Eosinophilic oesophagitis: relevance of mast cell infiltration.

AIMS: Eosinophilic oesophagitis (EoE) is a chronic inflammatory disease characterised clinically by symptoms of oesophageal dysfunction and histopathologically by a prominent eosinophilic inflammation. Despite eosinophils having a histologically predominant position, their role in the immunopathogenesis of the disease is still questionable. Several other inflammatory cells are involved and may also play a critical role. The purpose of this study was to characterise the mast cell infiltration, and to correlate it with the clinical state of EoE. METHODS AND RESULTS: Using immunohistochemistry and quantitative morphometry, we investigated eosinophils and mast cells extensively in oesophageal biopsies from patients with active EoE and from patients with EoE in remission, and compared the findings with healthy individuals. In EoE, epithelium and lamina propria were similarly infiltrated with eosinophils. In contrast, mast cells infiltration was limited to the epithelium, displaying a localised immune response. Interestingly, whereas epithelial mast cells and eosinophils were high in active EoE, some patients in remission, e.g. normalised epithelial eosinophils, showed remaining high numbers of mast cells. Patient clustering supported two groups of patients in clinical remission, differentiating based on presence or absence of epithelial mast cells. CONCLUSIONS: Active EoE is characterised in addition to the well-known tissue eosinophilia by a marked epithelium-restricted mast cell infiltration. Of interest, in a subgroup of patients, mast cell infiltration persisted despite clinical remission. To elucidate the clinical consequence of persistent epithelial mast cells infiltration further studies are required following patients in clinical remission longitudinally.

Probing the relevance of the accelerated aging mouse line SAMP8 as a model for certain types of neuropsychiatric symptoms in dementia.

Introduction: People with dementia (PwD) often present with neuropsychiatric symptoms (NPS). NPS are of substantial burden to the patients, and current treatment options are unsatisfactory. Investigators searching for novel medications need animal models that present disease-relevant phenotypes and can be used for drug screening. The Senescence Accelerated Mouse-Prone 8 (SAMP8) strain shows an accelerated aging phenotype associated with neurodegeneration and cognitive decline. Its behavioural phenotype in relation to NPS has not yet been thoroughly investigated. Physical and verbal aggression in reaction to the external environment (e.g., interaction with the caregiver) is one of the most prevalent and debilitating NPS occurring in PwD. Reactive aggression can be studied in male mice using the Resident-Intruder (R-I) test. SAMP8 mice are known to be more aggressive than the Senescence Accelerated Mouse-Resistant 1 (SAMR1) control strain at specific ages, but the development of the aggressive phenotype over time, is still unknown. Methods: In our study, we performed a longitudinal, within-subject, assessment of aggressive behaviour of male SAMP8 and SAMR1 mice at 4, 5, 6 and 7 months of age. Aggressive behaviour from video recordings of the R-I sessions was analysed using an in-house developed behaviour recognition software. Results: SAMP8 mice were more aggressive relative to SAMR1 mice starting at 5 months of age, and the phenotype was still present at 7 months of age. Treatment with risperidone (an antipsychotic frequently used to treat agitation in clinical practice) reduced aggression in both strains. In a three-chamber social interaction test, SAMP8 mice also interacted more fervently with male mice than SAMR1, possibly because of their aggression-seeking phenotype. They did not show any social withdrawal. Discussion: Our data support the notion that SAMP8 mice might be a useful preclinical tool to identify novel treatment options for CNS disorders associated with raised levels of reactive aggression such as dementia.

Cenerimod, a selective S1P1 receptor modulator, improves organ-specific disease outcomes in animal models of Sjögren's syndrome.

BACKGROUND: Sjögren's syndrome is a systemic autoimmune disease characterized by immune cells predominantly infiltrating the exocrine glands and frequently forming ectopic lymphoid structures. These structures drive a local functional immune response culminating in autoantibody production and tissue damage, associated with severe dryness of mucosal surfaces and salivary gland hypofunction. Cenerimod, a potent, selective and orally active sphingosine-1-phosphate receptor 1 modulator, inhibits the egress of lymphocytes into the circulation. Based on the mechanism of action of cenerimod, its efficacy was evaluated in two mouse models of Sjögren's syndrome. METHODS: Cenerimod was administered in two established models of Sjögren's syndrome; firstly, in an inducible acute viral sialadenitis model in C57BL/6 mice, and, secondly, in the spontaneous chronic sialadenitis MRL/lpr mouse model. The effects of cenerimod treatment were then evaluated by flow cytometry, immunohistochemistry, histopathology and immunoassays. Comparisons between groups were made using a Mann-Whitney test. RESULTS: In the viral sialadenitis model, cenerimod treatment reduced salivary gland immune infiltrates, leading to the disaggregation of ectopic lymphoid structures, reduced salivary gland inflammation and preserved organ function. In the MRL/lpr mouse model, cenerimod treatment decreased salivary gland inflammation and reduced T cells and proliferating plasma cells within salivary gland ectopic lymphoid structures, resulting in diminished disease-relevant autoantibodies within the salivary glands. CONCLUSIONS: Taken together, these results suggest that cenerimod can reduce the overall autoimmune response and improve clinical parameters in the salivary glands in models of Sjögren's syndrome and consequently may reduce histological and clinical parameters associated with the disease in patients.