Faculty Bibliography

Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T_reg) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T_reg cells depend on store-operated Ca²⁺ entry (SOCE), which is mediated by ORAI1 Ca²⁺ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3⁺ T_reg cell-specific deletion of Stim1 and Stim2 develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (T_H1) and interferon (IFN) signaling. CD4⁺ T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ-dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4⁺ T cell-induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4⁺ T cells from patients with SjD, which indicate enhanced T_H1 but reduced memory T_reg cell function. Together, our study provides evidence for a critical role of dysfunctional T_reg cells and IFN-γ-producing T_H1 cells in the pathogenesis of SjD.

Corneal cross-linking (CXL) has profoundly changed the management of keratoconus and other ectatic corneal diseases. Introduced in the late 1990s, CXL marked the first effective intervention to halt disease progression. This chapter describes the history of CXL, beginning with its conceptual foundations and preclinical studies conducted at the University of Dresden. Early experiments established the efficacy of riboflavin and UV-A light to induce collagen cross-linking, which improved corneal stiffness. Clinical translation followed with the Dresden protocol, demonstrating safety and efficacy. Long-term studies confirm sustained benefits, with advances in accelerated protocols and modifications for thin corneas extending eligibility to more patients. Additionally, CXL has expanded into infectious keratitis treatment and refractive surgery. Emerging innovations, such as customized and two-photon CXL, promise further applications. By examining the milestones in its evolution, this paper highlights the transformative impact of CXL on corneal disease management.

PURPOSE/OBJECTIVE:We present a patient with a primary vasoproliferative tumor (VPT) accompanied by vitreous haze and an epiretinal membrane (ERM). We report for the first time the vitreous cytokine profile from an eye with a primary VPT to explore the relationship between intraocular inflammation and these tumors. METHODS:Retrospective chart review of a single patient case. RESULTS:25-gauge pars plana vitrectomy with membrane peel and vitreous biopsy was performed. Peripheral vitreous shave exposed an inferior grey-red mass located at the ora serrata, consistent with VPT. Treatment with confluent, long duration endolaser was performed. Vitreous cytology was negative for malignancy. A 13-cytokine panel (Associated Regional and University Pathologists, Inc. Laboratories, Salt Lake City, UT) revealed elevated interleukin 6 (13.3 pg/mL; normal <=2.0) and interleukin 8 (6.0 pg/mL; normal <=3.0). At one month post-operative, visual acuity improved from 20/40 to 20/25 OD, with mild anterior vitreous inflammation and regression of the VPT. CONCLUSION/CONCLUSIONS:Pro-inflammatory and pro-angiogenic cytokines were elevated in the vitreous of this patient's eye with a primary VPT. We suggest that the endothelial cells and macrophages which comprise VPTs could secrete these cytokines into the vitreous, resulting in vitreous haze and an overzealous fibrotic response manifested as ERM formation.

PURPOSE/OBJECTIVE:The aim of this study was to identify successful recruitment strategies and obstacles reported by principal investigators (PIs) of the Zoster Eye Disease Study (ZEDS). METHODS:A web-based survey was created by a subset of ZEDS PIs and distributed to ZEDS PIs after study enrollment was closed. The survey queried investigators about recruitment strategies and obstacles, use of prophylactic oral antiviral medication, electronic medical records, telemedicine, COVID-19 effect, turnover of research staff, and recruitment outreach to minority and underserved populations. The survey allowed objective measures and free-text options. Analysis from centers with higher enrollment was compared with centers with lower enrollment to identify successful strategies and common obstacles. RESULTS:The most frequently cited helpful strategies were participation from ophthalmologists within the PI's institution (33/63, 52%), ophthalmology resident referrals (23/63, 37%), and chart review (23/63, 37%). Travel to participating clinical center (42/63, 67%) and ongoing prophylactic use of oral systemic antiviral medication (39/63, 62%) were common obstacles. Research coordinator turnover was identified as a contributor to reduced recruitment success by 49% (31/63) of PIs and made recruitment much harder for 22% (14/63). A small number of investigators used telemedicine (18/63, 29%) and few made efforts to recruit from minority and underserved populations (10/63, 16%). CONCLUSIONS:Our survey highlights the importance of internal ophthalmologist referral, chart review, and research coordinator commitment for successful clinical trial recruitment. We discuss the impact of prophylactic use of oral antiviral medication on recruitment. Future randomized clinical trials should mobilize the helpful recruitment strategies and improve outreach to underserved populations.

PURPOSE/OBJECTIVE:The purpose of this study was to characterize the morphological and immunological aspects of biointegration at the optic-cornea joint of a second-generation synthetic corneal device. METHODS:The initial prototype, single-piece optic-skirt configuration, is constructed from compact and flexible perfluoroalkoxy alkane with porous expanded polytetrafluoroethylene (ePTFE) overlying the skirt to allow skirt-cornea biointegration. The second-generation version was modified to add ePTFE around the optic wall to allow optic-cornea biointegration. Initial and amended second-generation devices were implanted into healthy rabbit eyes. Clinical examination, anterior segment optical coherence tomography, light microscopy, and immunofluorescence studies were performed to assess structural integrity and determine molecular signatures indicative of inflammation and tissue remodeling between the 2 prototypes. RESULTS:Recipient eyes with both device versions showed no epithelial defects or tissue retraction at 3 months postoperatively. Optical coherence tomography images demonstrated no appreciable perioptic space with either prototype. Histopathology of the initial device demonstrated lack of stromal adhesion at the optic-cornea joint with epithelium filling the perioptic space. Second-generation devices demonstrated full sealing of the recipient stroma along the optic stem. Although the routine histopathology did not demonstrate inflammatory cells in the recipient cornea with either device, immunohistochemistry stains demonstrated quiescent phenotype of stromal and epithelial cells only in the second-generation devices. CONCLUSIONS:Biointegration between the synthetic corneal device and recipient tissue at the optic-cornea joint seems to avert inflammation and may help prevent sterile tissue lysis and prolong retention.

PURPOSE:For structure-function research at the transition of aging to age-related macular degeneration, we refined the current consensus optical coherence tomography (OCT) nomenclature and evaluated a novel review software for investigational high-resolution OCT imaging (HR-OCT; <3 µm axial resolution). METHOD:Volume electron microscopy, immunolocalizations, histology, and investigational devices informed a refined OCT nomenclature for a custom ImageJ-based review tool to assess retinal band visibility. We examined effects on retinal band visibility of automated real-time averaging (ART) 9 and 100 (11 eyes of 10 healthy young adults), aging (10 young vs 22 healthy aged), and age-related macular degeneration (AMD; 22 healthy aged, 17 early (e)AMD, 15 intermediate (i)AMD). Intrareader reliability was assessed. RESULTS:Bands not included in consensus nomenclature are now visible using HR-OCT: inner plexiform layer (IPL) 1-5, outer plexiform layer (OPL) 1-2, outer segment interdigitation zone 1-2 (OSIZ, including hyporeflective outer segments), and retinal pigment epithelium (RPE) 1-5. Cohen's kappa was 0.54-0.88 for inner and 0.67-0.83 for outer retinal bands in a subset of 10 eyes. IPL-3-5 and OPL-2 visibility benefitted from increased ART. OSIZ-2 and RPE-1,2,3,5 visibility was worse in aged eyes than in young eyes. OSIZ-1-2, RPE-1, and RPE-5 visibility decreased in eAMD and iAMD compared to healthy aged eyes. CONCLUSIONS:We reliably identified 28 retinal bands using a novel review tool for HR-OCT. Image averaging improved inner retinal band visibility. Aging and AMD development impacted outer retinal band visibility. TRANSLATIONAL SIGNIFICANCE:Detailed knowledge of anatomic structures visible on OCT will enhance precision in research, including AI training and structure-function analyses.