Anti-Inflammatory and Anti-Apoptotic Effects of Acer Palmatum Thumb. Extract, KIOM-2015EW, in a Hyperosmolar-Stress-Induced In Vitro Dry Eye Model.

The aim of this study was to assess the anti-inflammatory and anti-apoptotic effects of KIOM-2015EW, the hot-water extract of maple leaves in hyperosmolar stress (HOS)-induced human corneal epithelial cells (HCECs). HCECs were exposed to hyperosmolar medium and exposed to KIOM-2015EW with or without the hyperosmolar media. Tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 production and apoptosis were observed, and the activation of mitogen-activated protein kinases (MAPKs) including extracellular signal regulated kinase (ERK), p38 and c-JUN N-terminal kinase (JNK) signaling and nuclear factor (NF)-κB was confirmed. Compared to isomolar medium, the induction of cell cytotoxicity significantly increased in HCECs exposed to hyperosmolar medium in a time-dependent manner. KIOM-2015EW-treatment significantly reduced the mRNA and protein expression of pro-inflammatory mediators and apoptosis. KIOM-2015EW-treatment inhibited HOS-induced MAPK signaling activation. Additionally, the HOS-induced increase in NF-κB phosphorylation was attenuated by KIOM-2015EW. The results demonstrated that KIOM-2015EW protects the ocular surface by suppressing inflammation in dry eye disease, and suggest that KIOM-2015EW may be used to treat several ocular surface diseases where inflammation plays a key role.

Topical Application of Apricot Kernel Extract Improves Dry Eye Symptoms in a Unilateral Exorbital Lacrimal Gland Excision Mouse.

The purpose of this study was to investigate the therapeutic effects of topical application of apricot kernel extract (AKE) in a unilateral exorbital lacrimal gland excision mouse model of experimental dry eye. Dry eye was induced by surgical removal of the lacrimal gland. Eye drops containing 0.5 or 1 mg/mL AKE were administered twice a day from day 3 to day 7 after surgery. Tear fluid volume and corneal irregularity scores were determined. In addition, we examined the immunohistochemical expression level of Muc4. The topical administration of AKE dose-dependently improved all clinical dry eye symptoms by promoting the secretion of tear fluid and mucin. Thus, the results of this study indicate that AKE may be an efficacious topical agent for treating dry eye disease.

Effects of chondrocyte-derived extracellular matrix in a dry eye mouse model.

PURPOSE: The occurrence of repetitive dry eye is accompanied by inflammation. This study investigated the anti-inflammatory effects of chondrocyte-derived extracellular matrix (CDECM) on the cornea and conjunctiva in a dry eye mouse model. METHODS: Dry eyes were experimentally induced in 12- to 16-week-old NOD.B10.H2(b) mice (Control) via subcutaneous injections of scopolamine (muscarinic receptor blocker) and exposure to an air draft for 10 days (desiccation stress [DS] 10D group). Tear volume and corneal smoothness were measured at 3, 5, 7, and 10 days after the instillation of PBS (PBS group) or CDECM (CDECM group). The corneas and conjunctivas were sectioned and stained with hematoxylin and eosin (H&E) and periodic acid Schiff (PAS). The expression of inflammatory markers (i.e., tumor necrosis factor-α [TNF-α], matrix metalloproteinase-2 [MMP-2], MMP-9, intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion molecule-1 [VCAM-1]) was detected by quantitative real-time (qRT)-PCR and western blotting. All data were statistically processed using SPSS version 18.0. RESULTS: The instillation of CDECM after the removal of the DS increased tear production by up to 3.0-fold, and corneal smoothness improved to 80% compared to the PBS group (p<0.05). In the CDECM group, the detachment of the corneal epithelial cells was reduced by 73.3% compared to the PBS group, and the conjunctival goblet cell density was significantly recovered to the control levels (p<0.05). The expression of inflammatory factors was decreased in the cornea and conjunctiva of the CDECM group compared to the PBS group. CONCLUSIONS: These observations suggest that CDECM induced effective anti-inflammatory improvements in the cornea and conjunctiva in this experimental model of dry eye.

Expression of SIRT1 and oxidative stress in diabetic dry eye.

OBJECTIVE: To explore the expression of SIRT1 with oxidative stress and observe physiological and pathological changes in the corneas as well as the association between SIRT1 and oxidative stress of diabetic dry eyes in mice. METHOD: Forty-eight C57BL/6Jdb/db mice at eight weeks of age were divided randomly into two groups: the diabetic dry eye group and the diabetic group. An additional forty-eight C57BL/6J mice at eight weeks of age were divided randomly into two groups: the dry eye group and the control group. Every mouse in the dry eye groups (diabetic and normal) was injected with scopolamine hydrobromide three times daily, combined with low humidity to establish a dry eye model. After the intervention, phenol red cotton string tests and corneal fluorescein staining were performed. In addition, HE staining and immunofluorescence were done. Expression of SIRT1 in the cornea was examined by real-time PCR and Western Blot and expression of FOXO3 and MnSOD proteins was detected by Western Blot. RESULTS: At one, four, and eight weeks post intervention, all of the groups except the controls showed significant decreases in tear production and increases in the corneal fluorescein stain (P<0.05 vs control). Between the experimental groups, the diabetic dry eye group had the least tear production and the highest corneal fluorescein stain score (P<0.05). As the disease progressed, all of the experimental groups showed obviously pathological changes in HE staining, particularly the diabetic dry eye group. In the 1(st) and 4(th) week, the expression of SIRT1, FOXO3, and MnSOD were significantly higher in the diabetic DE and DM groups but lower in the DE group compared to the controls (P<0.05). In the 8(th) week, the expression of SIRT1, FOXO3, and MnSOD was significantly down-regulated in the diabetic DE group and the DM group (P<0.05). Immunofluorescence showed similar results. CONCLUSION: In the condition of diabetic dry eye, tear production declined markedly coupled with seriously wounded corneal epithelium. Oxidative stress in the cornea was enhanced significantly and the expression of SIRT1 was decreased.

Chemokine receptors CCR6 and CXCR3 are necessary for CD4(+) T cell mediated ocular surface disease in experimental dry eye disease.

CD4(+) T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4(+) T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4(+) T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4(+) T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease.

Preoperative evaluation for periorbital surgery.

An effective preoperative evaluation is critical to the success of aesthetic surgery for the periorbital region. This review emphasizes important history questions and examination techniques, including advice for the nonophthalmologist surgeon, to help avoid ocular complications. Aesthetic surgery of the periocular area is a rewarding endeavor for both the patient and surgeon. Proper preoperative evaluation helps to avoid some of the pitfalls of operating in this delicate area and increases the likelihood of a positive outcome.

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-Sjögren's 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.

Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro.

PURPOSE: Benzalkonium chloride (BAK), the most commonly used preservative in eye drops, is known to induce ocular irritation symptoms and dry eye in long-term treated patients and animal models. As tear film hyperosmolarity is diagnostic of some types of dry eye disease, we determined in vitro on conjunctival epithelial cells the cytoxicity of BAK in hyperosmolar conditions through cell viability, apoptosis, and oxidative stress assays. METHODS: The Wong Kilbourne derivative of Chang conjunctival epithelial cells were cultured for 24 h or 48 h either in NaCl-induced hyperosmolar conditions (400-425-500 mOsM), in low concentrations of BAK (10(-4)%, 3.10(-4)%, and 5.10(-4)%), or in combination of both. We investigated cell viability through lysosomal integrity evaluation, cell death (cell membrane permeability and chromatin condensation), and oxidative stress (reactive oxygen species, superoxide anion) using spectrofluorimetry. Immunohistochemistry was performed for cytoskeleton shrinkage (phalloidin staining), mitochondrial permeability transition pore (cytochrome c release), the apoptosis effector active caspase-3, and the caspase-independent apoptosis factor AIF. We also observed early effects induced by the experimental conditions on the conjunctival cell layers using phase contrast imaging of live cells. RESULTS: As compared to standard culture solutions, hyperosmolar stress potentiated BAK cytotoxicity on conjunctival cells through the induction of oxidative stress; reduction of cell viability; cell membrane permeability increase; cell shrinkage with cell blebbing, as shown in phase contrast imaging of live cells; and chromatin condensation. Like BAK, but to a much lesser extent, hyperosmolarity increased cell death in a concentration-dependent manner through a caspase-dependent apoptosis characterized by a release of cytochrome c in the cytoplasm from mitochondria and the activation of caspase-3. Moreover, the caspase-independent apoptosis factor AIF was found translocated from mitochondria to the nucleus in both conditions. CONCLUSIONS: This study showed increased cytotoxic effects of BAK in hyperosmotic conditions, with characteristic cell death processes, namely caspase-dependent and independent apoptosis and oxidative stress. As BAK is known to disrupt tear film, which could promote evaporative dry eye and tear hyperosmolarity, BAK could promote the conditions enhancing its own cytotoxicity. This in vitro hyperosmolarity model thus highlights the risk of inducing a vicious cycle and the importance of avoiding BAK in patients with dry eye conditions.

[Phrynoderma secondary to vitamin A deficiency in a patient with biliopancreatic diversion]. / Frinoderma secundario a déficit de vitamina A en un paciente con derivación biliopancreática.

Biliopancreatic diversion (BPD) is a malabsorptivebariatric procedure can lead to the development of several nutritional complications, including fat-soluble vitamins deficiencies. Routine supplementation with vitamins and trace elements and a close follow-up long-term can prevent these nutritional risks. Vitamin A participates in ocular metabolism, epithelial differentiation, growth, and embryogenesis. Have been described several cases of ophthalmological and fetal complications associated with vitamin A deficiency in patients who have undergone BPD. Few information exists in literature about dermatologic manifestations that may occur in these patients. Phrynoderma is a type of follicular hyperkeratosis located on the extensor surfaces of the extremities whose main cause is vitamin A deficiency. We report an exceptional case of severe cutaneous and ocular complications in a patient who had undergone BPD with poor adherence to treatment and postoperative follow-up. Our patient presented simultaneously the characteristic skin lesions of phrynoderma with nytalopia and xerophthalmia in a setting of low serum levels of vitamin A. Treatment with high doses vitamin A obtained the resolution of both processes. We review and discuss the relationship between phrynoderma, malnutrition and vitamin A deficiency.

A method to extract cytokines and matrix metalloproteinases from Schirmer strips and analyze using Luminex.

PURPOSE: The Schirmer's test is commonly used in the clinic for the diagnosis of dry eye disease by measuring tear volume. This report describes a procedure which can be used to recover tears from the Schirmer strip for the measurement of multiple tear cytokines as well as matrix metalloproteinases (MMPs) by Luminex technology. METHODS: Cytokine and MMP recovery was determined by using spiked Schirmer strips presoaked with known cytokines or MMPs prepared in PBS with 1% BSA. In a clinical study, tears were collected from 5 subjects using Schirmer strips. Strips were stored on ice immediately after removal from the subject and stored dry at -20 °C for 16-24 h. Cytokines were extracted from the Schirmer strip in 0.5 M NaCl with 0.5% Tween-20. Concentrations of cytokines and MMPs in collected tear samples were analyzed by Luminex using both a 10-cytokine and a 5-MMP kit. RESULTS: The standard curves for the assay in both the kit assay buffer and extraction buffer were identical for 9 of the 10 cytokines and all 5 MMPs. In the clinical sample all the cytokines (interleukin 1α [IL-1α], IL-1ß, IL-1ra, IL-4, IL-6, IL-8, IL-10, IL-13, monocyte chemotactic protein-1 [MCP-1], and tumor necrosis factor-α [TNF-α]) and 5 MMPs (MMP-1, MMP-2, MMP-7, MMP-9, and MMP-10) tested were detected in at least 50% of the 10 subject samples. Recoveries from extracted Schirmer strips were >60% for 8 of the 10 cytokines and all MMPs. CONCLUSIONS: Numerous cytokines and MMPs were detected in the tear samples collected using the Schirmer strip, including many that have been implicated in ocular surface disease. This procedure may be used to evaluate the cytokine and MMP content in tear samples in clinical studies, especially for the evaluation of dry eye therapeutics. Because the Schirmer test is routine in the assessment of dry eye, this method offers the opportunity to evaluate both the quantity and quality of the tears.

Salivary gland involvement in chronic graft-versus-host disease: prevalence, clinical significance, and recommendations for evaluation.

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogren's syndrome. Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints [corrected]. The salivary flow rate was < or =0.2 mL/min in 27%, and < or =0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD.

Baseline profiles of ocular surface and tear dynamics after allogeneic hematopoietic stem cell transplantation in patients with or without chronic GVHD-related dry eye.

We evaluated ocular surface alterations in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with or without chronic GVHD-related dry eye in a prospective study. Fifty eyes of 25 post-HSCT patients and 28 eyes of 14 age-matched healthy controls were included. Meibomian gland (MG) obstruction, tear evaporation rate, corneal sensitivity (CS), Schirmer test-I, tear break-up time (BUT) and ocular surface vital staining were examined. Conjunctival impression and brush cytology specimens were collected to evaluate the goblet cell density (GCD) and the inflammatory cell numbers. Obvious MG obstruction, decreased CS and enhanced tear evaporation rate were found in post-HSCT patients compared with normal controls. In addition, decreased conjunctival GCD, increased conjunctival squamous metaplasia and inflammatory cells were noted in cGVHD-related dry eyes compared with normal controls and post-HSCT without dry eye subjects. Furthermore, the conjunctival inflammatory cells were significantly higher in severe dry eyes compared with mild dry eyes (P=0.03). We found comprehensive ocular surface alteration in post-HSCT patients, regardless of whether they had cGVHD-related dry eye or not. The results suggest that the extent of inflammatory process seems to have a pivotal role in the outcome of the cGVHD-related dry eye.

Hereditary gelsolin amyloidosis mimicking Sjögren's syndrome.

Hereditary gelsolin amyloidosis (AGel amyloidosis) belongs to the wide group of amyloidotic diseases, which comprise various hereditary but also sporadic forms, such as inflammation-associated AA amyloidosis, primary or myeloma-associated AL amyloidosis and common Alzheimer's disease and type II diabetes-associated local amyloidoses. AGel amyloidosis caused by a gelsolin G654A gene mutation is autosomally dominantly inherited and presents typically in the 30s with progressive corneal lattice dystrophy, followed by cutis laxa and cranial polyneuropathy. Here, we present a case of sicca syndrome, originally diagnosed as primary Sjögren's syndrome (SS) but later found to represent an initial disease manifestation of AGel amyloidosis, not recognised earlier. This case emphasises both the importance of specific amyloid stainings and comprehensive salivary gland histopathology as well as family history in SS differential diagnostics.

[Ocular surface investigations in dry eye]. / Méthodes d'évaluation de la surface oculaire dans les syndromes secs.

Dry eye is a complex clinicopathological entity involving tear film, lacrimal glands, eyelids, and a wide spectrum of ocular surface cells, including epithelial, inflammatory, immune, and goblet cells. From the tightly regulated lacrimal film functions and structure, a large variety of investigations have been developed, including tear meniscus measurements, fluorophotometry, meibometry, interference pattern analysis, evaporation rate, tear osmolarity, and thermography. Dry eye conditions also interfere with the ocular surface, causing corneal irregularities that may be explored using the techniques of videokeratography and in vivo confocal microscopy, or optical impairment, as confirmed by aberrometry. At the level of ocular surface cells, impression cytology remains a standard for assessing cell alterations. It has greatly benefited from new confocal microscopy, molecular biology, and flow cytometry techniques. Biological assessment of tear proteins or other mediators is also useful. Major limits should be acknowledged, however, such as technical issues in tear film collection, especially in dry eyes, and the lack of standardization of most measurements. Tear osmolarity, electrophoresis, and dosage of normal tear proteins, such as lysozyme or lactoferrin, remain the most useful tests. Finally, some extraocular explorations such as accessory gland biopsy or serum antinuclear antibody dosage may be useful for assessing the diagnosis of Sjögren's syndrome.

Cyclosporine inhibits apoptosis in experimental murine xerophthalamia conjunctival epithelium.

This study examined the inhibitory effect of topical cyclosporine (CsA) treatment on conjunctiva epithelial apoptosis in a murine model of xerophthalamia. Dry eye was induced in 3 groups of C57BL6 mice by subcutaneous injection of scopolamine (t.i.d) and exposure to an air draft and low-humidity environment for 16 h each day for 12 days. The dry eye control group received no topical treatment; another group received 1 microL of 0.05% CsA topically (t.i.d, dry eye+CsA); and the third group received 1 microL of the castor oil vehicle of CsA topically (t.i.d, dry eye + vehicle). Normal mice were used as untreated controls. Twelve days later, the mice were killed, and their conjunctivas were excised. The number of the conjunctival goblet cells was counted in tissue sections stained with periodic acid Schiff (PAS) reagent. Their conjunctiva epithelium had been investigated by immuno-histochemical staining to detect the goblet cells and the expression of Caspase-3, Bax and bcl-2. Our results showed that compared with dry eye control and dry eye mice + vehicle groups, the number of conjunctival epithelial goblet cells was significantly greater in the untreated controls and dry eye mice receiving CsA (P < 0.01 for both groups). There was no significant difference in the number of conjunctival epithelial goblet cells between the dry eye control and dry eye+vehicle group. It was also true of the number of conjunctival epithelial goblet cells when comparison was made between the normal group and the dry eye+CsA group. Expressions of Caspas-3 and Bax were increased and ex-pression of bcl-2 was decreased in conjunctival epithelial cells in dry eye control and dry eye mice+vehicle groups. There was a significant positive correlation between goblet cell number and the number of cells that expressed bcl-2, and a negative correlation between goblet cells and Caspase-3 and Bax expression. It is concluded that the topical use of CsA could significantly reduce conjunctival epithelial apoptosis and protect goblet cell against the loss in experimental murine xerophathalamia. Inhibition of apoptosis appears to be a key mechanism responsible for the therapeutic effect of CsA on xerophthalamia.

A primary Sjögren's syndrome patient with distal renal tubular acidosis, who presented with symptoms of hypokalemic periodic paralysis: Report of a case study and review of the literature.

Although renal tubular acidosis (RTA), secondary to autoimmune interstitial nephritis, develops in a large proportion of patients with Sjögren's syndrome (SS), most of the subjects are asymptomatic. Here, we shall present a 39-year-old female patient who came to us with hypokalemic periodic paralysis (HPP), and who was later diagnosed with distal RTA. The patient, who had xerostomia and xerophthalmia for a long period of time, was diagnosed with primary SS from serologic and histologic findings. The patient recovered by being prescribed potassium replacement therapy. Although renal biopsy was not performed, corticosteroids were administered because HPP indicated severe interstitial nephritis. HPP did not reoccur during a 2-year follow-up period. We also review cases with SS-related distal RTA and HPP.

[Tear film changes after phacoemulsification].

OBJECTIVE: To evaluate tear film changes after phacoemulsification. METHODS: This prospective randomized study involved 68 consecutive patients with age-related cataract (79 eyes) who underwent phacoemulsification. Tear break-up time, Schirmer I test (S I t) value, corneal fluorescein staining, tear film pattern by DR-1 tear interfermetry and the height of tear meniscus were measured preoperatively and 1 day and 2, 7, 14, 30, 180 days postoperatively. RESULTS: At 1 day and 2 days postoperatively, the mean tear break-up time reduced greatly, and the number of patients who showed III to V tear film pattern, the mean S I t value, the height of tear meniscus and fluorescein staining scores increased significantly (P < 0.001 for day 1, P < 0.005 for day 2). S I t value at 7 days postoperatively (P = 0.831) and the height of tear meniscus at 14 days returned to their preoperative values (P = 1.000). The tear break-up time, corneal fluorescein staining scores and the grades of tear film pattern all recovered at 30 days postoperatively (P > 0.05). At 30 days postoperatively, 19.3% of patients showed shorter tear break-up time and less S I t value than that of preoperative day. In addition, 1/9 of the patients with normal preoperative tear film experienced dry eye at 30 days postoperatively. The cases with tear break-up time < 10 seconds compared to patients with tear break-up time >/= 10 seconds were more easily to show tear instability postoperatively (relative risk 13.5, 8.25, 20.0, 39.0, 8.6, 3.9 at 1 day and 2, 7, 14, 30, 180 postoperative days, respectively). CONCLUSION: Phacoemulsification significantly alters the tear break-up time, S I t value, corneal fluorescein staining, tear film pattern and the height of tear meniscus. Some patients with normal tear film may experience dry eye after surgery. Patients with preexisting tear break-up time < 10 seconds are easily at risk of experiencing the tear film instability postoperatively.

Role of proinflammatory cytokines in the impaired lacrimation associated with autoimmune xerophthalmia.

PURPOSE: To determine the effects of the proinflammatory cytokines interleukin (IL)-1alpha, IL-1beta, and tumor necrosis factor (TNF)-alpha on neurally mediated lacrimal gland protein secretion and to determine whether the amount of IL-1beta protein is upregulated in inflamed lacrimal glands of the MRL/lpr mouse, a murine model of human Sjögren syndrome. METHODS: Lacrimal gland lobules of BALB/c mice were prepared and incubated for 2 hours in the presence or absence of recombinant human (rh)IL-1alpha, rhIL-1beta (10 ng/mL each), or rhTNFalpha (50 ng/mL). Peroxidase secretion in response to depolarizing KCl (75 mM) solution was measured by spectrofluorometric assay. In another set of experiments, saline, rhIL-1beta (1 microg), or an antibody against IL-1 receptor type I (IL-1RI), with or without rhIL-1beta, was injected (2 microL) into the lacrimal glands of anesthetized BALB/c mice. Twenty-four hours later, lacrimal gland lobules were prepared and peroxidase secretion was measured. The amount of IL-1beta protein in lacrimal gland acinar cell lysates prepared from 3-, 9-, and 13-week-old BALB/c, MRL/(+), and MRL/lpr mice was determined by ELISA. RESULTS: KCl-induced peroxidase secretion was inhibited in vitro 62%, 66%, and 53% by rhIL-1alpha, rhIL-1beta, and rhTNFalpha, respectively. In vivo, rhIL-1beta inhibited KCl-induced peroxidase secretion by 72%. This inhibitory effect of IL-1beta was completely reversed by an antibody against IL-1RI. Compared with 3-week-old mice, the amount of IL-1beta protein was upregulated 15- and 21-fold in lacrimal gland acinar cells isolated from 9- and 13-week-old MRL/lpr mice, respectively. CONCLUSIONS: Proinflammatory cytokines inhibit neurally mediated lacrimal gland secretion. The amount of IL-1beta protein is upregulated in acinar cells prepared from lacrimal glands infiltrated with lymphocytes. These results suggest that elevated levels of IL-1beta, as they occur in Sjögren syndrome exocrine glands, may impair the secretory function of these tissues.

Corneal melt as the initial presentation of primary Sjögren's syndrome.

Corneal melting is a rare complication of S ogren's syndrome (SS). Previously reported cases of corneal ulceration occurred in patients with established SS, usually secondary to RA. We describe the first case of corneal ulceration with stromal melting as the initial presentation of primary SS. A 79-year-old man without prior sicca symptoms developed a large sterile corneal ulcer that required extensive treatment over several months with ocular lubricants, systemic immunosuppressives, and surgical repair. Evaluation for an underlying connective tissue disease revealed positive antinuclear antibodies (1:640 speckled) and anti-SSA antibody. A lip biopsy established the diagnosis of SS. Ulceration later occurred in the contralateral eye. Two years after the last corneal ulcer and no longer taking prednisone, the patient's ocular disease remained quiescent taking azathioprine 175 mg and hydroxychloroquine 400 mg daily. This case highlights the potential for primary SS to present with serious ocular complications despite lack of a priori sicca symptoms, as well as the importance of immunosuppressive therapy in the treatment of this complication.

GVHD dry eyes treated with autologous serum tears.

Two cases of GVHD with severe dry eyes are reported where conventional therapy failed to control ocular signs and symptoms. Autologous serum tears, however, resulted in a beneficial clinical effect with marked attenuation of the symptoms. This therapy proved to be safe during 10 months of treatment. Bone Marrow Transplantation (2000).