Hiroto Obata

The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland.

The tarsal glands of Meibom (glandulae tarsales) are large sebaceous glands located in the eyelids and, unlike those of the skin, are unassociated with hairs. According to Duke-Elder and Wyler,1 they were first mentioned by Galenus in 200 AD and later, in 1666, they were described in more detail by the German physician and anatomist Heinrich Meibom, after whom they are named. Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension.2 Hence, meibomian lipids are essential for the maintenance of ocular surface health and integrity. Although they share certain principal characteristics with ordinary sebaceous glands, they have several distinct differences in anatomy, location, secretory regulation, composition of their secretory product, and function. Functional disorders of the meibomian glands, referred to today as meibomian gland dysfunction (MGD),3 are increasingly recognized as a discrete disease entity.4–8 In patients with dry eye disease, alterations in the lipid phase that point to MGD are reportedly more frequent than isolated alterations in the aqueous phase. In a study by Heiligenhaus et al.,9 a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. This result is in line with the observations by Shimazaki et al.10 of a prevalence of MGD in the absolute majority of eyes with ocular discomfort defined as dry eye symptoms. These observations noted that 64.6% of all such eyes and 74.5% of those excluding a deficiency of aqueous tear secretion were found to have obstructive MGD, or a loss of glandular tissue, or both.10 Horwath-Winter et al.11 reported MGD in 78% of dry eye patients or, if only non-Sjogren patients are considered, in 87% compared with 13% with isolated aqueous tear deficiency. It may thus be accepted that MGD is important, conceivably underestimated, and possibly the most frequent cause of dry eye disease due to increased evaporation of the aqueous tears.5,9–12 After some excellent reviews of MGD4,7,8,13,14 in the past, many new findings have been reported in recent years, and other questions remain to be identified and resolved. A sound understanding of meibomian gland structure and function and its role in the functional anatomy of the ocular surface15 is needed, to understand the contribution of the meibomian glands to dysfunction and disease. Herein, we seek to provide a comprehensive review of physiological and pathophysiological aspects of the meibomian glands.

Anatomy and histopathology of human meibomian gland.

Purpose To investigate histopathologic changes in human meibomian gland. Methods Human meibomian gland samples were obtained at autopsy from 50 men and 33 women aged from 17 to 87 years with a mean age (±SD) of 61±13 years. Pieces of tarsal plate measuring 3×3 mm including meibomian glands were excised from the center of both upper eyelids, then fixed and embedded in paraffin. Sections 4μ-pm thick were stained with hematoxylin and eosin and periodic acid-Schiff. Light microscopy was used to observe any histopathologic changes. Results The following histopathologic changes were observed: (1) cystic dilatation of acini and/or ducts, (2) atrophy of acini, (3) basement membrane thickening of acini, (4) granulation tissue, and (5) lipogranulomatous inflammation. Conclusion Various histopathologic changes were observed in the human meibomian gland. Hyperkeratinization of ductal epithelium and atrophy of acinar cells may cause meibomian gland dysfunction.

Perturbation of transforming growth factor (TGF)-ß1 association with latent TGF-β binding protein yields inflammation and tumors

Transforming growth factor-β (TGF-β) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-β is often released as part of an inactive tripartite complex consisting of TGF-β, the TGF-β propeptide, and a molecule of latent TGF-β binding protein (LTBP). The interaction of TGF-β and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-β from this state is crucial for signaling. To examine the contribution of LTBP to TGF-β function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1C33S/C33S mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-β1 levels. However, the inflammatory response and decreased lifespan were not as severe as observed with Tgfb1−/− animals. Tgfb1C33S/C33S mice exhibited decreased levels of active TGF-β1, decreased TGF-β signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-β complex is important for proper TGF-β1 function and that Tgfb1C33S/C33S mice are hypomorphs for active TGF-β1. Moreover, although mechanisms exist to activate latent TGF-β1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP.

ST2 gene expression is proliferation-dependent and its ligand, IL-33, induces inflammatory reaction in endothelial cells

ST2 gene products that are members of IL-1 receptor family are expressed in various cells such as growth-stimulated fibroblasts and Th2 helper T-cells, and recently, IL-33, which belongs to IL-1 family, was identified as the ligand for ST2L, the receptor type product of the ST2 gene. Subsequently, IL-33 and ST2L have been reported to be involved in Th2 immunity and inflammation, however, their functions on non-immunological cells are still obscure. Among non-immunological adhesive cells, vascular endothelial cells were reported to express both ST2 gene products and IL-33, therefore, we investigated the expression manner of the ST2 gene in vascular endothelial cells and the effect of IL-33 on endothelial cells. ST2 gene was expressed in each of the vascular endothelial cell types tested, and the expression was growth-dependent and down-regulated when the cells were differentiated to form vascular structures on the extracellular membrane matrix. IL-33 scarcely affected the growth and tube formation of the endothelial cells, but induced IL-6 and IL-8 secretion from endothelial cells with the rapid activation of extracellular signal-regulated kinase (ERK) 1/2, so IL-33 is supposed to involve in inflammatory reaction of vascular endothelial cells through its receptor, ST2L.

Accumulation of Secretory Vesicles in the Lacrimal Gland Epithelia Is Related to Non-Sjögren's Type Dry Eye in Visual Display Terminal Users

Previous observations in a rat model of a non-Sjögrens syndrome (non-SS) type of dry eye seen in users of visual display terminals (VDT) indicated that secretory vesicle (SV) accumulation in the lacrimal gland epithelia contributes to the condition. Here, to examine this possibility in humans, we compared the lacrimal gland histology and percent SV area in the cytoplasm of acinar epithelial cells using light microscopy and transmission electron microscopy, in patients with VDT work-related non-SS dry-eye (VDT group), SS-induced dry-eye, and autopsied normal controls. In addition, the VAMP8 (vesicle-associated membrane protein 8, an exocrine-pathway molecule) and Rab3D (mature vesicle marker) were histochemically examined in lacrimal gland tissue sections. The lacrimal gland acini were larger in the VDT group than in the SS group, and the percent SV area was significantly higher in the VDT group than in the normal controls (P = 0.021) or SS group (P = 0.004). Immunostaining revealed abnormal distributions of VAMP8 in the VDT and SS groups. Rab3D was more strongly expressed in the cytoplasm of acinar epithelial cells in the VDT group than in that of normal controls. The duration of VDT use was significantly longer in the VDT group than in the other groups. These findings suggest that excessive SV accumulation in the acinar epithelia may contribute to the reduced tear secretion in VDT users.

Severity and determinants of pinguecula in a hospital-based population

Objectives: Pinguecula is a relatively frequent disease; however, there have been no reports about the grade of pinguecula. We investigated the relationship between age and the prevalence and severity of pinguecula by using a grading system and compared the grade of pinguecula between men and women and between the nasal and temporal halves of the conjunctiva. Methods: This was a prospective, randomized study of 1,040 patients aged 1 to 95 years, including 520 men and 520 age-matched women. The age, gender, medical history, ocular history, and grade of pingueculae located on the nasal and temporal conjunctiva were determined in all subjects. Results: The prevalence of pinguecula increased dramatically with age. The mean grade was higher in male patients than in female patients for pingueculae located on both the nasal conjunctiva (P = 0.00072) and the temporal conjunctiva (P = 0.00035). However, there was no significant difference in the grade of pinguecula between the nasal and temporal conjunctiva. Conclusions: This was the first assessment of the grade of pinguecula in a large series of patients. Our findings strongly suggest that pinguecula is an age-dependent lesion that occurs from young adulthood onward. The present grading system should also be useful for future clinical studies of pinguecula.

Pinguecula and contact lenses.

PurposeTo assess the relationship between age and the incidence and severity (determined by a grading system) of pinguecula in contact lens (CL) wearers, and to compare the grade of pinguecula between CL wearers and non-wearers.MethodsA total of 600 CL wearers (94 wore hard CLs (HCLs) and 506 wore soft CLs (SCLs)) aged 11–60 years and 579 non-wearers aged 10–60 years were enrolled. The age, gender, medical history, ocular history, and grade of pinguecula at two locations (nasal and temporal) were determined in all subjects.ResultsThere was an age-related increase in the grade of pinguecula among both CL wearers and non-wearers. The grade of pinguecula at the temporal conjunctiva was higher in CL wearers than in non-wearers (P=0.01907), whereas it was higher in HCL wearers than SCL wearers at both the nasal and temporal conjunctiva (P<0.00001 and P<0.00001).ConclusionsThis was the first assessment of the severity of pinguecula in a large consecutive series of CL wearers. Our results suggest that the use of CLs is an important risk factor for pinguecula.

Correlations between choroidal abnormalities, Lisch nodules, and age in patients with neurofibromatosis type 1.

To evaluate correlations between choroidal abnormalities, Lisch nodules, and age in patients with neurofibromatosis type 1 (NF1), we examined ten cases with NF1 using near-infrared reflectance imaging. Patients ranged in age from 4 to 39 years. The angle used for near-infrared reflectance imaging was 55°. We counted the total number of choroidal abnormalities in an area within a 55° angle centered on the fovea and the total number of Lisch nodules on the iris by slit-lamp examination. No positive correlation was found between the number of Lisch nodules and patient age (Spearman’s rank correlation coefficient ρ=0.117, P=0.7414). Choroidal abnormalities tended to increase with age (ρ=0.6150), but this difference was not statistically significant (P=0.0650). A positive correlation was found between the number of choroidal abnormalities and Lisch nodules (ρ=0.783, P=0.0267). In conclusion, choroidal abnormalities tend to increase with patient age and are correlated with the number of Lisch nodules.

Classification of secondary corneal amyloidosis and involvement of lactoferrin.

PURPOSE To classify secondary corneal amyloidosis (SCA) by its clinical appearance, to analyze the demographics of the patients, and to determine the involvement of lactoferrin. DESIGN Retrospective, observational, noncomparative, multicenter study. PARTICIPANTS Twenty-nine eyes of 29 patients diagnosed with SCA by corneal specialists at 9 ophthalmologic institutions in Japan were studied. METHODS The clinical appearance of SCA was determined by slit-lamp biomicroscopy and was classified into 3 types. The demographics of the patients, for example, age, gender, and the duration of the basic disease (trichiasis, keratoconus, and unknown), were determined for each clinical type. Surgically excised tissues were stained with Congo red and antilactoferrin antibody. The postoperative prognosis also was determined. MAIN OUTCOME MEASURES Clinical appearance of the 3 types of SCA, along with the gender, age, and duration of the basic diseases were determined. RESULTS Classification of SCA into 3 types based on clinical appearance found 21 cases with gelatinous drop-like dystrophy (GDLD)-like appearance (GDLD type), 3 cases with lattice corneal dystrophy (LCD)-like appearance (LCD type), and 5 cases with the combined type. Patients with the GDLD type were younger (average age: 40.9 years for the GDLD type, 74.3 years for the LCD type, and 46.8 years for the combined type), predominantly women (85.7% for the GDLD type, 33.3% for the LCD type, and 60% for the combined type), and had the basic disease over a longer time (average duration: 22.1 years for the GDLD type, 14.0 for the LCD type, and 11.4 for the combined type). The distribution of the basic diseases (trichiasis vs. keratoconus vs. unknown) was not significantly different for each type. Surgical treatments, for example, phototherapeutic keratectomy, lamellar keratoplasty, and simple keratectomy, resulted in a good resolution in all surgically treated cases. One subject dropped out of the study. Spontaneous resolution was seen in one subject after epilation of the cilia. Amorphous materials in the excised tissues showed positive staining results by Congo red and by antilactoferrin antibody. CONCLUSIONS Secondary corneal amyloidosis can be classified into 3 clinical types based on its clinical appearance. Larger numbers of females and lactoferrin expression were seen in all 3 types. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Conjunctivochalasis: associations with pinguecula in a hospital-based study

Purpose:  To assess the relationship between the prevalence and severity of conjunctivochalasis and pinguecula.