Autoimmune Granulomatous Inflammation of Lacrimal Glands and Axonal Neuritis Following Treatment With Ipilimumab and Radiation Therapy.
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SUBMITTER: Ileana Dumbrava E
PROVIDER: S-EPMC6086752 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundDimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system.Methods and findingsExperimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78) of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2)-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2)-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.ConclusionsWe conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.
| S-EPMC4664277 | biostudies-literature
Project description:PurposeTo analyze the changes in the lacrimal gland (LG) miRNAome from male nonobese diabetic (NOD) mice with autoimmune dacryoadenitis compared with LG from healthy male BALB/c and dacryoadenitis-free female NOD mice.MethodsLG from these mice were collected for small RNA sequencing to identify dysregulated miRNAs; hits were validated by RT-qPCR in male NOD and BALB/c LG. Dysregulation of validated species within immune cell-enriched cell fractions and epithelial-enriched cell fractions from LG was probed by RT-qPCR. Ingenuity pathway analysis identified putative miRNA targets, which were examined in publicly available mRNA-seq datasets. Western blotting and confocal imaging of immunofluorescence enabled validation of some molecular changes at the protein level.ResultsMale NOD LG exhibited 15 and 13 significantly up- and downregulated miRNAs, respectively. Dysregulated expression of 14 of these miRNAs (9 upregulated, 5 downregulated) was validated in male NOD versus BALB/c LG by RT-qPCR. Seven of the upregulated miRNAs were increased owing to their abundance in immune cell-enriched cell fractions, whereas four downregulated miRNAs were largely expressed in epithelial-enriched cell fractions. Ingenuity pathway analysis predicted the upregulation of IL-6 and IL-6-like pathways as an outcome of miRNA dysregulation. Increased expression of several genes in these pathways was confirmed by mRNA-seq analysis, whereas immunoblotting and immunofluorescence confirmed Ingenuity pathway analysis-predicted changes for IL-6Rα and gp130/IL-6st.ConclusionsMale NOD mouse LG exhibit multiple dysregulated miRNAs owing to the presence of infiltrating immune cells, and decreased acinar cell content. The observed dysregulation may increase IL-6Rα and gp130/IL-6st on acini and IL-6Rα on specific lymphocytes, enhancing IL-6 and IL-6-like cytokine signaling.
| S-EPMC10080918 | biostudies-literature
Project description:Fingolimod, a sphingosine-1-phosphate receptor modulator with well-described immunomodulatory properties involving peripheral immune cell trafficking, was the first oral agent approved for the treatment of relapsing remitting multiple sclerosis. Analogous immunomodulatory treatment options for chronic peripheral autoimmune neuropathies are lacking.We tested fingolimod in the animal model of experimental autoimmune neuritis in Lewis rat. Six to eight-week-old female rats were immunized with P2 peptide and from this day on treated with fingolimod. Histology of the sciatic nerve was done to analyze T cell and macrophage cell count, intercellular adhesion molecule (ICAM) and amyloid precursor protein (APP) expression, as well as apoptotic Schwann cell counts.Preventive oral treatment with 0.1 mg/kg up to 3 mg/kg fingolimod once daily dissolved in rapeseed oil completely ameliorated clinical neuritis signs. It reduced circulating peripheral blood T cells and infiltrating T cells and macrophages in the sciatic nerve, whereas at the same time, it preserved blood-nerve barrier impermeability. Most importantly, fingolimod showed beneficial properties on the pathogenic process as indicated by fewer apoptotic Schwann cells and a lower amount of amyloid precursor protein indicative of axonal damage at the peak of disease course.Taken together, orally administered low-dose fingolimod showed an impressive immunomodulatory effect in the rat model of experimental autoimmune neuritis. Our current observations introduce fingolimod as an attractive treatment option for neuritis patients.
| S-EPMC5406994 | biostudies-literature
Project description:PurposeTo test the hypothesis that expression of Na(+)/K(+)-ATPase subunits in the lacrimal glands (LGs) of rabbits with induced autoimmune dacryoadenitis (IAD) changes.MethodsLGs were obtained from adult female rabbits with IAD and age-matched female control rabbits. The LGs were processed for laser capture microdissection (LCM), real time RT-PCR, western blot, and immunofluorescence for the detection of mRNA and proteins of the α1, α2, β1, β2, and β3 subunits of Na(+)/K(+)-ATPase.ResultsIn the rabbits with IAD, mRNA levels of α1, β1, and β3 from whole LGs were significantly lower. In samples of acini and epithelial cells from various duct segments, collected by LCM, mRNA levels of α1, β1, β2, and β3 were significantly lower in the rabbits with IAD, although mRNA for α2 could not be detected. However, western blots demonstrated that all five subunits were significantly higher in the rabbits with IAD, although their distribution patterns were similar to those of the control rabbits, as demonstrated by immunofluorescence.ConclusionsThe data presented herein demonstrated significant changes in mRNA and protein expressions of Na(+)/K(+)-ATPase subunits in rabbits with IAD, suggesting that these changes may play a role in the pathogenesis of Sjögren's syndrome and altered LG secretion, as observed in these animals.
| S-EPMC3171493 | biostudies-literature
Project description:Purpose:While the association between the gut microbiome and the immune system has been studied in autoimmune disorders, little is known about ocular disease. Previously we reported that IRT5, a mixture of five probiotic strains, could suppress autoimmune dry eye. In this study, we investigated the mechanism by which IRT5 performs its immunomodulatory function in a mouse model of autoimmune dry eye. Methods:NOD.B10.H2b mice were used as an autoimmune dry eye model. Either IRT5 or PBS was gavaged orally for 3 weeks, with or without 5 days of antibiotic pretreatment. The effects on clinical features, extraorbital lacrimal gland and spleen proteins, and fecal microbiota were analyzed. Results:The ocular staining score was lower, and tear secretion was higher, in the IRT5-treated groups than in the PBS-treated groups. After IRT5 treatment, the downregulated lacrimal gland proteins were enriched in the biological processes of defense response and immune system process. The relative abundances of 33 operational taxonomic units were higher, and 53 were lower, in the feces of the IRT5-treated groups than in those of the PBS-treated groups. IRT5 administration without antibiotic pretreatment also showed immunomodulatory functions with increases in the Lactobacillus helveticus group and Lactobacillus hamsteri. Additional proteomic assays revealed a decrease of proteins related to antigen-presenting processes in the CD11b+ and CD11c+ cells of spleen in the IRT5-treated groups. Conclusions:Changes in the gut microbiome after IRT5 treatment improved clinical manifestations in the autoimmune dry eye model via the downregulation of antigen-presenting processes in immune networks.
| S-EPMC7401425 | biostudies-literature
Project description: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.
| S-EPMC10003158 | biostudies-literature
Project description:Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 receptor antibody used for immunotherapy in cancer. Several immune-related adverse events are known. Steroid responsive encephalopathy associated with autoimmune thyroiditis is an autoimmune encephalopathy associated with Hashimoto's Disease and elevated serum levels of the related antibodies (anti-thyroid-peroxidase antibody or anti-thyroglobulin antibody). Our case implies that steroid responsive encephalopathy associated with autoimmune thyroiditis may be another previously unreported side effect of ipilimumab therapy.We report the case of a 64 years old caucasian patient with prostatic cancer who received ipilimumab therapy in a clinical trial. He presented with aphasia, tremor and ataxia, myocloni, hallucinations, anxiety and agitation in turns with somnolence. Cranial nerves, deep tendon reflexes, motor and sensory functions were normal. Electroencephalography showed background slowing but no epileptic discharges. Brain magnetic resonance imaging was normal and showed no signs of hypophysitis. Cerebrospinal fluid findings ruled out infection and neoplastic meningitis. Anti-thyroid antibodies (anti-thyroid-peroxidase antibody and anti-thyroglobulin antibody) were heavily increased. Assuming steroid responsive encephalopathy associated with autoimmune thyroiditis the patient was treated with 1,000 mg methylprednisolone i.v. for 3 days and continued with 1 mg/kg orally. On the 3rd day of treatment the patient's condition started to improve. Within the next few days he gradually returned to his previous state, and electroencephalography eventually showed only slight slowing. Seven months later the patient's condition was stable, and anti-thyroid antibodies were no more detectable.Steroid responsive encephalopathy associated with autoimmune thyroiditis may be a hitherto unrecognized complication of ipililumab treatment and should be taken into consideration in patients developing central nervous symptoms undergoing this treatment.
| S-EPMC4514969 | biostudies-literature
Project description:BackgroundTear deficiency due to lacrimal gland (LG) dysfunction is one of the major causes of dry eye disease (DED). Therefore, LG stem cell-based therapies have been extensively reported to regenerate injured lacrimal tissue; however, the number of stem cells in the LG tissue is low, and 2D long-term cultivation reduces the differentiation capacity of stem cells. Nevertheless, 3D LG organoids could be an alternative for a DED therapy because it is capable of prolonged growth while maintaining the characteristics of the LG tissue. Here, we report the development of LG organoids and their application as cell therapeutics.MethodsDigested cells from human LG tissue were mixed with Matrigel and cultured in five different media modified from human prostate/salivary organoid culture media. After organoid formation, the growth, specific marker expression, and histological characteristics were analyzed to authenticate the formation of LG organoids. The secretory function of LG organoids was confirmed through calcium influx or proteomics analysis after pilocarpine treatment. To explore the curability of the developed organoids, mouse-derived LG organoids were fabricated and transplanted into the lacrimal tissue of a mouse model of DED.ResultsThe histological features and specific marker expression of LG organoids were similar to those of normal LG tissue. In the pilocarpine-treated LG organoid, levels of internal Ca2+ ions and β-hexosaminidase, a lysosomal protein in tear fluid, were increased. In addition, the secreted proteins from pilocarpine-treated lacrimal organoids were identified through proteomics. More than 70% of the identified proteins were proven to exosome through gene ontology analysis. These results indicate that our developed organoid was pilocarpine reactive, demonstrating the function of LG. Additionally, we developed LG organoids from patients with Sjogren's syndrome patients (SS) and confirmed that their histological features were similar to those of SS-derived LG tissue. Finally, we confirmed that the mouse LG organoids were well engrafted in the lacrimal tissue two weeks after transplantation.ConclusionThis study demonstrates that the established LG organoids resemble the characteristics of normal LG tissue and may be used as a therapy for patients with DED.
| S-EPMC8059179 | biostudies-literature
Project description:PurposeSleep loss markedly affects the structure and function of the lacrimal gland and may cause ocular surface disease as a common public health problem. This study aims to investigate the circadian disturbance caused by sleep loss leading to dysfunction of extraorbital lacrimal glands (ELGs).MethodsA mouse sleep deprivation (SD) model for sleep loss studies was built in C57BL/6J male mice. After four weeks, the ELGs were collected at three-hour intervals during a 24-hour period. The Jonckheere-Terpstra-Kendall algorithm was used to determine the composition, phase, and rhythmicity of transcriptomic profiles in ELGs. Furthermore, we compared the non-sleep-deprived and SD-treated mouse ELG (i) reactive oxygen species (ROS) by fluorescein staining, (ii) DNA damage by immunostaining for γ-H2Ax, and (iii) circadian migration of immune cells by immunostaining for CD4, CD8, γδ-TCR, CD64, and CX3CR1. Finally, we also evaluated (i) the locomotor activity and core body temperature rhythm of mice and (ii) the mass, cell size, and tear secretion of the ELGs.ResultsSD dramatically altered the composition and phase-associated functional enrichment of the circadian transcriptome, immune cell trafficking, metabolism, cell differentiation, and neural secretory activities of mouse ELGs. Additionally, SD caused the ROS accumulation and consequent DNA damage in the ELGs, and the ELG dysfunction caused by SD was irreversible.ConclusionsSD damages the structure, function, and diurnal oscillations of ELGs. These results highlight comprehensive characterization of insufficient sleep-affected ELG circadian transcriptome that may provide a new therapeutic approach to counteract the effects of SD on ELG function.
| S-EPMC9233287 | biostudies-literature
Project description:BACKGROUND:Autoimmune neuropathies are common PNS disorders and effective treatment is challenging. Environmental influence and dietary components are known to affect the course of autoimmune diseases. Capsaicin as pungent component of chili-peppers is common in human nutrition. An influence of capsaicin on autoimmune diseases has been postulated. METHODS:We tested capsaicin in the animal model of experimental autoimmune neuritis (EAN) in Lewis rat. Rats were immunized with P2-peptide and were treated with capsaicin in different preventive settings. Electrophysiological, histological, and molecular biological analyses of the sciatic nerve were performed to analyze T-cell and macrophage cell count, TRPV1, and cytokine expression. Moreover, FACS analyses including the intestinal immune system were executed. RESULTS:We observed an immunomodulatory effect of an early preventive diet-concept, where a physiological dosage of oral capsaicin was given 10 days before immunization in EAN. A reduced inflammation of the sciatic nerve was significant detectable clinically, electrophysiologically (CMAPs reduced in control group p?<?0.01; increase of nerve conduction blocks in control group p?<?0.05), histologically (significant reduction of T-cells, macrophages and demyelination), and at cytokine level. In contrast, this therapeutic effect was missing with capsaicin given from the day of immunization onwards. As possible underlying mechanism, we were able to show changes in the expression of the capsaicin receptor in the sciatic nerve and the small intestine, as well as altered immune cell populations in the small intestine. CONCLUSION:This is the first report about the immunomodulatory effect of the common nutrient, capsaicin, in an experimental model for autoimmune neuropathies.
| S-EPMC5916583 | biostudies-literature