AS101 regulates the Teff/Treg balance to alleviate rabbit autoimmune dacryoadenitis through modulating NFATc2.

Sjögren's syndrome (SS) dry eye can cause ocular surface inflammation and lacrimal gland (LG) damage, leading to discomfort and potential vision problems. The existing treatment options for SS dry eye are currently constrained. We investigated the possible therapeutic effect and the underlying mechanism of AS101 in autoimmune dry eye. AS101 was injected subconjunctivally into a rabbit model of autoimmune dacryoadenitis and its therapeutic effects were determined by evaluating clinical and histological scores. The expressions of effector T cells (Teff)/regulatory T cells (Treg)-related transcription factors and cytokines, inflammation mediators, and transcription factor NFATc2 were measured by quantitative real-time PCR and/or Western blot both in vivo and in vitro. Additionally, the role of NFATc2 in the immunomodulatory effects of AS101 on T cells was explored by co-culturing activated peripheral blood lymphocytes (PBLs) transfected with NFATc2 overexpression lentiviral plasmid with AS101. AS101 treatment potently ameliorated the clinical severity and reduced the inflammation of LG. Further investigation revealed that AS101 treatment led to decreased expression of Th1-related genes (T-bet and IFN-γ) and Th17-related genes (RORC, IL-17A, IL-17F, and GM-CSF) and increased expression of Treg-related gene Foxp3 in vivo and in vitro. Meanwhile, AS101 suppressed the expression of TNF-α, IL-1ß, IL-23, IL-6, MMP-2, and MMP-9. Mechanistically, AS101 downregulated the expression of NFATc2 in inflamed LGs. Overexpression of NFATc2 in activated PBLs partially blunted the effect of AS101 on Teff suppression and Treg promotion. In conclusion, AS101 is a potential regulator of Teff/Treg cell balance and could be an effective treatment agent for SS dry eye.

Gonococcal dacryoadenitis complicated by orbital cellulitis: a case report.

Gonococcal dacryoadenitis is uncommon, and its diagnosis may be delayed especially if there is a low index of clinical suspicion. Making an early diagnosis is extremely important because in some cases the organism may spread contiguously, leading to vision-threatening sequelae such as corneal perforation. The authors present a case report of a patient diagnosed with gonococcal dacryoadenitis complicated by orbital cellulitis. Our case demonstrates that in all cases of purulent dacryoadenitis, urgent evaluation, cultures and treatment is crucial, and it is prudent to consider gonococcal dacryoadenitis as a rare but possible differential in patients who are sexually active with an unexplained cause for dacryoadenitis.

[Cell technologies as a basis for the development of regenerative principles for the treatment of lacrimal gland diseases]. / Kletochnye tekhnologii kak osnova razrabotki regeneratornykh printsipov lecheniya zabolevanii sleznoi zhelezy.

The lacrimal gland (LG) is a tubuloacinar exocrine gland composed of acinar, ductal, and myoepithelial cells. Three-dimensional distribution of acinar lobules, ducts, and myoepithelial cells is necessary for the effective functioning of the organ. LG is the main organ of immune surveillance of the ocular surface system. The embryogenesis of the gland is regulated by the interaction of genetic mechanisms, internal epigenetic (enzyme systems, hormones) and exogenous factors. There is no doubt that there is a clear genetic program for the implementation of the complex process of embryonic development. The mechanisms regulating LG organogenesis initiate the work of a huge number of structural oncogenes, transcription and growth factors, etc. Studying the expression and selective activity of regulatory genes during organ development, their participation in the differentiation of different cell types is a current trend at the nexus of clinical genetics, molecular biology, embryology and immunocytochemistry. Due to its relatively simple structure and accessibility, human LG is a suitable object for potential application in regenerative medicine. Development of a universal protocol for obtaining functional differentiated secretory epithelium of LG capable of expressing tissue-specific markers is an urgent task. Determining the nature and origin of stem cells and progenitor cells will allow the isolation and multiplication of these cells in culture. After obtaining a functionally active culture of LG cells, it is possible to create a model of autoimmune diseases.

Heterochronic Parabiosis Causes Dacryoadenitis in Young Lacrimal Glands.

Aging is associated with inflammation and oxidative stress in the lacrimal gland (LG). We investigated if heterochronic parabiosis of mice could modulate age-related LG alterations. In both males and females, there were significant increases in total immune infiltration in isochronic aged LGs compared to that in isochronic young LGs. Male heterochronic young LGs were significantly more infiltrated compared to male isochronic young LGs. While both females and males had significant increases in inflammatory and B-cell-related transcripts in isochronic and heterochronic aged LGs compared to levels isochronic and heterochronic young LGs, females had a greater fold expression of some of these transcripts than males. Through flow cytometry, specific subsets of B cells were increased in the male heterochronic aged LGs compared to those in male isochronic aged LGs. Our results indicate that serum soluble factors from young mice were not enough to reverse inflammation and infiltrating immune cells in aged tissues and that there were specific sex-related differences in parabiosis treatment. This suggests that age-related changes in the LG microenvironment/architecture participate in perpetuating inflammation, which is not reversible by exposure to youthful systemic factors. In contrast, male young heterochronic LGs were significantly worse than their isochronic counterparts, suggesting that aged soluble factors can enhance inflammation in the young host. Therapies that aim at improving cellular health may have a stronger impact on improving inflammation and cellular inflammation in LGs than parabiosis.

Marginal Zone B (MZB) Cells: Comparison of the Initial Identification of Immune Activity Leading to Dacryoadenitis and Sialadenitis in Experimental Sjögren's Syndrome.

Although multiple mouse strains have been advanced as models for Sjögren's syndrome (SS), which is a human systemic autoimmune disease characterized primarily as the loss of lacrimal and salivary gland functions, the C57BL/6.NOD-Aec1Aec2 recombinant inbred (RI) mouse derived from the NOD/ShiLtJ line is considered one of the more appropriate models exhibiting virtually all the characteristics of the human disease. This mouse model, as well as other mouse models of SS, have shown that B lymphocytes are essential for the onset and development of observed clinical manifestations. Recently, studies carried out in the C57BL/6.IL14α transgenic mouse have provided clear evidence that the marginal zone B (MZB) cell population is directly involved in the early pathological events initiating the development of the clinical SS disease, as well as late-stage lymphomagenesis resulting in B-cell lymphomas. Since MZB cells are difficult to study in vivo and in vitro, we carried out a series of ex vivo investigations that utilize temporal global RNA transcriptomic analyses to profile differentially expressed genes exhibiting temporal upregulation during the initial onset and subsequent development of pathophysiological events within the lacrimal and salivary gland tissues per se or associated with the leukocyte cell migrations into these glands. The initial transcriptomic analyses revealed that while the upregulated gene expression profiles obtained from lacrimal and salivary glands overlap, multiple genetic differences exist between the defined activated pathways. In the current study, we present a concept suggesting that the initial pathological events differ between the two glands, yet the subsequent upregulated TLR4/TLR3 signal transduction pathway that activates the type-1 interferon signature appears to be identical in the two glands and indicates an autoimmune response against dsRNA, possibly a virus. Here, we attempt to put these findings into perspective and determine how they can impact the design of future therapeutic protocols.

Systemic eosinophilic disease presenting as dacryoadenitis.

Eosinophilic disease with orbital involvement is rare. We present two patients with dacryoadenitis associated with local and systemic eosinophilia. A 32-year-old man presented with episodic dacryoadenitis, lower respiratory inflammation and peripheral eosinophilia. Lung and lacrimal gland biopsies demonstrated eosinophilic infiltrate without granuloma, necrosis, or vasculitis. He improved with oral corticosteroids and Mepolizumab, an IL-5 inhibitor. The second case involved a 33-year-old man who similarly presented with episodic dacryoadenitis, pulmonary inflammation and pain/swelling in the hands and feet. Lacrimal gland biopsy demonstrated a predominantly eosinophilic infiltrate without granuloma or vasculitis. Symptoms improved with oral corticosteroids. Although neither patient was provided a definitive diagnosis, both were determined to have an eosinophilic condition on the spectrum of eosinophilic asthma or eosinophilic granulomatosis with polyangiitis.

Orbital inflammation following COVID-19 vaccination: A case series and literature review.

PURPOSE: The purpose of the study was to report three cases of orbital inflammation following administration of the COVID-19 vaccination, manifesting as Tolosa-Hunt syndrome (THS) and orbital myositis. METHOD: A retrospective case series and literature review of patients who developed orbital inflammation following a COVID-19 vaccination. RESULTS: One patient presented with Tolosa-Hunt syndrome (THS) 14 days following her third (booster) COVID-19 vaccination, one patient developed orbital myositis 10 days following his first COVID-19 vaccination and one patient developed recurrent orbital myositis 1 and 7 days following her second and fourth COVID-19 vaccination. All patients received the Comirnaty vaccine (Pfizer-BioNTech). A thorough systemic autoimmune disease workup in both patients was unremarkable. Two patients had a prior history of orbital inflammation, with previous involvement of other different orbital structures. Characteristic MRI features for each pathology were observed, supporting the clinical presentation of THS and orbital myositis. There was complete resolution of THS following corticosteroids, with no recurrence at 2 months. Meanwhile, one case of orbital myositis self-resolved at 2 months without use of systemic corticosteroids, while the other patient with orbital myositis required treatment with intra-orbital steroid injections and oral corticosteroids. CONCLUSION: Orbital inflammation has been recognised as a rare adverse effect following COVID-19 vaccination. We present a case series of THS and orbital myositis as varied presentations of this entity.

[The role of miRNA in the pathogenesis of diseases associated with functional dysregulation of the lacrimal gland]. / Rol' mikroRNK v patogeneze zabolevanii, svyazannykh s narusheniem funktsii sleznoi zhelezy.

At this time, the mechanism causing lacrimal gland dysfunction is not understood completely. In diseases associated with lacrimal gland involvement (Sjogren's syndrome, sarcoidosis, IgG4-associated disease, etc.) patients have been observed to experience elevated cellular apoptosis, active production of autoantibodies to glandular tissue, increased level of pro-inflammatory cytokines, functional disruption of signaling molecules leading to changes in tear production. Difficulties in differential diagnosis of lacrimal gland dysfunction in above-listed diseases are associated, on the one hand, with similarity of the clinical picture of ophthalmological manifestations, and on the other hand - with complicated morphological interpretation of changes in the glandular tissues. In this view, miRNA is a promising diagnostic and prognostic marker that would help with differential diagnosis as well as with choosing the treatment tactics. Methods of molecular profiling and identification of "molecular phenotypes" of lacrimal gland and ocular surface damage will allow the use of miRNA as biomarkers and prognostic factors for personalized treatment.

Bacterial dacryoadenitis: clinical features, microbiology, and management of 45 cases, with a recent uptick in incidence.

PURPOSE: To review the clinical features, microbiology, management, and incidence of bacterial dacryoadenitis at our institution. METHODS: This was a case series examining patients with bacterial dacryoadenitis from 2004 to 2020. Charts were reviewed for demographics, comorbidities, presenting symptoms and signs, radiology, microbiology, and management. Main outcomes included need for surgical intervention or inpatient admission. RESULTS: Forty-five patients with bacterial dacryoadenitis had a mean age of 46.1 years. Presenting symptoms included eyelid edema (100%), extraocular motility restriction (53.3%), and purulent discharge (75.5%). Based on computed tomography or magnetic resonance imaging, 9 (20.5%) patients presented with definite abscess and 15 (34%) presented with a phlegmon or early abscess. Eleven patients (24.4%) required surgical drainage. Twenty patients (44.4%) required admission, for an average stay of 4 days (range 2-8 days). Common organisms included Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus. Presence of an early abscess or phlegmon correlated with need for drainage (p < 0.01). Extraocular motility restriction correlated with need for drainage (p = 0.02) and admission (p = 0.05). The incidence of bacterial dacryoadenitis at our institution increased as a percentage of confirmed dacryoadenitis cases; from 2004 to 2010 the incidence was 0 to 9.1% per year, while from 2010 to 2019 the incidence ranged from 7.7 to 36.2%. In 2019, our institution had 17 cases (incidence 36.2%) of bacterial dacryoadenitis. CONCLUSIONS: Bacterial dacryoadenitis is a major cause of dacryoadenitis, and its incidence may be increasing. It can resolve with minimal complications if managed appropriately, although some patients may require surgical drainage or admission for intravenous antibiotics.

Bilateral dacryoadenitis as the initial presentation of ANCA-associated vasculitis in a pediatric patient.

A 14-year-old female presented with 2 weeks of progressive right eye pain, erythema, and proptosis. Examination demonstrated an enlarged palpable mass along the right superior lateral orbit and bilateral conjunctival petechiae. Of note, she was asymptomatic on the left side, and the petechiae were present only on the superior bulbar conjunctiva with eyelid eversion. Imaging demonstrated bilateral lacrimal gland enhancement. Testing was significant for elevated inflammatory markers, but otherwise negative workup. Biopsy of the right lacrimal gland demonstrated acute-on-chronic inflammation without evidence of lymphoproliferative disease. On repeat testing, myeloperoxidase antibody levels (MPO/p-ANCA) were elevated, indicative of an underlying immune-mediated vasculitis. This case illustrates a rare presentation of ANCA-associated vasculitis in a pediatric patient. It further demonstrates the phenomenon of initial negative serology and subsequent auto-antibody seroconversion in a patient with localized granulomatosis with polyangiitis.

Actinomyces ductular dacryoadenitis resulting in a lacrimal gland abscess.

Lacrimal gland ductulitis is a rare infection of the lacrimal gland ductules. Individuals affected report a history of chronic mucopurulent conjunctivitis with "stringy" discharge. All patients are clinically noted to have an inflamed lacrimal gland ductule. Prior reports have suggested Actinomyces species as the "probable" etiology.We report the findings of a 42-year-old male found to have lacrimal gland ductulitis with a lacrimal gland abscess, confirmed by radiologic studies. Surgical drainage was necessitated and performed. Histopathologic analysis confirmed colonization by Actinomyces species, as well as the presence of sulfur granules. To our knowledge, this is the first report of Actinomyces lacrimal gland ductulitis resulting in a secondary lacrimal gland abscess.

Recurrent orbital inflammation associated with VEXAS syndrome.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly recognised adult-onset multisystem autoinflammatory disease caused by a somatic mutation in the UBA1 gene in myeloid or erythroid precursor cells. This report describes an atypical presentation of recurrent dacryoadenitis associated with VEXAS syndrome and provides a review of the literature. A 68-year-old male presented with three episodes of unilateral alternating dacryoadenitis followed by bilateral involvement over a 4-year period. Each episode of orbital inflammation was characterised by upper lid swelling, oedema and enlarged lacrimal glands. In addition, he experienced intermittent flares of angioedema-like lesions involving the face and extremities, recurrent jaw aches, rash, progressive pulmonary fibrosis, and myelodysplastic syndrome. His inflammatory symptoms lessened with prednisolone but were refractory to methotrexate. Mycophenolate was subsequently trialled with a reasonable clinical response. Genetic testing established the diagnosis of VEXAS syndrome and tofacitinib, a JAK inhibitor, was commenced with resolution of inflammatory symptoms.

Acute dacryoadenitis in a patient with SARS-CoV-2 infection.

We describe a retrospective case report of dacryoadenitis associated with orbital inflammatory disease in a patient with confirmed SARS-CoV-2 infection.A 22-year-old previously fit and healthy male presented with 4-day history of right ocular redness, eyelid swelling and blurred vision associated with discomfort and pain in the lacrimal gland area. He was found to have right acute dacryoadenitis based on clinical examination and orbital imaging. One day after initiation of oral antibiotic and non-steroidal anti-inflammatory therapy, he developed worsening of the orbital inflammation and partial ophthalmoplegia. Oral steroids were commenced resulting in rapid resolution of symptoms within a few days and clinical stability at 2 months.The patient did not have any systemic features of COVID-19 but he was in close contact with his mother and with his partner who both had respiratory symptoms and tested positive for SARS-CoV-2 antigen (PCR testing) 4 weeks prior. PCR testing from nasopharyngeal swab was negative for SARS-CoV-2 RNA; however, the serological test was positive for IgM/IgG SARS-CoV-2 antibodies. Extensive laboratory workup including infectious and autoimmune screening and chest x-ray were unremarkable.Orbital inflammatory disease due to infectious process or immunological response may potentially occur in COVID-19 patients, although the causal relationship remains uncertain.

Ultrasonography of IgG4-related dacryoadenitis and sialadenitis: Imaging features and clinical usefulness.

OBJECTIVES: To clarify the ultrasonographic features of immunoglobulin G4 (IgG4)-related dacryoadenitis and sialadenitis (IgG4-DS) and their usefulness in clinical diagnostic sessions. METHODS: By re-evaluating 96 consecutive patients with IgG4-related disease, we identified 54 patients (male:female = 37:17; median age, 69.5 years) who underwent lacrimal or submandibular gland (LG or SG, respectively) ultrasonography and computed tomography (CT). Their clinical and ultrasonographic features were retrospectively analysed. Radio-pathological correlations were also examined in LG (23 cases) and SG lesions (20 cases). Additionally, the diagnostic accuracy of CT for LG/SG lesions was evaluated. RESULTS: Abnormal ultrasonographic findings were detected in 33 (LGs) and 38 (SGs) patients, and most of them were observed bilaterally. All lesions were well demarcated and demonstrated diffuse low-echoic areas (rocky pattern) or multiple low-echoic nodules surrounded by high-echoic linear shadows (cobblestone pattern) corresponding to intra-lobular inflammation and inter-lobular fibrosis. Moreover, 42% (LGs; 14/33) and 42% (SGs; 16/38) patients had glandular lesions without clinical symptoms associated with the affected glands. The diagnostic accuracy of CT was ∼80% for LG and 55% for SG. CONCLUSIONS: Ultrasonographic findings in IgG4-DS included diffuse or nodular low-echoic areas with linear high-echoic structures corresponding to inflamed lobules and inter-lobular fibrosis. These findings can help detect IgG4-DS.

Rabbit models of dry eye disease: Current understanding and unmet needs for translational research.

Dry eye disease (DED) is emerging as an eye health pandemic, affecting millions worldwide. The development of novel drugs, drug delivery systems, and targeted therapies for addressing the inflammation in DED necessitates progress in experimental models of DED. Animal models of DED have been created for simulating the two clinically described forms of DED: lacrimal insufficiency and the evaporative DED models. Although most DED models have relied upon rodents, the larger eye size and longer life span of rabbits and the closer resemblance to human lacrimal glands, render rabbits a promising near-ideal model for studying DED. Since the first rabbit DED model was described, numerous modifications including the use of topical epitheliotoxic drugs, neural abolition, activated lymphocytes injection, and surgical dacryoadenectomy have been introduced. The stability of these models, whether short-term or long-term, accordingly guides their experimental or therapeutic utility. A rabbit autoimmune dacryoadenitis model has successfully simulated DED signs and features of lacrimal gland inflammation, as observed in Sjogren's syndrome, that improved with mesenchymal stem cell therapy. This review summarizes the comparative microscopic anatomy of rabbit and human lacrimal glands, various existing rabbit DED models and their respective suitability for understanding pathogenetic mechanism of DED or for experimental drug testing. Also, the insights gained from animal models in dry eye management is described along with the future perspectives. There is still a pressing need of developing rabbit models for studying the pathogenesis of complex ocular surface changes in evaporative and aqueous deficiency DED other than autoimmune dacryoadenitis.

Involvement of two or more sets of lacrimal glands and/or major salivary glands is related to greater systemic disease activity due to multi-organ involvement in IgG4-related dacryoadenitis/sialadenitis.

OBJECTIVES: In IgG4-related dacryoadenitis and/or sialadenitis (IgG4-DS), involvement of two or more sets of lacrimal glands (LGs) and/or major salivary glands (MSGs) is regarded as a specific finding with diagnostic significance. This study aimed to clarify the influence of this factor on the overall clinical picture of IgG4-DS. METHODS: We retrospectively reviewed the medical records of 130 patients with IgG4-related disease, 97 of whom were diagnosed with IgG4-DS. We determined their clinical features according to the presence/absence of involvement of ≥2 sets of LGs and/or MSGs and compared the results with those obtained in 33 DS-limited patients. RESULTS: The IgG4-DS patients comprised 60 men and 37 women (median age 65 years). The median serum IgG4 level at diagnosis was 548 mg/dL. The patients with involvement of ≥2 sets (n = 44) had significantly more affected organs, lower serum C3 and C4 levels, and a tendency to have higher serum IgG levels and IgG4-RD responder index than did those without it (n = 53). In the 33 DS-limited patients, these two groups had no significant differences in clinical features. CONCLUSIONS: Involvement of ≥2 sets of LGs and/or MSGs suggests greater systemic disease activity mainly reflected by involvement of more organs.

IgG4-related Dacryoadenitis and Sialadenitis with Palatal Gland Swelling.

Many cases of immunoglobulin G4-related disease (IgG4-RD) involve swelling of the salivary glands, often affecting the parotid and submandibular glands in the head and neck region, in addition to the lacrimal glands. Cases of IgG4-RD characterized by swelling of the palatal glands, however, are extremely rare. Here, we describe a case of IgG4-RD involving bilateral swelling of the palatal glands. An 83-year-old man presented at our hospital with bilateral swelling of the lacrimal and submandibular glands. A solid bilateral swelling of normal colour and unclear boundaries was observed in the hard palate. The lesion was diagnosed as IgG4-RD and steroid therapy initiated. A subsequent decrease in swelling of the palatal, lacrimal, and submandibular glands was confirmed by magnetic resonance imaging. These results indicate that dentists should suspect IgG4-RD in patients presenting with bilateral swelling of the palatal glands.

Arginase 1 is involved in lacrimal hyposecretion in male NOD mice, a model of Sjögren's syndrome, regardless of dacryoadenitis status.

KEY POINTS: Few reports have explored the possibility of involvement of non-inflammatory factors in lacrimal hyposecretion in Sjögren's syndrome (SS). RNA-sequencing analysis revealed that only four genes, including arginase 1, were downregulated in the lacrimal gland of SS model male mice (NOD mice) after onset of lacrimal hyposecretion and dacryoadenitis. Even in non-dacryoadenitis-type NOD mice, tear secretion and arginase 1 expression remained low. An arginase 1 inhibitor reduced tear secretion and partially reduced saliva secretion in BALB/c mice. The results indicate that a non-inflammatory factor, arginase 1, is involved in lacrimal hyposecretion in male NOD mice, regardless of dacryoadenitis status. ABSTRACT: Lacrimal fluid (tears) is important for preservation of the ocular surface, and thus lacrimal hyposecretion in Sjögren's syndrome (SS) leads to reduced quality of life. However, the cause(s) of lacrimal hyposecretion remains unknown, even though many studies have been conducted from the perspective of inflammation. Here, we hypothesized that a non-inflammatory factor induces lacrimal hyposecretion in SS pathology, and to elucidate such a factor, we conducted transcriptome analysis of the lacrimal glands in male non-obese diabetic (NOD) mice as an SS model. The NOD mice showed inflammatory cell infiltration and decreased pilocarpine-induced tear secretion at and after 6 weeks of age compared to age-matched BALB/c mice. RNA-sequencing analysis revealed that only four genes, including arginase 1, were downregulated, whereas many genes relating to inflammation were upregulated, in the lacrimal glands of male NOD mice after onset of lacrimal hyposecretion and dacryoadenitis (lacrimal gland inflammation). Changes in the level of arginase 1 expression were confirmed by real-time RT-PCR and western blot analysis. Furthermore, non-dacryoadenitis-type NOD mice were used to investigate the relationships among arginase 1 expression, lacrimal hyposecretion and dacryoadenitis. Interestingly, these NOD mice retained the phenotype of dacryoadenitis with regard to tear secretion and arginase 1 expression level. An arginase 1 inhibitor reduced tear secretion and partially reduced saliva secretion in BALB/c mice. In conclusion, a non-inflammatory factor, arginase 1, is involved in lacrimal hyposecretion in male NOD mice, regardless of dacryoadenitis status. These results shed light on the pathophysiological role of arginase 1 in SS (dry eye).

Human umbilical cord mesenchymal stem cells alleviate ongoing autoimmune dacryoadenitis in rabbits via polarizing macrophages into an anti-inflammatory phenotype.

Mesenchymal stem cells (MSCs) exhibit beneficial effects on autoimmune dacryoadenitis. However, the underlying mechanisms are not fully understood. In this study, we investigated the therapeutic effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on rabbit autoimmune dacryoadenitis, an animal model of Sjögren's syndrome (SS) dry eye, and explored whether the effects of MSCs were related to their modulation on macrophage polarization. We have showed that systemic infusion of hUC-MSCs after disease onset efficiently diminished the chronic inflammation in diseased LGs and improved the clinical symptoms. Further analysis revealed that hUC-MSC treatment significantly inhibited the expression of pro-inflammatory M1 macrophage markers iNOS, TNF-α and IL-6, and promoted the expression of anti-inflammatory M2 macrophage markers Arg1, CD206, IL-10, IL-4 and TGF-ß in LGs. Mechanistically, hUC-MSCs activated AKT pathway in macrophages, resulting in upregulation of M2-associated molecule Arg1, which was partly abolished by PI3K inhibitor, LY294002. Together, our data indicated that hUC-MSCs can skew macrophages into an M2 phenotype via affecting AKT pathway. These data may provide a new insight into the mechanisms of hUC-MSCs in the therapy of SS dry eye.

MicroRNA expression profile of Lacrimal Glands in rabbit autoimmune dacryoadenitis model.

Purpose: To identify the differential expression of microRNAs (miRs) and the related gene networks and signal pathways in lacrimal glands (LGs) of rabbit autoimmune dacryoadenitis. Methods: Autoimmune dacryoadenitis in rabbits was induced by transferring activated peripheral blood lymphocytes (PBLs). The LGs of normal and model group rabbits were collected for small RNA sequencing. The most differentially expressed miRs were validated by quantitative real time-polymerase chain reaction (qRT-PCR). Further, bioinformatics analysis including target gene prediction, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Results: A total of 15 miRs were differentially expressed in the LGs of rabbit autoimmune dacryoadenitis relative to normal controls. GO and KEGG analysis revealed that most target genes of these dysregulated miRs were implicated in MAPK signaling pathway. Conclusion: Our results showed for the first time the differentially expressed miRs and the related pathways involved in the pathogenesis of rabbit autoimmune dacryoadenitis. These results may contribute to elucidating molecular pathogenesis of Sjögren's syndrome (SS) dry eye.