Immunohistochemical expression of the cation channel TRPC6 in the submandibular and lacrimal gland and in salivary gland tumors.

BACKGROUND: Canonical transient receptor potential channels play a crucial role in cancer cell proliferation. While TRPC6 subtype detection in submandibular glands and the relevance of some TRPC channels in this gland have been shown in animal models, its histological detection in human lacrimal and submandibular glands, as well as related tumors, lacks systematic study. Studying TRPC6 in humans could lead to new therapeutic options. This research aimed to immunohistochemically detect TRPC6 in human samples of physiological lacrimal and submandibular glands and of adenoid cystic carcinoma and mucoepidermoid carcinoma. METHODS: Seven fixed body donors and samples of six cancer patients were examined. The ten tissue samples collected from the submandibular and lacrimal glands were then processed into histological slides and stained with hematoxylin-eosin. Tumor samples were provided as sections. TRPC6 presence was determined by immunohistochemistry, which was performed by indirect detection with a primary TRPC6 antibody, a secondary HRP-conjugated antibody and the chromogen diaminobenzidine. RESULTS: Results confirm TRPC6 expression in all ten physiological gland samples: all samples showed a immunohistochemical signal with varying intensity. No significant gender-specific differences could be observed. TRPC6 was detected in four of six submandibular adenoid cystic carcinoma and the mucoepidermoid carcinoma samples, especially in tumor cells' cytoplasma and nuclei. Excretory ducts consistently showed TRPC6. Mucous tubules, their nuclei and the nuclei of adipocytes generally showed no signal while serous acini and their nuclei showed a weak TRPC6 signal. CONCLUSION: The discovery of TRPC6 in glandular tissue indicates a role in salivary gland function and calcium homeostasis is a basis for further research into its significance for tumor development in adenoid cystic carcinoma and mucoepidermoid carcinoma of salivary glands. TRPC6 could be used as a target for treatment of these tumors. However, the correlation between TRPC6 and submandibular and lacrimal gland diseases requires further exploration.

Exorbital Lacrimal Gland Ablation and Regrafting Induce Inflammation but Not Regeneration or Dry Eye.

The study evaluated the regenerative responses of the lacrimal functional unit (LFU) after lacrimal gland (LG) ablation. The LG of Wistar rats was submitted to G1) partial LG ablation, G2) partial ablation and transplantation of an allogeneic LG, or G3) total LG ablation, (n = 7-10/group). The eye wipe test, slit lamp image, tear flow, and histology were evaluated. RT-PCR analyzed inflammatory and proliferation mediators. The findings were compared to naïve controls after 1 and 2 months (M1 and M2). G3 presented increased corneal sensitivity, and the 3 groups showed corneal neovascularization. Histology revealed changes in the LG and corneal inflammation. In the LG, there was an increase in MMP-9 mRNA of G1 and G2 at M1 and M2, in RUNX-1 at M1 and M2 in G1, in RUNX-3 mRNA at M1 in G1, and at M2 in G2. TNF-α mRNA rose in the corneas of G1 and G2 at M2. There was an increase in the IL-1ß mRNA in the trigeminal ganglion of G1 at M1. Without changes in tear flow or evidence of LG regeneration, LG ablation and grafting are unreliable models for dry eye or LG repair in rats. The surgical manipulation extended inflammation to the LFU.

Inhibition of Cathepsin S in Autoimmune CD25KO Mouse Improves Sjögren Disease-Like Lacrimal Gland Pathology.

Purpose: CD25KO mice are a model of Sjögren disease (SjD) driven by autoreactive T cells. Cathepsin S (CTSS) is a protease crucial for major histocompatibility complex class II presentation that primes T cells. We investigated if a diet containing CTSS inhibitor would improve autoimmune signs in CD25KO mice. Methods: Four-week female CD25KO mice were randomly chosen to receive chow containing a CTSS inhibitor (R05461111, 262.5 mg/kg chow) or standard chow for 4 weeks. Cornea sensitivity was measured. Inflammatory score was assessed in lacrimal gland (LG) histologic sections. Flow cytometry of LG and ocular draining lymph nodes (dLNs) investigated expression of Th1 and Th17 cells. Expression of inflammatory, T- and B-cell, and apoptotic markers in the LG were assessed with quantitative PCR. The life span of mice receiving CTSS inhibitor or standard chow was compared. CD4+ T cells from both groups were isolated from spleens and adoptively transferred into RAG1KO female recipients. Results: Mice receiving CTSS inhibitor had better cornea sensitivity and improved LG inflammatory scores. There was a significant decrease in the frequency of CD4+ immune cells and a significant increase in the frequency of CD8+ immune cells in the dLNs of CTSS inhibitor mice. There was a significant decrease in Th1 and Th17 cells in CTSS inhibitor mice in both LGs and dLNs. Ifng, Ciita, and Casp8 mRNA in CTSS inhibitor mice decreased. Mice that received the CTSS inhibitor lived 30% longer. Adoptive transfer recipients with CTSS inhibitor-treated CD4+ T cells had improved cornea sensitivity and lower inflammation scores. Conclusions: Inhibiting CTSS could be a potential venue for the treatment of SjD in the eye and LG.

Long-term high fructose intake reprograms the circadian transcriptome and disrupts homeostasis in mouse extra-orbital lacrimal glands.

This study aims to explore the effects of long-term high fructose intake (LHFI) on the structure, functionality, and physiological homeostasis of mouse extra-orbital lacrimal glands (ELGs), a critical component of ocular health. Our findings reveal significant reprogramming of the circadian transcriptome in ELGs following LHFI, alongside the activation of specific inflammatory pathways, as well as metabolic and neural pathways. Notably, LHFI resulted in increased inflammatory infiltration, enhanced lipid deposition, and reduced nerve fiber density in ELGs compared to controls. Functional assessments indicated a marked reduction in lacrimal secretion following cholinergic stimulation in LHFI-treated mice, suggesting impaired gland function. Overall, our results suggest that LHFI disrupts lacrimal gland homeostasis, potentially leading to dry eye disease by altering its structure and secretory function. These insights underscore the profound impact of dietary choices on ocular health and highlight the need for strategies to mitigate these risks.

Mechanistic elucidation of QiJu-DiHuang Wan in management of age-related dry eye through metabolomics and network pharmacology.

BACKGROUND: QiJu-DiHuang Wan (QJDHW), a frequently employed Chinese herbal formula, is used to treat blurred vision. Even so, it is unclear how it works in treating age-related dry eyes. OBJECTIVE: The aim of this research is to explore the potential mechanisms of QJDHW in treating dry eye using UHPLC-QE-MS, metabolomics, and network pharmacology. METHODS: Six male SD rats were segregated into control and QJDHW groups. Following intervention, The primary active ingredients in QJDHW-containing serum were identified using UHPLC-QE-MS. Metabolomics and network pharmacology were utilized to investigate potential targets and pathways involved following QJDHW use. Primary lacrimal epithelial cells were used for validation. RESULTS: A total of 425 active ingredients of QJDHW were identified, along with 210 active ingredients in QJDHW-containing serum. A comparison of QJDHW-containing serum and control serum samples revealed 40 metabolic differentiators. A total of 24 metabolites were found in QJDHW and QJDHW-containing serum. Network pharmacology identified 3,144 targets for dry eye disease, and 102 metabolite action targets were found for QJDHW-entering components. KEGG Enrichment Analysis revealed significance of HIF-1, apoptosis, cell cycle and PI3K-Akt, among others. HIF-1 and PI3K-Akt were chosen for verification in the oxidative damage model of lacrimal epithelial cells. CONCLUSION: The main active ingredients of QJDHW and its containing serum were elucidated by UHPLC-QE-MS demonstrating that QJDHW treats age-associated dry eye by inhibiting HIF1α/NF-κB through ROS inhibition and PI3K/p-AKT activation.

Bilateral Lacrimal Gland Lymphoma - Case Presentation.

Lacrimal gland lymphomas are rare orbital tumors, constituting a minor fraction of all orbital and ocular adnexal malignancies. This case study presents an 83-year-old male with bilateral lacrimal gland tumors, more prominent in the left orbit, causing decreased visual acuity, red eye, excessive tearing, and diplopia. Initial ophthalmological evaluations and imaging suggested bilateral lacrimal gland lymphoma, confirmed by histopathology as diffuse large B-cell non-Hodgkin lymphoma of the MALT type. Due to the significant tumor size and risk of visual function loss, surgical intervention was performed, followed by corticosteroid therapy. Postoperatively, a marked improvement in symptoms and a reduction in tumor size were observed. This case underscores the importance of comprehensive diagnostic approaches, including clinical, imaging, and histopathological evaluations, highlighting the need for a multidisciplinary approach in managing rare orbital tumors like lacrimal gland lymphoma. The patient's postoperative and follow-up care included oncological management to monitor and ensure long-term disease control and patient well-being. Abbreviations: RE = right eye, LE = left eye, CT = Computer tomography, MRI = Magnetic Resonance Imaging, TOD = intraocular pressure of right eye, TOS = intraocular pressure of left eye, US = ultrasound.

Clinicopathologic features and outcomes of bilateral lacrimal gland lesions.

BACKGROUND: The present study reviewed the clinicopathological features and outcomes of bilateral lacrimal gland lesions. METHODS: The data of 113 patients who underwent lacrimal gland biopsy at the West China Hospital of Sichuan University, China, between January 1, 2010, and December 31, 2021, are presented in this case series. The patients all presented with bilateral lacrimal gland lesions. The collected data included patient demographics, clinical features, the results of laboratory examinations, imaging presentations, histopathological diagnoses, treatments, and outcomes. RESULTS: The mean age of the 113 enrolled patients was 47.4 ± 14.9 years (range, 11-77 years) with a predominance of females (54.9%, n = 62). The lacrimal gland was the source of the majority of biopsy tissue (98.2%, n = 111). The most prevalent etiology was immunoglobulin G4-related ophthalmic disease (IgG4-ROD) (32.7%, n = 37), followed by idiopathic orbital inflammation (IOI) (28.3%, n = 32), mucosa-associated lymphoid tissue (MALT) lymphoma (17.7%, n = 20), reactive lymphoid hyperplasia (RLH) (10.6%, n = 12), and mantle cell lymphoma (4.4%, n = 5). Patients with IOI were significantly younger than those with IgG4-ROD and MALT lymphoma (t = 2.932, P = 0.005; t = 3.865, P<0.001, respectively). Systemic symptoms were more prevalent among patients with IgG4-ROD (χ2 = 7.916, P = 0.005). The majority of patients were treated with surgery (53.1%, n = 60), with surgery combined with corticosteroid therapy (21.2%, n = 24) being the second most common treatment. The majority of patients (91.2%, n = 103) attained complete resolution, stable disease, or significant improvement. CONCLUSION: In conclusion, there are several aetiologies associated with bilateral lacrimal gland lesions, the most prevalent being IgG4-ROD, IOI, and MALT lymphoma. Systemic symptoms were more common in patients with IgG4-ROD. The majority of patients who presented with bilateral lesions of the lacrimal glands responded satisfactorily to treatment, with favorable results.

Effects of common eye diseases in children and their treatment measures on ocular surface homeostasis: A review.

Ocular surface homeostasis plays a vital role in maintaining of eye health. Dry eye disease is one of the prominent and typical manifestations of disruption of ocular surface homeostasis that leads to the worsening of ocular surface homeostasis that leads to the worsening of ocular surface disease when it interacts with other pathogenic factors. However, disruption in ocular surface homeostasis in children is often overlooked because of the current methods of assessing ocular surface homeostasis. This review summarizes the main factors affecting ocular surface homeostasis in children, with the aim of drawing the attention of clinicians to the disruption of ocular surface homeostasis in children when dealing with such diseases. Ocular surface homeostasis involves several interrelated components, each of which plays a nonnegligible role in ocular surface homeostasis. Unlike adults, children have a stronger lacrimal gland secretion capacity and milder symptoms when there is a slight disruption of the ocular surface homeostasis. In addition, children's expressive abilities were weaker. Therefore, dry eye in children is often ignored by doctors and parents, and clinicians should pay more attention to the protection of ocular surface homeostasis when treating children with these diseases. Therefore, there is a need for diagnostic criteria for dry eye disease specific to children.

Precise longitudinal monitoring of corneal change through in vivo confocal microscopy in a rat dry eye disease model.

Purpose: While lacrimal gland removal is commonly used in animal models to replicate dry eye disease, research into systematically monitoring dry eye disease's longitudinal pathological changes is limited. In vivo confocal microscopy (Heidelberg Retina Tomograph 3 with a Rostock Cornea Module, Heidelberg Engineering Inc., Franklin, MA) can non-invasively reveal corneal histopathological structures. To monitor dry-eye-disease-related changes in corneal structures, we developed a precise monitoring method using in vivo confocal microscopy in a rat double lacrimal gland removal model. Methods: Five Sprague-Dawley rats (age 8-9 weeks, male) underwent double lacrimal gland removal. Modified Schirmer's tear test, blink tests, and in vivo confocal microscopy images were acquired pre-surgery and at 1, 2, and 4 weeks post-surgery. Three individual stromal nerves were selected per eye as guide images, and images of the corresponding sub-basal nerve plexus area were acquired via volume acquisition. The same area was re-imaged in subsequent weeks. Results: After double lacrimal gland removal, tear production was reduced by 60%, and the blink rate increased 10 times compared to pre-surgery. Starting from 1 week after surgery, in vivo confocal microscopy showed increased sub-basal nerve plexus nerve fiber density with inflammatory cell infiltration at the sub-basal nerve plexus layer and remained at an elevated level at 2 and 4 weeks post-surgery. Conclusions: We demonstrated that our precise monitoring method revealed detailed changes in the corneal nerves, the epithelium, and the stroma.

[A case of eyelid fistula after cosmetic lateral canthoplasty].

A 35-year-old female presented with a chief complaint of exudates from the outer corner of the left eye for more than half a year after cosmetic lateral canthoplasty. A fistula was seen in the skin of the left eye 5 mm from the lateral canthus, with clear fluid inside it. Left eyelid fistula was diagnosed and surgically removed. The histopathological examination confirmed that the tissue connected with the fistula was lacrimal gland tissue. No recurrence was found during the 2-month follow-up.

Systematic review and meta-analysis of the diagnostic performance of lacrimal gland ultrasound elastography in primary Sjögren's syndrome.

OBJECTIVE: This research conducted a comprehensive evaluation of the effectiveness of ultrasonic elastography (USE) in detecting lacrimal gland involvement in individuals suffering from primary Sjögren's syndrome (pSS). METHODS: A comprehensive search was undertaken across multiple databases including PubMed, the Cochrane Library, EMBASE, Wanfang, Web of Science, and the Chinese National Knowledge Infrastructure, to gather relevant literature pertaining to the application of USE in diagnosing pSS from January 1, 2000, to October 1, 2023. Pooled data were used to calculate sensitivity, specificity, and diagnostic odds ratios. Several summary metrics were used to evaluate SWE's performance in detecting pSS, including the area under the receiver operating characteristic curve, diagnostic odds ratios, sensitivities, and specificities. RESULTS: Five pertinent studies included a total of 273 patients. Shear wave elastography (SWE) demonstrated a pooled sensitivity of 0.88 (95% CI 0.77-0.94) and specificity of 0.94 (95% CI 0.88-0.98), with an area under the receiver operating characteristic curve of 0.97 (95% CI 0.95-0.98). SWE exhibited a positive likelihood ratio of 15.86 (95% CI 6.99-36.00) and a negative likelihood ratio of 0.13 (95% CI 0.07-0.25). No evidence of publication bias was observed (p = 0.70). CONCLUSION: SWE demonstrates a remarkable degree of precision in detecting lacrimal gland involvement in individuals suffering from pSS.

Update on lacrimal apparatus dysfunction associated with differentiated thyroid cancer after I-131 therapy.

PURPOSE: The most prevalent lacrimal apparatus dysfunctions associated with differentiated thyroid cancer(DTC) after I-131 therapy are dry eye and nasolacrimal duct obstruction(NLDO), leading to ocular discomfort and lower quality of life for patients. It is crucial to diagnose and manage lacrimal apparatus dysfunction associated with I-131 therapy for DTC. Therefore, this review aims to comprehensively summarize and analyze the advances in mechanisms and therapeutic options underlying lacrimal apparatus dysfunction induced by I-131 therapy for DTC. METHODS: A comprehensive search of CNKI, PubMed, and Wed of Science was performed from the database to December of 2023. Key search terms were "Thyroid cancer", "I-131", "Complications", "Dry eye", "Epiphora", "Tear", "Nasolacrimal duct" and "NLDO". RESULTS: The research indicates that I-131 therapy for DTC causes damage to the lacrimal glands and nasolacrimal duct system, resulting in symptoms such as dry eye, epiphora, and mucoid secretions. Moreover, recent research has focused on exploring relevant risk factors of the condition and experimental and clinical treatments. However, there is some controversy regarding the mechanisms involved, whether it is due to the passive flow of I-131 in tears, active uptake of I-131 by the sodium-iodide symporter (NIS) in the lacrimal sac and nasolacrimal duct, or secondary metabolic and hormonal disturbances caused by I-131. CONCLUSION: It is crucial for early detection and preventive measures by ophthalmologists and the need for further studies to elucidate the mechanisms underlying the disease.

The Aging Lacrimal Gland of Female C57BL/6J Mice Exhibits Multinucleate Macrophage Infiltration Associated With Lipid Dysregulation.

Purpose: Loss of function of the lacrimal gland (LG), which produces the aqueous tear film, is implicated in age-related dry eye. To better understand this deterioration, we evaluated changes in lipid metabolism and inflammation in LGs from an aging model. Methods: LG sections from female C57BL/6J mice of different ages (young, 2-3 months; intermediate, 10-14 months; old,  ≥24 months) were stained with Oil Red-O or Toluidine blue to detect lipids. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis and western blotting of LG lysates determined differences in the expression of genes and proteins related to lipid metabolism. A photobleaching protocol to quench age-related autofluorescence was used in LG sections to evaluate changes in immunofluorescence associated with NPC1, NPC2, CTSL, and macrophages (F4/80, CD11b) with age using confocal fluorescence microscopy. Results: Old LGs showed increased lipids prominent in basal aggregates in acinar cells and in extra-acinar sites. LG gene expression of Npc1, Npc2, Lipa, and Mcoln2, encoding proteins involved in lipid metabolism, was increased with age. NPC1 was also significantly increased in old LGs by western blotting. In photobleached LG sections, confocal fluorescence microscopy imaging of NPC1, NPC2, and CTSL immunofluorescence showed age-associated enrichment in macrophages labeled to detect F4/80. Although mononuclear macrophages were detectable in LG at all ages, this novel multinucleate macrophage population containing NPC1, NPC2, and CTSL and enriched in F4/80 and some CD11b was increased with age at extra-acinar sites. Conclusions: Lipid-metabolizing proteins enriched in F4/80-positive multinucleated macrophages are increased in old LGs adjacent to sites of lipid deposition in acini.

The Role of Aquaporin 4 in Lacrimal Gland Ductal Fluid Secretion in Mice.

Purpose: Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4 mRNA levels have been observed in experimental dry eye and during pregnancy, the impact of AQP4 in LG ductal fluid production remains unclear. In our recent work, the role of AQP4 in LG ductal fluid secretion was investigated utilizing wild type (WT) and AQP4 knock out (KO) mice. Methods: Tear production was assessed in both WT and KO animals. Immunostaining was used to identify AQP4 protein. Duct segments were harvested from LGs of WT and KO mice. Fluid secretion and filtration permeability (Pf) were quantified using video-microscopy. Ductal tear production, elicited by a cell-permeable cAMP analogue (8-bromo cAMP), carbachol, vasoactive intestinal peptide (VIP), and phenylephrine (PHE), were assessed in both WT and KO ducts. Results: A higher expression of AQP4 protein was noted in the duct cells from WT mice when compared to acinar cells. Pf did not show notable alterations between WT and AQP4 KO ducts. Carbachol elicited comparable secretory responses in ducts from both WT and KO animals. However, 8-bromo cAMP, VIP, and PHE stimulation resulted in decreased secretion in ducts from AQP4 KO LGs. Conclusions: Our findings underscore the functional relevance of AQP4 in the fluid production of mouse LG ducts. AQP4 seems to play different roles in fluid secretions elicited by different secretagogues. Specifically, cAMP-mediated, and adrenergic agonist-related secretions were reduced in AQP4 KO ducts.

Diagnosis and Treatment of Lacrimal Gland Prolapse: A Narrative Review.

BACKGROUND: Lacrimal gland prolapse (LGP) is considered to be one of the causes for upper eyelid contour abnormality that should be recognized and treated properly to yield satisfactory outcomes in blepharoplasty. To describe current findings about the prevalence, pre- and intraoperative diagnosis of LGP and its treatment options. METHODS: PubMed and Google Scholar were thoroughly searched for articles published describing the diagnosis and treatment of LGP. RESULTS: The reported prevalence of LGP by various authors varies between 10 and 60% based on their preoperative or intraoperative reports. Techniques such as dacryoadenopexy, modified dacryoadenopexy, and dacryoplasty have been described to secure the prolapsed lacrimal gland back into its original position. Additionally, creating a Whitnall's barrier has also been suggested as a method to reposition the gland. While all these surgical procedures have shown promising immediate results, there is a lack of published data on their long-term outcomes. CONCLUSION: Diagnosis and proper treatment of LGP could enhance the cosmetic results of upper eyelid blepharoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Developing a model for aqueous deficient dry eye secondary to periglandular cicatrizing conjunctivitis.

PURPOSE: The current study used various techniques to develop a rabbit animal model of lacrimal gland damage caused by scarring conjunctivitis in the periglandular area. METHODS: Left eyes of New Zealand white rabbits were injected with 0.1 ml of 1M NaOH subconjunctivally around superior and inferior lacrimal gland orifices (Group 1, n = 4), touched with 1M NaOH for 100 s to the superior and inferior fornices with conjunctival denuding (Group 2; n = 4), and electrocauterization to the ductal opening area (Group 3; n = 4). The ocular surface staining, Schirmer I, lacrimal gland, and conjunctival changes were observed at baseline,1, 4, 8, and 12 weeks. The degree of glandular inflammation, conjunctival fibrosis (Masson Trichrome), and goblet cell density (PAS) were also assessed. RESULTS: At 12 weeks, the lacrimal glands of group 1 rabbits with periglandular injection showed severe inflammation with mean four foci/10HPF and a significant mean reduction in the Schirmer values by 7.6 mm (P = 0.007). Lacrimal glands had diffuse acinar atrophy, loss of myoepithelial cells, and ductular dilatation. The overlying conjunctiva showed fibrosis, goblet cell loss, and corneal vascularization in the inferotemporal quadrant. No lacrimal gland or ocular surface changes were observed in groups 2 and 3 at 12 weeks, except for localized subconjunctival fibrosis. CONCLUSION: Periglandular injection of 0.1 ml of 1M NaOH induced extensive lacrimal gland damage with reduced secretion and scarring in the subconjunctival plane compared to direct cauterization or direct NaOH contact to the ductal orifices of the rabbit lacrimal gland.

Single-cell RNA-sequencing reveals the transcriptional landscape of lacrimal gland in GVHD mouse model.

PURPOSE: To investigate the global transcriptional landscape of lacrimal gland cell populations in the GVHD mouse model. METHODS: Single-cell RNA sequencing and further bioinformatic analysis of dissociated lacrimal gland (LG) cells from the mouse model were performed. Parts of transcriptional results were confirmed by immunofluorescence staining. RESULTS: We identified 23 cell populations belonging to 11 cell types. In GVHD LG, the proportion of acinar cells, myoepithelial cells, and endothelial cells was remarkably decreased, while T cells and macrophages were significantly expanded. Gene expression analysis indicated decreased secretion function, extracellular matrix (ECM) synthesis, and increased chemokines of myoepithelial cells. A newly described epithelial population named Lrg1high epithelial cells, expressing distinct gene signatures, was exclusively identified in GVHD LG. The fibroblasts exhibited an inflammation gene pattern. The gene pattern of endothelial cells suggested an increased ability to recruit immune cells and damaged cell-cell junctions. T cells were mainly comprised of Th2 cells and effective memory CD8+ T cells. GVHD macrophages exhibited a Th2 cell-linked pattern. CONCLUSIONS: This single-cell atlas uncovered alterations of proportion and gene expression patterns of cell populations and constructed cell-cell communication networks of GVHD LG. These data may provide some new insight into understanding the development of ocular GVHD.

IL-27 promotes pathogenic T cells in a mouse model of Sjögren's disease.

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice.

Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats.

Diabetes mellitus is a prevalent disease that is often accompanied by ocular surface abnormalities including delayed epithelial wound healing and decreased corneal sensitivity. The impact of diabetes on the lacrimal functional unit (LFU) and the structures responsible for maintaining tear homeostasis, is not completely known. It has been shown that the Opioid Growth Factor Receptor (OGFr), and its ligand, Opioid Growth Factor (OGF), is dysregulated in the ocular surface of diabetic rats leading to overproduction of the inhibitory growth peptide OGF. The opioid antagonist naltrexone hydrochloride (NTX) blocks the OGF-OGFr pathway, and complete blockade following systemic or topical treatment with NTX restores the rate of re-epithelialization of corneal epithelial wounds, normalizes corneal sensitivity, and reverses dry eye in diabetic animal models. These effects occur rapidly and within days of initiating treatment. The present study was designed to understand mechanisms related to the fast reversal (<5 days) of dry eye by NTX in type 1 diabetes (T1D) by investigating dysregulation of the LFU. The approach involved examination of the morphology of the LFU before and after NTX treatment. Male and female adult Sprague-Dawley rats were rendered hyperglycemic with streptozotocin, and after 6 weeks rats were considered to be a T1D model. Rats received topical NTX twice daily to one eye for 10 days. During the period of treatment, tear production and corneal sensitivity were recorded. On day 11, animals were euthanized and orbital tissues including conjunctiva, eyelids, and lacrimal glands, were removed and processed for histologic examination including immunohistochemistry. Male and female T1D rats had significantly decreased tear production and corneal insensitivity, significantly decreased number and size of lacrimal gland acini, decreased expression of aquaporin-5 (AQP5) protein and decreased goblet cell size. Thus, 10 days of NTX treatment restored tear production and corneal sensitivity to normal values, increased AQP5 expression, and restored the surface area of goblet cells to normal. NTX had no effect on the number of lacrimal gland acini or the number of conjunctival goblet cells. In summary, blockade of the OGF-OGFr pathway with NTX reversed corneal and lacrimal gland complications and restored some components of tear homeostasis confirming the efficacy of topical NTX as a treatment for ocular defects in diabetes.