Changes in Corneal Subbasal Nerves after Punctal Occlusion in Dry Eye Disease.

PURPOSE: To evaluate corneal subbasal nerve plexus by in vivo confocal microscopy (IVCM) following punctal occlusion in patients with moderate to severe dry eye disease (DED). MATERIALS AND METHODS: Patients with grade 3 or 4 severity of DED based on Delphi Panel dry eye severity grading scheme were enrolled in the study. Permanent inferior punctal occlusion was performed. A comprehensive ophthalmic evaluation, including Ocular Surface Disease Index (OSDI) questionnaire, tear break-up time (TBUT), corneal fluorescein staining, conjunctival Rose bengal staining, Schirmer's test, and corneal sensation by Cochet-Bonnet esthesiometry, were performed at baseline, and 1 and 3 months after punctal occlusion. Furthermore, density and number of corneal subbasal nerves were evaluated by IVCM. RESULTS: Forty-one eyes of 23 patients with a mean age of 46.3 ± 9.0 years were enrolled. Corneal fluorescein staining, Rose bengal staining, and TBUT significantly improved at 3 months following punctal occlusion (p < .015). Corneal esthesiometry significantly increased at both postoperative visits (p < .03), and OSDI scores improved only at 3-month follow-up (p < .005). Nerve density and total number significantly increased 3 months after punctal occlusion (p < .045). Baseline nerve density had significant correlations with TBUT, fluorescein staining, Rose bengal staining (p < .012), but not with esthesiometry, Schirmer scores, or OSDI scores (p > .329). CONCLUSIONS: Corneal subbasal nerve density and total number increased following punctal occlusion in patients with moderate to severe DED. These findings were associated with improvements in corneal sensation, and signs and symptoms of DED. This emphasizes the effect of punctal occlusion in regeneration of corneal subbasal nerve plexus.

Ectopic lacrimal gland in the lacrimal sac mimicking tumour: literature review.

An 80-year-old man referred with repeated episode of dacryocystitis from the left lacrimal drainage system and palpable swelling. For many years, he has being presented with epiphora unilaterally with chronic dacryocystitis. Investigations with dye-test revealed subocclusion of the natural passage of the tears, and CT and MRI scans revealed solid mass in the lacrimal sac. The lacrimal sac was opened by endonasal endoscopic approach, the sacral mass was identified and completely removed. The histopathological examination showed lacrimal gland in ectopic position. Patient followed for 18 months with complete recovery of symptoms. In our differential diagnosis, the ectopic lacrimal gland is also identified, when a mass in the lacrimal sac and duct is present. Successful surgical excision required considerable multidisciplinary teamwork between ophtalmologist-ENT (Otolaryngologist) and radiologist. Endonasal endoscopic approach is perfectly safe with direct control and ensures a smooth postoperative recovery.

Reliability of endoscopic dye transit test for prediction of functional success after diode laser and external dacryocystorhinostomy / Confiabilidade do teste endoscópico do corante na predição do sucesso funcional após dacriocistorinostomia com laser diodo e externa

ABSTRACT Purpose: To determine the reliability of the endoscopic dye transit test for the prediction of functional success after dacryocystorhinostomy. Methods: A cross-sectional study was conducted with 50 patients who underwent external dacryocystorhinostomy Group or transcanalicular dacryocystorhinostomy Group and had anatomically patent ducts during irrigation, with a minimum 6-month follow-up. The external dacryocystorhinostomy, defined as the time from instillation of the dye into the conjunctival sac until its flow from the rhinostomy site, was performed in all patients. Positive predictive value of the endoscopic dye transit test to assess functional success was analyzed. The cutoff point was determined using a receiver operating characteristic curve. Results: Of the 50 patients, 44 (88%) exhibited subjective improvement or complete resolution of epiphora (functional success). The best cutoff point for the endoscopic dye transit test was 60 s. Of 39 patients with endoscopic dye transit test £60 s, 38 (97.4%) exhibited functional success, demonstrating a 97.4% positive predictive value. Conclusion: The endoscopic dye transit test £60 s is a reliable tool to predict functional success and good prognosis after external or laser transcanalicular dacryocystorhinostomy.

RESUMO Objetivo: Determinar a confiabilidade do teste endoscópico do corante na predição do sucesso funcional após dacriocistorrinostomia. Métodos: Estudo transversal com 50 pacientes submetidos ao grupo de dacriocistorrinostomia externa ou grupo dacriocistorrinostomia transcanalicular e que possuíam dutos anatomicamente patentes pela irrigação, com seguimento mínimo de 6 meses. A dacriocistorrinostomia externa, definida como o tempo desde a instilação do corante no saco conjuntival até o fluxo do local da rinostomia, foi realizada em todos os pacientes. O valor preditivo positivo do teste endoscópico do corante para avaliar o sucesso funcional foi analisado. O ponto de corte foi determinado usando uma curva característica de operação do receptor. Resultados: Dos 50 pacientes, 44 (88%) apresentaram melhora subjetiva ou resolução completa da epífora (sucesso funcional). O melhor ponto de corte para o teste endoscópico do corante foi de 60 s. Dos 39 pacientes com teste endoscópico do corante £60 s, 38 (97,4%) apresentaram sucesso funcional, demonstrando um valor preditivo positivo de 97,4%. Conclusão: O teste en­doscópico do corante £60 s é uma ferramenta confiável para predizer o sucesso funcional e o bom prognóstico após dacriocistorrinostomia transcanalicular externa ou a laser.

Dacryocystorhinostomy: Evolution of endoscopic techniques after 498 cases.

INTRODUCTION: Endoscopic dacryocystorhinostomy is a well-known surgical practice used to treat nasolacrimal duct obstruction and widely considered as a valid alternative to external approaches. PURPOSE: We present a retrospective case series of 498 endoscopic dacryocystorhinostomies on 401 patients, from July 2004 to May 2018, at the Department of Otolaryngology, San Raffaele Hospital, Milan, Italy. METHODS: Of the 498 procedures, 426 were unilateral and 72 were bilateral dacryocystorhinostomy. All patients underwent routine preoperative workup including fluorescein test (Jones test 1-2), probing and irrigation of the lacrimal way, nasal endoscopy, and maxilla-facial computed tomography scan. Surgical technique was based on nasal endoscopic dacryocystorhinostomy followed by positioning of a Catalano's silicone stent, which was left in place for about 3 months. Anatomical success was defined as a patent ostium on irrigation, whereas functional success was defined as free lacrimal flow on functional test and resolution of epiphora. RESULTS: Anatomic success was achieved in 91.54% cases in primary dacryocystorhinostomy and in 89.36% after revision, whereas functional success was obtained in 90.4% in primary and 85.1% in secondary dacryocystorhinostomies. After a second revision of endoscopic dacryocystorhinostomy, anatomical success was achieved in 90.1% and functional success in 88.7% of procedures. CONCLUSION: Our results confirm that endoscopic dacryocystorhinostomy can be considered as a valid surgical approach to primary nasolacrimal duct obstruction and revision cases. The key aspects in achieving functional and anatomical results are meticulous surgical procedure and precise follow-up.

Congenital nasolacrimal duct obstruction continues trend for spontaneous resolution beyond first year of life.

PURPOSE: To investigate spontaneous resolution of congenital nasolacrimal duct obstruction (CNLDO) beyond 12 months of age in Japanese infants. METHODS: Retrospective, observational case series. We retrospectively reviewed the clinical records of patients diagnosed with CNLDO beyond 12 months of age at Kyoto Prefectural University Hospital, Kyoto, Japan. This study involved 155 cases of CNLDO in 133 Japanese infants diagnosed with CNLDO. All patients chose intervention with either dacryoendoscopic guided probing and stenting or conservative management. The proportion and age of patients who had spontaneous CLNDO resolution were analysed. RESULTS: The patients were divided into two groups: (1) 62 patients with 70 obstructed nasolacrimal ducts (45%) in whom spontaneous resolution occurred and (2) 71 patients with 85 obstructed nasolacrimal ducts (55%) who underwent dacryoendoscopic guided probing and stenting. The mean age of spontaneous resolution was 17.8±5.3 months (range: 12.0-35.4 months). Dacryoendoscopic guided probing and stenting were successful in 83/85 (97.6%) of cases. CONCLUSIONS: Spontaneous resolution of CNLDO can occur in 45% of infants over the age of 12 months. Dacryoendoscopic guided stenting also has high success rates in this patient group, and both treatment options can be proposed to caregivers.

Reliability of endoscopic dye transit test for prediction of functional success after diode laser and external dacryocystorhinostomy.

PURPOSE: To determine the reliability of the endoscopic dye transit test for the prediction of functional success after dacryocystorhinostomy. METHODS: A cross-sectional study was conducted with 50 patients who underwent external dacryocystorhinostomy Group or transcanalicular dacryocystorhinostomy Group and had anatomically patent ducts during irrigation, with a minimum 6-month follow-up. The external dacryocystorhinostomy, defined as the time from instillation of the dye into the conjunctival sac until its flow from the rhinostomy site, was performed in all patients. Positive predictive value of the endoscopic dye transit test to assess functional success was analyzed. The cutoff point was determined using a receiver operating characteristic curve. RESULTS: Of the 50 patients, 44 (88%) exhibited subjective improvement or complete resolution of epiphora (functional success). The best cutoff point for the endoscopic dye transit test was 60 s. Of 39 patients with endoscopic dye transit test £60 s, 38 (97.4%) exhibited functional success, demonstrating a 97.4% positive predictive value. CONCLUSION: The endoscopic dye transit test £60 s is a reliable tool to predict functional success and good prognosis after external or laser transcanalicular dacryocystorhinostomy.

Amblyopia risk factors in congenital nasolacrimal duct obstruction: A longitudinal case-control study.

PURPOSE: To investigate longitudinal changes in risk factors for amblyopia in children treated with congenital nasolacrimal duct obstruction (CNLDO). METHODS: Retrospective observational case control study. A total of 446 children under 4 years of age who underwent probing and/or intubation for CNLDO between January 2004 and January 2018, and 446 age-matched controls were included. Cycloplegic refraction and ocular alignment were investigated at the time of treatment and after at least one year of symptom improvement. Children were classified as having amblyopia risk factors on the basis of the American Association for Pediatric Ophthalmology and Strabismus guideline in 2013. MAIN OUTCOME MEASURES: The prevalence of amblyogenic refractive errors, and determinants associated with the presence of amblyogenic refractive errors in CNLDO patients. RESULTS: The prevalence of amblyogenic refractive errors in CNLDO patients (5.4%) was similar to that of the control group (6.5%) (P = 0.571). After one year of symptom improvement in CNLDO patients, the prevalence of amblyogenic refractive errors was 4.7%. There was no difference in the prevalence of amblyogenic refractive errors between unilateral and bilateral CNLDO patients. Multivariate analysis revealed that manifest strabismus was the only risk factor related with the presence of amblyogenic refractive errors (odds ratio = 6.383, confidence interval = 1.205-33.826, P = 0.029). CONCLUSIONS: This study found no evidence to suggest that the prevalence of amblyopia risk factors is higher in CNLDO patients compared with normal controls. Manifest strabismus was the only determinant associated with the presence of amblyogenic refractive errors.

Prolactin and Prolactin-inducible protein (PIP) in the pathogenesis of primary acquired nasolacrimal duct obstruction (PANDO).

Primary acquired nasolacrimal duct obstruction (PANDO) is a syndrome of unknown etiology, predominantly affecting post-menopausal females, characterized by progressive inflammation, fibrosis and subsequent obstruction of the nasolacrimal duct. Numerous factors have been proposed as possible etiologic factors and include anatomical configuration, ocular and nasal infections, peri-lacrimal vascular disorders, hormonal influence, lacrimal drainage lymphoid tissue, gastroesophageal reflux disease, topical medications, swimming pool exposure, smoking, genetic factors, autonomic and lysosomal dysregulation. The authors hypothesize Prolactin (PRL) and Prolactin-inducible protein (PIP) play a role in the etiopathogenesis of primary acquired nasolacrimal duct obstruction.

Evaluation of the effect of inferior turbinate outfracture on nasolacrimal transit time by saccharin test.

AIM: To evaluate the effect of inferior turbinate outfracture on nasolacrimal transit time by saccharin test. MATERIALS AND METHODS: Twenty patients who underwent septoplasty + unilateral radiofrequency ablation and outfracture of inferior turbinate were enrolled into study. They had no complaints about their eyes and denied previous ocular surgery. Their nasolacrimal saccharin transit times (NSTTs) were estimated preoperatively and postoperatively in the 1st and 2nd months. The non-fractured side eye was measured only once preoperatively. The fractured-side eye was measured three times. These times were compared statistically. RESULTS: There were 8 men and 12 women. Mean age was 29.04. Killian incision was used in 14 and hemitransfixion incision was used in 6 patients. Median NSTT was 484, 461, 490 and 446 s for the non-fracture side, preoperatively and postoperatively in the 1st and 2nd months, respectively. There was no statistically significant difference between the two eyes preoperatively, and in the fractured side preoperatively and postoperatively in the 2nd month. There were significant differences between median NSTT in postoperative 1st month and median NSTT in the preoperative measure, and between postoperative 1st and 2nd months (p < 0.05). Median NSST in the 1st month was longer than the others. CONCLUSION: Outfracture of inferior turbinate had no permanent effect on NSTT 2 months after surgery in patients that had a healthy nasolacrimal system.

Surfactant proteins: Role in lacrimal drainage disorders.

Surfactants are complex mixtures of phospholipids and proteins produced by type II alveolar cells of the lungs and play a crucial role in pulmonary physiology. Six types of surfactant proteins (SP) are known; SP-A, SP-B, SP-C, SP-D, SP-G and SP-H. The major role of SP is in reducing surface tension and various immunological functions. SP-A, SP-B, SP-C and SP-D have been demonstrated in the tear film and the epithelium of the lacrimal sac (LS) and nasolacrimal ducts (NLD). All surfactant proteins except SP-G were also isolated from the canalicular tissues. The authors hypothesize that surfactant proteins play a significant role in the pathogenesis of lacrimal drainage disorders; functional nasolacrimal duct obstruction (FNLDO) and infective dacryocystitis.

Novel taste test for nasolacrimal duct obstruction using denatonium benzoate: a randomized controlled pilot study.

OBJECTIVE: To evaluate a novel, simple, noninvasive method (known as the "bitter taste test") of establishing nasolacrimal duct patency in healthy asymptomatic eyes. DESIGN: Double-blind, randomized controlled pilot study. PARTICIPANTS: Healthy asymptomatic medical students, residents, and allied health staff at our institution. METHODS: Participants, aged 18-35 years (n = 28) with assumed normal lacrimal function, were randomized to the interventional group (100 parts per million denatonium benzoate in sterile water, n = 14) or to the control group (sterile water only, n = 14). All participants were pretreated with topical tetracaine in their right conjunctival cul-de sac, followed by 3 drops of the experimental solution spaced 1 minute apart. The primary outcome was whether participants reported a strong, persistent bitter taste. The secondary outcome was the time-to-taste. All participants received lacrimal irrigation. The Fisher's exact test was done using GraphPad online software. RESULTS: All participants in the interventional group reported the presence of the bitter solution. None of the participants in the control group reported bitterness (p < 0.001, Fisher's exact test). Time-to-taste was within 15 minutes for 71% of the intervention group (n = 10); within 30 minutes for 79% (n = 11); and within 2 hours for 100% (n = 14). The bitterness typically persisted for 1-2 hours. All participants had normal lacrimal systems to irrigation. No adverse events were reported. CONCLUSIONS: The bitter taste test demonstrates a promising ability to assess nasolacrimal duct patency under physiologic conditions in healthy participants. Further research is needed to validate this method in a clinical sample of patients with nasolacrimal duct obstruction.

Spontaneous Resolution and Timing of Intervention in Congenital Nasolacrimal Duct Obstruction.

Importance: Although the overall rate of spontaneous resolution in congenital nasolacrimal duct obstruction (CNLDO) and efficacy of probing have been documented in the literature, the optimal timing of intervention has not been established. Objective: To report new findings regarding spontaneous resolution in a large cohort of children with CNLDO. Design, Setting, and Participants: The medical records of 1998 consecutive infants diagnosed with CNLDO from January 1, 1995, through December 31, 2004, while residing in Olmsted County, Minnesota, were retrospectively reviewed. Data were analyzed between January 1, 2015, and January 2017. Main Outcomes and Measures: Rate of spontaneous resolution over time and by sex. Results: The cohort, diagnosed at a median age of 1.2 months (interquartile range, 0.4-3.6), was 48% girls (n = 959) and 89% white (n = 1626; 173 were unreported). Among the 1998 cases, 1669 (83.5%) spontaneously resolved, 289 (14.5%) underwent treatment, and the remaining 40 (2.0%) were lost to follow-up. Of the 1958 infants followed up, CNLDO in 925 (47.3%) spontaneously resolved by age 3 months, in 1300 (66.4%) by 6 months, in 1472 (75.7%) by 9 months, and in 1516 (78.4%) by 12 months. The rate of resolution was 35% faster (95% CI, 23%-47%; P < .001) at less than 1 month vs 3 months, 43% faster (95% CI, 27%-64%; P < .001) at 3 months vs 6 months, 39% faster (95% CI, 16%-64%; P < .001) at 6 months vs 9 months, and 1% slower at 9 months vs 12 months (hazard ratio, 0.99; 95% CI, 0.80-1.22; P = .78). Congenital nasolacrimal duct obstruction resolved in boys 0.5 months (95% CI, 0.2-0.8; P < .001) faster than girls (median, 2.9 vs 3.4 months), and unilateral obstructions resolved 0.2 months (95% CI, 0.1-0.4; P = .002) faster than bilateral (median, 3.1 vs 3.3 months) ones. Children probed at 15 months or older had decreased odds of resolution after probing (odds ratio, 0.11; 95% CI, 0.01-0.89; P = .04) compared with children probed at age 12 to 14 months. Conclusions and Relevance: Based on this large cohort of children with CNLDO, probing between age 9 and 15 months may be reasonable given that the rate of spontaneous resolution plateaued after 9 months and initial probing success declined after 15 months. This time frame supports both an earlier and narrower range of ages for intervention compared with the current practice of probing after age 1 year.

A Novel Treatment for Nasolacrimal Air Regurgitation Into the Eye With CPAP: The Total Face Mask.

ABSTRACT: We present a patient who experienced insufflation of air under the left eyelid when using continuous positive airway pressure (CPAP) via an oronasal mask. The patient had a lacrimal stent in place for many years, which was a predisposing factor for this complication. Lacrimal stents are frequently used in the treatment of epiphora (excessive tearing) secondary to obstruction of the lacrimal drainage system. In this case, we review the pathophysiology of air regurgitation into the eye with CPAP use and methods previously described to address this rare complication. We also present a novel intervention for this rare complication, the total face mask. By additionally covering the eyes, a total face mask allows equalization of pressure on both sides of the lacrimal system. With a total face mask, our patient was able to successfully use CPAP.

The Relationship between Primary Acquired Nasolacrimal Duct Obstruction and Gastroesophageal Reflux.

Purpose/Aim of the study: To evaluate if there is any relationship or coincidence between gastroesophageal reflux disease (GERD) and primary acquired nasolacrimal duct obstruction (PANDO). MATERIAL AND METHODS: We enrolled 180 patients with PANDO, confirmed by positive regurgitation on sac squeezing or by irrigation test. In the control group, any patient with lacrimal drainage obstruction was excluded. For diagnosis of gastroesophageal reflux we used a (Gerd Q) questionnaire by R. Jones. RESULTS: According to Gerd Q, prevalence of gastroesophageal reflux in patients with PANDO was 20% (36 out of 180 patients) and in the control group, it was 10.6% (19 out of 180 patients), which was significantly higher in the presence of PANDO (p valve = 0.013). In women, 28 patients (23.5%) in the case group versus 13 patients (10.9%) in the control group has gastroesophageal reflux (p value = 0.01), which was not significant among men (p value = 0.870). When we considered age as an independent variable, results reveled significant value only for patients over 60 years old (p value = 0.008). CONCLUSION: The prevalence of gastroesophageal reflux disease was significantly higher in patients with PANDO. This statistical relationship was greater among women and patients over 60 years old. In this study, we found an association between GERD and PANDO.

Anisometropia and Refractive Status in Children with Bilateral Congenital Nasolacrimal Duct Obstruction.

OBJECTIVE: To evaluate the state of refraction in children with bilateral congenital nasolacrimal duct obstruction (CNLDO). STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from April 2014 to April 2016. METHODOLOGY: Children with bilateral CNLDO were studied. Patients' refractive status were evaluated by performing cycloplegic refraction, followed by appropriate management plan. The refractive errors of both eyes were noted and compared for any significant anisometropia. RESULTS: One hundred and seventeen (n=117) children with median age (IQR) of 32 (12) months having bilateral CNLDO were enrolled. Children with bilateral CNLDO had insignificant interocular difference in terms of spherical equivalent (SE) and cylindrical refractive errors (p>0.05). The rate of the anisometropia (>1 D difference between the two eyes) was 5.98% (n=7) in children with bilateral CNLDO. CONCLUSION: Performing cycloplegic refraction routinely in patients with bilateral CNLDO is not as urgent as compared to ones with unilateral CNLDO. Further, avoidance of early surgical intervention in children with bilateral CNLDO will spare the parents from the emotional trauma and positively influence the health economics worldwide.

Pediatric endonasal dacryocystorhinostomy: A multicenter series of 116 cases.

We report our experience with pediatric endonasal dacryocystorhinostomy (DCR). Multicenter, retrospective, noncomparative study. Cases of pediatric endonasal DCR during 2006-2011 were included from six oculoplastic units. Patients over the age of 16 years were excluded. The outcomes of pediatric endonasal DCR are presented. Indication for surgery, demographics, previous interventions, intraoperative or postoperative complications, follow-up duration, and success rate (defined as significant improvement of epiphora) were evaluated. In total, 116 endonasal DCRs were performed for 103 patients. The mean follow-up period was 8 months (range 3 months to 4 years), with 1 patient lost to follow-up. There were 48 males (mean age 5 years and 9 months) and 50 females (range of 4 months to 16 years), with a total of 98 cases of congenital nasolacrimal duct obstruction (CNLDO) (84.5%) and 18 cases of acquired nasolacrimal duct obstruction (ANLDO) (15.5%). Previous interventions included probing 75.9% (88/116), massaging 43.1% (50/116), and intubation 39.7% (46/116). There were no intraoperative complications. There was one case of postoperative pyogenic granuloma. There were no cases of postoperative infection and postoperative hemorrhage. Ninety percent of procedures were considered successful. Complete symptom resolution was observed in 78% (90/116), significant improvement in 12% (14/116), partial improvement in 2% (2/116), and no improvement in 8% (9/116). In our series, we demonstrated that endonasal DCR is a safe operation and has an overall success rate of 90% for pediatric NLDO.

Comparing outcomes of pediatric and adult external dacryocystorhinostomy in Nepal: Is age a prognostic factor?

We determine whether age is a prognostic factor for surgical outcomes of external dacryocystorhinostomy (Ex-DCR). This retrospective cohort study conducted at Tilganga Institute of Ophthalmology (Kathmandu, Nepal) compared pediatric Ex-DCR procedures (age ≤ 15 years) to adult Ex-DCR procedures (age > 15 years) and was performed between January 2013 and December 2013, with a minimum follow-up period of 6 months. Primary outcome measure was rate of success, defined as complete resolution of subjective symptom(s) of epiphora (subjective success), combined with patent lacrimal passage on syringing (anatomical success) at last follow-up visit. Other outcome measures included clinical presentation, diagnosis, intraoperative complications and post-operative complications. In total, 154 Ex-DCR procedures were included, with an age range of 8 months to 81 years (mean age 36.4 ± 21.0 years). In all, 38 pediatric Ex-DCR procedures were compared to 116 adult procedures. Success rates were 97% in the pediatric group and 95% in the adult group, with no clinically or statistically significant difference in success rate or complication rate between groups (p > 0.05). Our study yielded high success rates of Ex-DCR in both pediatric and adult age groups suggesting that Ex-DCR remains an optimal treatment choice for all age groups. With no difference in surgical outcomes between pediatric and adult patients, including complication rate, we conclude that age is not a prognostic factor for Ex-DCR failure. We do not recommend adjuvant therapy for pediatric patients.

Smad4 in T cells plays a protective role in the development of autoimmune Sjögren's syndrome in the nonobese diabetic mouse.

We investigated the role of Smad4, a signaling molecule of the TGF-beta pathway, in T cells on the pathology of Sjögren's syndrome (SS) in nonobese diabetic (NOD) mice, an animal model of SS. T cell-specific Smad4-deleted (Smad4fl/fl,CD4-Cre; Smad4 tKO) NOD mice had accelerated development of SS compared with wild-type (Smad4+/+,CD4-Cre; WT) NOD mice, including increased lymphocyte infiltration into exocrine glands, decreased tear and saliva production, and increased levels of autoantibodies at 12 weeks of age. Activated/memory T cells and cytokine (IFN-γ, IL-17)-producing T cells were increased in Smad4 tKO NOD mice, however the proportion and function of regulatory T (Treg) cells were not different between Smad4 tKO and WT NOD mice. Effector T (Teff) cells from Smad4 tKO NOD mice were less sensitive than WT Teff cells to suppression by Treg cells. Th17 differentiation capability of Teff cells was similar between Smad4 tKO and WT NOD mice, but IL-17 expression was increased under inducible Treg skewing conditions in T cells from Smad4 tKO NOD mice. Our results demonstrate that disruption of the Smad4 pathway in T cells of NOD mice increases Teff cell activation resulting in upregulation of Th17 cells, indicating that Smad4 in T cells has a protective role in the development of SS in NOD mice.