Regulatory T cells (Tregs) play a central role in the induction and maintenance of immune homeostasis and self-tolerance. Tregs constantly express the high-affinity receptor to IL-2. IL-2 is a ...pleiotropic cytokine and a key survival factor for Tregs. It maintains Tregs' suppressive function by promoting Foxp3 expression and subsequent production of immunoregulatory cytokines. Administration of low-dose IL-2 is shown to be a promising approach to prevent allograft rejection and to treat autoimmune and inflammatory conditions in experimental models. The combination of IL-2 with its mAb (JES6-1) has also been shown to increase the
of IL-2 and further enhance Treg frequencies and function. Low-dose IL-2 therapy has been used in several clinical trials to treat conditions such as hepatitis C vasculitis, graft-versus-host disease, type 1 diabetes, and systemic lupus erythematosus. In this paper, we summarize our findings on low-dose IL-2 treatment in corneal allografting and review recent studies focusing on the use of low-dose IL-2 in transplantation, autoimmunity, and other inflammatory conditions. We also discuss potential areas of further investigation with the aim to optimize current low-dose IL-2 regimens.
To assess overall prevalence, annual prevalence, and incidence of dry eye disease (DED) in a large, representative population in the United States.
Prevalence and incidence study.
Retrospective ...analysis using the Department of Defense (DOD) Military Health System (MHS) data on beneficiary medical claims from United States DOD military and civilian facilities, January 1, 2003 through March 31, 2015. Patient Population: Using an algorithm, medical diagnostic codes indicative of DED and prescriptions for cyclosporine ophthalmic emulsion identified a DED population from 9.7 million MHS beneficiaries (DOD service members, retirees, and dependents, aged 2-80+ years). Main Outcome Measures: DED overall prevalence (2003-2015), annual prevalence (2005-2012), and annual incidence (2008-2012) stratified by sex, age group, and International Statistical Classification of Diseases and Related Health Problems, Ninth Revision diagnosis code grouping.
DED prevalence was 5.28% overall, 7.78% among female beneficiaries, 2.96% among male beneficiaries and increased with age from 0.20% for ages 2-17 years, to 11.66% for individuals aged 50+ years. Annual prevalence increased from 0.8% to 3.0% overall, from 1.4% to 4.5% in female beneficiaries, and from 0.3% to 1.6% in male beneficiaries. Annual prevalence increased across age groups starting at age 18-39, 0.1%-0.6%, to age 50+, 1.8%-6.0%. Annual incidence increased from 0.6% to 0.9% overall, from 0.8% to 1.2% in female beneficiaries, and from 0.3% to 0.6% in male beneficiaries. Across age groups, annual incidence increased starting at age 18-39 (0.2%-0.3%), to age 50+ (1.0%-1.6%).
DED overall prevalence, annual prevalence, and incidence were found to increase over time for all demographics. These findings highlight the continued importance of research and therapeutic development for this common condition.
•This study captures a uniquely broad view of the epidemiology of dry eye disease across all ages.•This study provides the first evidence of an increase in incidence/prevalence over time.•This study provides the first evidence of an increase in incidence starting in young adulthood.
The ocular surface is a unique mucosal immune compartment in which anatomical, physiological, and immunological features act in concert to foster a particularly tolerant microenvironment. These ...mechanisms are vital to the functional competence of the eye, a fact underscored by the devastating toll of excessive inflammation at the cornea – blindness. Recent data have elucidated the contributions of specific anatomical components, immune cells, and soluble immunoregulatory factors in promoting homeostasis at the ocular surface. We highlight research trends at this distinctive mucosal barrier and identify crucial gaps in our current knowledge.
Immune privilege protects the eye from sight-threatening immunoinflammatory responses. The factors that orchestrate ocular immune privilege continue to be defined. Current work in the field is focused on the immunoregulatory processes that conspire to limit the effector response.
Our understanding of epithelium-derived immunoregulatory factors, ocular surface dendritic cells, neuroimmune crosstalk, the ocular surface microbiome, memory type 17 T helper (Th17) cells in autoimmunity, and CD4+ T cell plasticity at the ocular surface has deepened markedly over recent years.
Recent findings suggest novel treatment strategies to suppress autoimmunity and promote allotolerance, for instance by modulating CD4+ T cell chemotaxis and expanding regulatory T cell populations.
To evaluate occurrence of subtarsal fibrosis in patients with graft-vs-host disease (GVHD) and to determine its association with ocular surface epitheliopathy.
Cross-sectional study.
We enrolled 40 ...patients with moderate or severe dry eye disease, including 20 patients with chronic ocular GVHD and 20 patients without (as the control group). All patients had a comprehensive ophthalmic assessment including evaluation for subtarsal fibrosis, corneal and conjunctival staining, tear break-up time (TBUT), and Schirmer test. Furthermore, meibomian gland drop-out area and densities of epithelial and stromal immune cells were measured using meibography and in vivo confocal microscopy, respectively.
Subtarsal fibrosis was not seen in any eye of the non-GVHD group. However, 16 eyes (40%) of 10 patients (50%) in the GVHD group had subtarsal fibrosis (P < .001) with an average involvement of 28.9% ± 13.7% of the tarsal area. Fibrosis was more frequent in the upper lids (35%) than in the lower lids (5%). Regression analyses showed that corneal fluorescein staining was significantly associated with the extent of fibrosis (P < .001, β = 0.14) and TBUT (P < .001, β = −0.53) but not with other clinical or imaging parameters. Conjunctival lissamine green staining also had a statistically significant association with the extent of fibrosis (P = .04, β = 0.12) but not other clinical or imaging parameters. Eyes with subtarsal fibrosis had a more severe ocular surface epitheliopathy compared with eyes without fibrosis.
Subtarsal fibrosis is present in a significant percentage of patients with chronic ocular GVHD, likely contributing to the ocular surface damage in these patients.
CD4
CD25
Foxp3
Regulatory T cells (Tregs) play a critical role in immune tolerance. The plasticity and functional adaptability of Tregs in an inflammatory microenvironment has been demonstrated in ...autoimmunity. Here, using a double transgenic mouse model that permits Foxp3 lineage tracing, we investigated the phenotypic plasticity of Foxp3
Tregs in a well-characterized murine model of corneal transplantation. In order to subvert the normal immune privilege of the cornea and foster an inflammatory milieu, host mice were exposed to desiccating stress prior to transplantation. Treg frequencies and function were decreased following desiccating stress, and this corresponded to decreased graft survival. A fraction of Tregs converted to IL-17
or IFNγ
'exFoxp3' T cells that were phenotypically indistinguishable from effector Th17 or Th1 cells, respectively. We investigated how Foxp3 expression is modulated in different Treg subsets, demonstrating that neuropilin-1
peripherally-derived Tregs are particularly susceptible to conversion to IL-17
/IFNγ
exFoxp3 cells in response to cues from their microenvironment. Finally, we show that IL-6 and IL-23 are implicated in the conversion of Tregs to exFoxp3 cells. This report demonstrates that the pathological conversion of Tregs contributes to the loss of corneal immune privilege.
Corneal transplantation is one of the most prevalent and successful forms of solid tissue transplantation. Despite favorable outcomes, immune-mediated graft rejection remains the major cause of ...corneal allograft failure. Although low-risk graft recipients with uninflamed graft beds enjoy a success rate ∼90%, the rejection rates in inflamed graft beds or high-risk recipients often exceed 50%, despite maximal immune suppression. In this review, we discuss the critical facets of corneal alloimmunity, including immune and angiogenic privilege, mechanisms of allosensitization, cellular and molecular mediators of graft rejection, and allotolerance induction.
To evaluate density and morphology of corneal epithelial immune dendritic cells (DCs) in different subtypes of dry eye disease (DED) using in vivo confocal microscopy (IVCM).
This retrospective study ...included 59 eyes of 37 patients with DED and 40 eyes of 20 age-matched healthy controls. Based on clinical tests, eyes with DED were categorized into two subtypes: aqueous-deficient (n = 35) and evaporative (n = 24). For all subjects, images of laser scanning in vivo confocal microscopy (IVCM) of the central cornea were analyzed for DC density and DC morphology (DC size, number of dendrites, and DC field). These DC parameters were compared among all dry eye and control groups.
Compared with the controls, patients with DED had significantly higher DC density, larger DC size, higher number of dendrites, and larger DC field (all P < 0.001). Comparison between aqueous-deficient and evaporative subtypes demonstrated that DC density was significantly higher in aqueous-deficient subtype (189.8 ± 36.9 vs. 58.9 ± 9.4 cells/mm2, P = 0.001). However, there were no significant differences in morphologic parameters between DED subtypes. When aqueous-deficient DED with underlying systemic immune disease (Sjögren's syndrome and graft versus host disease) were compared with nonimmune conditions, the immunologic subgroup showed significantly higher DC density, DC size, and number of dendrites (all P < 0.05).
Corneal IVCM demonstrated differential changes in DC density and morphologic DC parameters between subtypes of DED. These changes, which reflect the degree of immune activation and inflammation in DED, can be used for clinical practice and endpoints in clinical trials.
To evaluate functional vision, general health status, and work productivity in individuals with and without dry eye disease (DED).
Cross-sectional study.
Setting: General US population (2018). Study ...Population: Adults ≥18 years with (n = 1003) or without (n = 1006) self-reported DED. Main Outcome Measures: All respondents completed the National Eye Institute Visual Function Questionnaire (VFQ) and the EuroQol 5-dimensions 5-levels (EQ-5D-5L). All respondents with DED completed the eye dryness score (EDS) visual analogue scale, Ocular Comfort Index (OCI), and Work Productivity and Activity Impairment (WPAI) questionnaire. Half of respondents with DED completed the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire; the other half completed the Dry Eye Questionnaire 5 (DEQ-5) and Standardized Patient Evaluation of Eye Dryness (SPEED), McMonnies, and Symptom Assessment in Dry Eye (SANDE) questionnaires. All analyses were descriptive.
Respondents with DED reported more comorbidities, greater exposure to adverse environmental conditions, and lower (worse) mean (standard deviation) scores on the modified Rasch-scored 28-item VFQ (VFQ-28R) total score (68.8 11.9 vs 81.2 12.7) and EQ-5D-5L (0.82 0.13 vs 0.88 0.14) than respondents without DED. Respondents with DED and EDS ≥60 (highest discomfort) fared worse on OCI, VFQ-28R, and WPAI than respondents with DED and EDS <40 (lowest discomfort). Similar findings were observed with IDEEL, DEQ-5, SPEED, McMonnies, and SANDE scores.
There is a substantial burden of DED on functional vision, general health status, and productivity; and further, these parameters appear to worsen with increasing EDS.
•According to a US survey, dry eye disease negatively impacts functional vision.•Also according to this survey, dry eye disease negatively impacts health status.•The burden of dry eye disease is substantial and increases with eye dryness score.
The cornea is the most commonly transplanted tissue in the body. Corneal grafts in low-risk recipients enjoy high success rates, yet over 50% of high-risk grafts (with inflamed and vascularized host ...beds) are rejected. As our understanding of the cellular and molecular pathways that mediate rejection has deepened, a number of novel therapeutic strategies have been unveiled. This manuscript reviews therapeutic approaches to promote corneal transplant survival through targeting (1) corneal lymphangiogenesis and hemangiogenesis, (2) antigen presenting cells, (3) effector and regulatory T cells, and (4) mesenchymal stem cells.
Th17 cells are critical effectors mediating the ocular surface autoimmunity in dry eye disease (DED). Increased IFN-γ has also been implicated in DED; however, it remains unclear to what extent Th1 ...cells contribute to DED pathogenesis. In this study, we investigated the cellular source of IFN-γ and assessed its contribution to corneal epitheliopathy in DED mice. We discovered a significant IL-17A
IFN-γ
(Th17/1) population and determined that these cells are derived from Th17 precursors. Adoptive transfer of Th17/1, but not Th1, cells confers the disease to naive recipients as effectively as do Th17 cells alone. DED-induced IL-12 and IL-23 are required for in vivo transition of pathogenic Th17 cells to IFN-γ producers. Furthermore, using IFN-γ-deficient Th17 cells, we demonstrate the disease-amplifying role of Th17-derived IFN-γ in DED pathogenesis. These results clearly demonstrate that Th17 cells mediate ocular surface autoimmunity through both IL-17A and IFN-γ.
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