Inborn Errors of Immunity and Autoimmune Disease.

Autoimmunity may be a manifestation of inborn errors of immunity, specifically as part of the subgroup of primary immunodeficiency known as primary immune regulatory disorders. However, although making a single gene diagnosis can have important implications for prognosis and management, picking patients to screen can be difficult, against a background of a high prevalence of autoimmune disease in the population. This review compares the genetics of common polygenic and rare monogenic autoimmunity, and explores the molecular mechanisms, phenotypes, and inheritance of autoimmunity associated with primary immune regulatory disorders, highlighting the emerging importance of gain-of-function and non-germline somatic mutations. A novel framework for identifying rare monogenic cases of common diseases in children is presented, highlighting important clinical and immunologic features that favor single gene disease and guides clinicians in selecting appropriate patients for genomic screening. In addition, there will be a review of autoimmunity in non-genetically defined primary immunodeficiency such as common variable immunodeficiency, and of instances where primary autoimmunity can result in clinical phenocopies of inborn errors of immunity.

Asymmetric Intrastromal Corneal Ring Segments with Progressive Base Width and Thickness for Keratoconus: Evaluation of Efficacy and Analysis of Epithelial Remodeling.

Purpose: The aim of this study is to describe visual outcomes and epithelial remodeling following the implantation of asymmetric intracorneal ring segments (ICRSs) of variable thickness and base width for the management of duck-type keratoconus. Methods: A prospective observational study of patients with duck-type keratoconus was conducted. All patients received one ICRS AJL PRO + implant (AJL Ophthalmic). We analyzed demographic and clinical data, anterior segment optical coherence tomography (AS-OCT) data and Scheimpflug camera images obtained with a Placido disc MS-39 (CSO, Firenze, Italy) one and six months after surgery to determine keratometric and aberrometric outcomes and epithelial remodeling. Results: We studied 33 keratoconic eyes. ICRS implantation significantly improved both corrected distance visual acuity (CDVA) and uncorrected distance visual acuity at six months, as assessed with the logMAR (minimum angle of resolution) system, from 0.32 ± 0.19 to 0.12 ± 0.12 (p < 0.001) and from 0.75 ± 0.38 to 0.37 ± 0.24 (p < 0.001), respectively. Overall, 87% of implanted eyes gained ≥ 1 line of CDVA, and 3% of patients (n = 1) lost one line of CDVA; 55% of eyes attained a manifest refraction spherical equivalent between +1.50 and -1.50 D. Epithelial remodeling was greater at the wider and thicker end (+11.33 µm ± 12.95; p < 0.001 relative to the initial value) than at the narrower and thinner end (+2.24 µm ± 5.67; p = 0.01). Coma aberration was significantly reduced from 1.62 ± 0.81 µm to 0.99 ± 0.59 µm (p < 0.001). Conclusions: AJL-PRO + ICRS implantation for duck-type keratoconus improves refractive, topographic, aberrometric and visual parameters and induces progressive epithelial thickening along the segment.

Laser Doppler holography of the anterior segment for blood flow imaging, eye tracking, and transparency assessment.

Laser Doppler holography (LDH) is a full-field blood flow imaging technique able to reveal human retinal and choroidal blood flow with high temporal resolution. We here report on using LDH in the anterior segment of the eye without making changes to the instrument. Blood flow in the bulbar conjunctiva and episclera as well as in corneal neovascularization can be effectively imaged. We additionally demonstrate simultaneous holographic imaging of the anterior and posterior segments by simply adapting the numerical propagation distance to the plane of interest. We used this feature to track the movements of the retina and pupil with high temporal resolution. Finally, we show that the light backscattered by the retina can be used for retro-illumination of the anterior segment. Hence digital holography can reveal opacities caused by absorption or diffusion in the cornea and eye lens.

Comparative Study of Asymmetric Versus Non-asymmetric Intrastromal Corneal Ring Segments for the Management of Keratoconus.

PURPOSE: To compare the outcomes obtained with models of asymmetric and non-asymmetric intracorneal ring segments (ICRS) in keratoconic eyes with asymmetric topo-graphic patterns. METHODS: In this prospective observational study, ICRS were implanted alternately in patients with the same tomographic patterns of keratoconus assigned to four groups. Patients with the "duck" phenotype received one asymmetric or non-asymmetric ICRS and patients with the "snowman" pheno-type received two asymmetric or non-asymmetric ICRS. Visual, refractive, astigmatism, keratometric, and corneal aberrometry changes were evaluated over a 6-month follow-up period. RESULTS: Sixty-eight eyes were analyzed. No significant difference was observed between the use of one asymmetric and one non-asymmetric ICRS in duck phenotypes. In snowman keratoconus, the inferior-superior index decreased significantly (P = .03) with asymmetric but not with non-asymmetric ICRS implantation. Total corneal higher order aberrations and coma rates were lower, but not significantly so, after the implantation of two asymmetric ICRS in snowman phenotypes (2.85 ± 0.89 to 2.60 ± 0.91 µm, P = .20 and 2.64 ± 0.93 to 2.39 ± 0.98 µm, P = .21), and significantly higher after the implantation of two non-asymmetric ICRS (2.56 ± 1.28 to 3.08 ± 1.62 µm, P = .02 and 2.34 ± 1.27 to 2.84 ± 1.62 µm, P = .02). CONCLUSIONS: Asymmetric ICRS did not improve the outcomes of ICRS implantation in duck keratoconus. However, the implantation of two asymmetric ICRS was more effective than that of two non-asymmetric ICRS for decreasing vertical asymmetry and preventing increases in corneal aberration in the snowman phenotype of keratoconus. [J Refract Surg. 2021;37(8):552-561.].

Postoperative Corneal Epithelial Remodeling After Intracorneal Ring Segment Procedures for Keratoconus: An Optical Coherence Tomography Study.

PURPOSE: To assess epithelial corneal remodeling by anterior segment optical coherence tomography (AS-OCT) after intracorneal ring segments (ICRS) implantation in keratoconic eyes. METHODS: This prospective observational study included patients with keratoconus receiving ICRS of different arc lengths according to their tomographic pattern. AS-OCT and corneal topography (Scheimpflug camera) were performed before and 1, 3, and 6 months after surgery. Corneal pachymetry mapping was performed and total corneal and epithelial thicknesses (3-mm central and 16 points on 6-mm zone) were measured over the pupil center using AS-OCT. Topographic parameters were also assessed. RESULTS: A total of 68 keratoconic eyes were analyzed (Amsler-Krumeich stages 1 to 4) in four groups of 17 eyes: 210° ICRS, 320° ICRS, double 160° ICRS, and single 160° ICRS. Corneal pachymetry mapping revealed that epithelial thickness increased significantly in the internal zones juxtaposed to the ICRS without smoothing during the postoperative period (P < .05). Mean maximum epithelial thickness increased from 67 ± 6 to 79 ± 7 µm for 210° ICRS, 66 ± 9 to 82 ± 4 µm for 320° ICRS, 63 ± 6 to 78 ± 7 µm for double 160° ICRS, and 62 ± 5 to 77 ± 5 µm for single 160° ICRS (P < .0001). Significant epithelial thickening at the apex of the cone was observed in all groups (P < .05). CONCLUSIONS: Significant epithelial thickening occurs after ICRS implantation adjacent to the ICRS to compensate for the ridge created with a thickening of epithelium over the cone due to regularization of the stromal surface. [J Refract Surg. 2021;37(6):404-413.].

Haematopoietic stem cell transplantation for primary immunodeficiency syndromes: A 5-year single-centre experience.

AIM: Haematopoietic stem cell transplantation (HSCT) is a central therapy in the treatment of primary immunodeficiency diseases (PIDs). Over the past 5 years, outcomes have been greatly improved due to earlier diagnosis, improved donor availability, advancements in graft manipulation and the use of less toxic preparative regimens. We present a 5-year audit of HSCT for PID at a single Australian tertiary hospital. METHODS: Retrospective case note review identified diagnosis, pre-transplant medical morbidity, transplant protocol, engraftment, adverse events, post-transplant immune reconstitution and general health. RESULTS: A total of 22 patients with PID underwent 24 HSCTs at our institution between 2012 and 2016. The most common indications were severe combined immunodeficiency, chronic granulomatous disease and familial haemophagocytic lymphohistiocytosis, with a genetic diagnosis in all but two patients. Reduced intensity or reduced toxicity conditioning was used in 91% of cases, and 75% of the donors were unrelated. Transplant-related mortality at day +100 was 9.5%, and cumulative overall survival was 86%. There were three mortalities, all secondary to viral infection, one of which occurred in the context of graft failure. Two patients remained on immune support, with the remainder achieving adequate immune reconstitution. CONCLUSIONS: The outcomes for HSCT for PIDs performed at Sydney Children's Hospital were in line with the world's best practice. HSCT should be considered a potential therapeutic option for all Australian PID patients with a valid disease indication.

Maternal cigarette smoking is associated with reduced high-density lipoprotein cholesterol in healthy 8-year-old children.

AIMS: Smoking in pregnancy is common. Its effects on lipoprotein levels and arterial structure in childhood are not well characterized. We aimed to determine the effects of maternal smoking in pregnancy on lipoprotein levels and arterial wall thickness in healthy pre-pubertal children. METHODS AND RESULTS: A community-based longitudinal study with prospective ascertainment of exposure to smoking in pregnancy and environmental tobacco smoke (ETS) since birth and then lipoprotein and arterial measurements at age 8 years. In 616 newborn infants (gestation >36 weeks and birth weight >2.5 kg) data were collected prospectively by questionnaire on smoking in pregnancy and ETS exposure in childhood. At age 8-years, 405 of the children had measurements of lipoproteins, blood pressure (BP) and carotid intima-media thickness. Children born to mothers who smoked in pregnancy had lower HDL cholesterol [1.32 vs. 1.50 mmol/L, 95% confidence interval (CI) for difference -0.28 to -0.08, P = 0.0005], higher triglycerides (1.36 vs. 1.20 mmol/L, 95% CI for ratio 1.01-1.30, P = 0.04) and higher systolic BP (102.1 vs. 99.9 mmHg, 95% CI for difference 0.6-3.8, P = 0.006). After adjustment for maternal passive smoking, post-natal ETS exposure, gender, breast feeding duration, physical inactivity, and adiposity, smoking in pregnancy remained significantly associated with lower HDL cholesterol (difference = -0.22 mmol/L, 95% CI -0.36 to -0.08, P = 0.003) but not with higher systolic BP. Neither smoking in pregnancy nor post-natal ETS exposure was associated with alterations of carotid artery wall thickness. CONCLUSION: Smoking in pregnancy is independently associated with significantly lower HDL cholesterol in healthy 8-year-old children.

Severe obesity is associated with impaired arterial smooth muscle function in young adults.

The degree of arterial dilatation induced by exogenous nitrates (nitrate-mediated dilatation, NMD) has been similar in obese and normal-weight adults after single high-dose glyceryl trinitrate (GTN). We examined whether NMD is impaired in obesity by performing a GTN dose-response study, as this is a potentially more sensitive measure of arterial smooth muscle function. In this cross-sectional study, subjects were 19 obese (age 31.0 ± 1.2 years, 10 male, BMI 44.1 ± 2.1) and 19 age- and sex-matched normal-weight (BMI 22.4 ± 0.4) young adults. Blood pressure (BP), triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL)-cholesterol, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), carotid intima-media thickness (CIMT), and flow-mediated dilatation (FMD) were measured. After incremental doses of GTN, brachial artery maximal percent dilatation (maximal NMD) and the area under the dose-response curve (NMD AUC) were calculated. Maximal NMD (13.4 ± 0.9% vs. 18.3 ± 1.1%, P = 0.002) and NMD AUC (54,316 ± 362 vs. 55,613 ± 375, P = 0.018) were lower in obese subjects. The obese had significantly higher hs-CRP, insulin, and CIMT and lower HDL-cholesterol. Significant bivariate associations existed between maximal NMD or NMD AUC and BMI-group (r = -0.492, P = 0.001 or r = -0.383, P = 0.009), hs-CRP (r = -0.419, P = 0.004 or r = -0.351, P = 0.015), and HDL-cholesterol (r = 0.374, P = 0.01 or r = 0.270, P = 0.05). On multivariate analysis, higher BMI-group remained as the only significant determinant of maximal NMD (r² = 0.242, ß = -0.492, P = 0.002) and NMD AUC (r² = 0.147, ß = -0.383, P = 0.023). In conclusion, arterial smooth muscle function is significantly impaired in the obese. This may be important in their increased cardiovascular risk.