M. Reza Dana

Prevalence of dry eye syndrome among US women.

PURPOSE Dry eye syndrome (DES) is believed to be one of the most common ocular problems in the United States (US), particularly among older women. However, there are few studies describing the magnitude of the problem in women and how this may vary with demographic characteristics. DESIGN Cross-sectional prevalence survey. METHODS STUDY POPULATION we surveyed 39,876 US women participating in the Womens Health Study about a history of diagnosed DES and dry eye symptoms. MAIN OUTCOME MEASURE we defined DES as the presence of clinically diagnosed DES or severe symptoms (both dryness and irritation constantly or often). We calculated the age-specific prevalence of DES and adjusted the overall prevalence to the age distribution of women in the US population. We used logistic regression to examine associations between DES and other demographic factors. RESULTS The prevalence of DES increased with age, from 5.7% among women < 50 years old to 9.8% among women aged > or = 75 years old. The age-adjusted prevalence of DES was 7.8%, or 3.23 million women aged > or = 50 in the US. Compared with Whites, Hispanic (odds ratio [OR] = 1.81, confidence interval [CI] = 1.18-2.80) and Asian (OR = 1.77, CI = 1.17-2.69) women were more likely to report severe symptoms, but not clinically diagnosed DES. There were no significant differences by income (P([trend]) =.78), but more educated women were less likely to have DES (P([trend]) =.03). Women from the South had the highest prevalence of DES, though the magnitude of geographic differences was modest. CONCLUSIONS Dry eye syndrome leading to a clinical diagnosis or severe symptoms is prevalent, affecting over 3.2 million American women middle-aged and older. Although the condition is more prevalent among older women, it also affects many women in their 40s and 50s. Further research is needed to better understand DES and its impact on public health and quality of life.

VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment.

Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1(+) lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A(164/164) or VEGF-A(188/188) (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A-mediated lymphangiogenesis. Either systemic depletion of all bone marrow-derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis.

Immunity causing blindness: five different paths to herpes stromal keratitis

Herpes stromal keratitis (HSK) is a blinding infectious disease that results from an array of immunopathogenic processes, including herpes simplex virus 1 (HSV-1)-specific T helper 1 (Th1) and Th2 cells, cytotoxic T cells and antibodies. As discussed here by Wayne Streilein and colleagues, strategies designed to prevent and treat this syndrome must be aware of the fact that the disease is multifactorial in its cause and pathogenesis.

Androgen Deficiency, Meibomian Gland Dysfunction, and Evaporative Dry Eye

Abstract: Objective. We have recently discovered that women with primary and secondary Sjögrens syndrome are androgen‐deficient. We hypothesize that this hormone insufficiency contributes to the meibomian gland dysfunction, tear film instability, and evaporative dry eye that are characteristic of this autoimmune disorder. If our hypothesis is correct, we predict: (1) that androgens regulate meibomian gland function, control the quality and/or quantity of lipids produced by this tissue, and promote the formation of the tear films lipid layer; and (2) that androgen deficiency, due to an attenuation in androgen synthesis (e.g., during Sjögrens syndrome, menopause, aging, complete androgen‐insensitivity syndrome [CAIS] and anti‐androgen use), will lead to meibomian gland dysfunction and evaporative dry eye. The following studies were designed to test these predictions. Methods. Experimental procedures included clinical studies, animal models, and histological, biochemical, molecular biological, and biomedical engineering techniques. Results. Our results demonstrate that: (1) androgens regulate the meibomian gland. This tissue contains androgen receptor mRNA, androgen receptor protein within acinar epithelial cell nuclei, and Types 1 and 2 5α‐reductase mRNAs. Moreover, androgens appear to modulate lipid production and gene expression in mouse and/or rabbit meibomian glands; and (2) androgen deficiency may lead to meibomian gland dysfunction, altered lipid profiles in meibomian gland secretions, tear film instability, and evaporative dry eye. Thus, we have found that anti‐androgen therapy in men is associated with meibomian gland disease, a decreased tear film breakup time, and functional dry eye. Furthermore, we have discovered that androgen receptor dysfunction in women with CAIS is associated with meibomian gland changes and a significant increase in the signs and symptoms of dry eye. Of interest, we have also found that androgen deficiency is associated with significant and striking alterations in the neutral and polar lipid patterns of human meibomian gland secretions. Conclusions. Our findings show that the meibomian gland is an androgen target organ and that androgen deficiency may promote meibomian gland dysfunction and evaporative dry eye. Overall, these results support our hypothesis that androgen deficiency may be an important etiologic factor in the pathogenesis of evaporative dry eye in women with Sjögrens syndrome.

Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity.

There are no studies so far linking molecular regulation of lymphangiogenesis and induction of adaptive immunity. Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting (dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants. Regulating the function of VEGFR-3 may therefore be a mechanism for modulating adaptive immunity in the periphery.

Corneal immunity is mediated by heterogeneous population of antigen‐presenting cells

Corneal antigen‐presenting cells (APC), including dendritic cells (DC), were thought to reside exclusively in the peripheral cornea. Here, we present recent data from our group demonstrating that the central cornea is indeed endowed with a heterogeneous population of epithelial and stromal DC, which function as APC. Although the corneal periphery contains mature and immature resident bone marrow‐derived CD11c+ DC, the central cornea is endowed exclusively with immature and precursor DC, both in the epithelium and the stroma, wherein Langerhans cells and monocytic DC reside, respectively. During inflammation, a majority of resident DC undergo maturation by overexpressing major histocompatibility complex class II and B7 (CD80/CD86) costimulatory molecules. In addition to the DC, macrophages are present in the posterior corneal stroma. In transplantation, donor‐derived DC are able to migrate to host cervical lymph nodes and activate host T cells via the direct pathway when allografts are placed in inflamed host beds. These data revise the tenet that the cornea is immune‐privileged as a result of lack of resident lymphoreticular cells and suggest that the cornea is capable of diverse cellular mechanisms for antigen presentation.

Draining lymph nodes of corneal transplant hosts exhibit evidence for donor major histocompatibility complex (MHC) class II-positive dendritic cells derived from MHC class II-negative grafts.

To examine the widely accepted dogmas that corneal grafts lack passenger leukocytes or cells capable of migrating directly to lymph nodes (LNs), we tracked the migration of corneal graft-derived transgenic green fluorescent protein (GFP; Iab) cells into the draining LNs of allogeneic (Iad) recipients. GFP+ cells were identified in cervical LNs several hours after transplantation, and this traffic was significantly enhanced when grafts were placed in inflamed recipient beds. Draining cells were Iab+, CD45+, and CD11c+, and examination of ungrafted corneas revealed numerous similarly CD45+CD11c+CD3−CD8α− cells that uniformly lacked major histocompatibility complex (MHC) class II expression; transmission electron microscopy confirmed the presence of morphologically similar cells. After transplantation, or placement in culture, these CD11c+ cells became class II+ in a time-dependent manner and were capable of allostimulatory function. However, the stimulatory capacity of these cornea-derived dendritic cells (DCs) was suppressed compared with splenic controls. These results demonstrate for the first time that the cornea is endowed with resident DCs that are universally MHC class II− but that are capable of expressing class II antigen after surgery and migrating to draining LNs of allografted hosts. These data refute the tenet that the cornea is immune privileged due to lack of resident lymphoreticular cells or due to antigenic sequestration from systemic immunity.

Topical Omega-3 and Omega-6 Fatty Acids for Treatment of Dry Eye

OBJECTIVE To study the efficacy of topical application of alpha-linolenic acid (ALA) and linoleic acid (LA) for dry eye treatment. METHODS Formulations containing ALA, LA, combined ALA and LA, or vehicle alone, were applied to dry eyes induced in mice. Corneal fluorescein staining and the number and maturation of corneal CD11b(+) cells were determined by a masked observer in the different treatment groups. Real-time polymerase chain reaction was used to quantify expression of inflammatory cytokines in the cornea and conjunctiva. RESULTS Dry eye induction significantly increased corneal fluorescein staining; CD11b(+) cell number and major histocompatibility complex Class II expression; corneal IL-1alpha and tumor necrosis factor alpha (TNF-alpha) expression; and conjunctival IL-1alpha, TNF-alpha, interferon gamma, IL-2, IL-6, and IL-10 expression. Treatment with ALA significantly decreased corneal fluorescein staining compared with both vehicle and untreated controls. Additionally, ALA treatment was associated with a significant decrease in CD11b(+) cell number, expression of corneal IL-1alpha and TNF-alpha, and conjunctival TNF-alpha. CONCLUSIONS Topical ALA treatment led to a significant decrease in dry eye signs and inflammatory changes at both cellular and molecular levels. CLINICAL RELEVANCE Topical application of ALA omega-3 fatty acid may be a novel therapy to treat the clinical signs and inflammatory changes accompanying dry eye syndrome.

Visual Outcomes Prognosticators in Juvenile Rheumatoid Arthritis-associated Uveitis

PURPOSE The purpose of the study is to delineate the visual prognosticators in juvenile rheumatoid arthritis-associated uveitis. METHODS The records of 43 patients with juvenile rheumatoid arthritis-associated uveitis who were observed for at least 6 months were studied retrospectively. Bivariate and multivariate statistical models were applied to more than 40 parameters to determine the relative odds of visual rehabilitation among patients with each characteristic. RESULTS Thirty-seven (86%) patients were females and 6 (14%) males. The mean known age of uveitis onset was 13 years, with females having, on average, 4 years earlier onset of disease compared to males (P = 0.04). Ninety-three percent had chronic, 5% had recurrent, and 2% had an acute monophasic disease course. Of the 76 affected eyes, 93% were nongranulomatous and 97% had iridocyclitis. The mean overall duration of uveitis was 146 months, with females suffering from a significantly longer duration of active disease than did males (P < 0.001). Nineteen (44%) patients underwent cataract extraction, and 16 (37%) underwent vitrectomy. Thirty (70%) of the patients experienced visual improvement with their therapy. When controlling for potential confounders, male sex (P = 0.006), shorter duration of uveitis (P = 0.007), older age at disease onset (P = 0.02), and a shorter delay in presentation to a subspecialist (P = 0.02) were associated significantly with visual acuity improvement. Visual acuity at presentation (P = 0.001), use of systemic nonsteroidal anti-inflammatory drugs (P = 0.01), older age at disease onset (P = 0.02), absence of glaucomatous neuropathy (P = 0.02), and male sex (P = 0.03) were correlated strongly with a final visual acuity outcome of 20/40 or better. CONCLUSION Juvenile rheumatoid arthritis-associated uveitis is a serious disease with a guarded visual prognosis. It is hoped that increased awareness of its prognosticators will lead to treatment and referral patterns that have the best chance of minimizing the likelihood of visual impairment in patients with juvenile rheumatoid arthritis.

Epidemiology of Dry Eye Syndrome

Dry eye syndrome (DES) represents a heterogeneous group of conditions that share inadequate lubrication of the ocular surface as their common denominator. DES is characterized by symptoms of ocular dryness and discomfort due to insufficient tear quantity or quality caused by low tear production and/or excessive tear evaporation. Symptoms can be debilitating 1 and, when severe, may affect psychological health and ability to work. No cure exists for DES, which is one of the leading causes of patient visits to ophthalmologists and optometrists in the United States. Because of the presumed high prevalence of DES and the attendant health care burden, the National Eye Institute (NEI) has identified tear film and dry eye research as important areas in need of further study.