important implications for quantitative assessments of angle closure eyes.

Project description:PurposeTo characterize the relationship between mean and sectoral variation of anterior chamber angle (ACA) width using anterior segment optical coherence tomography (AS-OCT).MethodsSubjects aged 50 years or older were identified from the Chinese American Eye Study (CHES), a population-based epidemiological study in Los Angeles, CA. Each subject underwent a complete ocular examination including gonioscopy and AS-OCT imaging. Primary angle closure disease (PACD) was defined as inability to visualize pigmented trabecular meshwork in 3 or more quadrants. Four AS-OCT images from one eye per subject were analyzed and parameters describing ACA width were measured at 500 and 750 μm from the scleral spur: angle opening distance (AOD), trabecular iris space area (TISA), and scleral spur angle (SSA). The relationship between mean and sectoral variation of ACA width was assessed using locally-weighted scatterplot smoothing (LOWESS) regression and change-point analyses and Spearman correlation coefficients.Results674 eyes (337 with PACD, 337 without PACD) from 674 subjects were analyzed. Overall, sectoral variation of ACA width decreased as mean ACA width decreased. This relationship was divided into two phases based on the change-point analysis. Sectoral variation of ACA width was strongly and significantly correlated (P < 0.001) with mean ACA width with below parameter-specific change points for most parameters: AOD500 (r = 0.599), AOD750 (r = 0.246), TISA500 (r = 0.734), TISA750 (r = 0.664), SSA500 (r = 0.661), SSA750 (r = 0.394). Correlations were weaker but still significant (P < 0.004) above these change points for most parameters: AOD500 (r = 0.321), AOD750 (r = 0.550), TISA500 (r = 0.122), TISA750 (r = 0.275), SSA500 (r = -0.036), SSA750 (r = 0.313). Correlations to the left and right of the change points strengthened when sectoral variation of ACA width was adjusted for mean ACA width.ConclusionsCorrelations between mean and sectoral variation of ACA width strengthen as the severity of angle narrowing worsens. This relationship likely reflects anatomical changes related to chronic angle closure and may be relevant for refining current definitions and management of PACD.

Dataset Information

Investigation of Cytotoxic T Lymphocyte Function during Allorejection in the Anterior Chamber of the Eye.

Publications

Investigation of Cytotoxic T Lymphocyte Function during Allorejection in the Anterior Chamber of the Eye.

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