Modulation of Liver Inflammation and Fibrosis by Interleukin-37

Background and Aims: Chronic inflammation induces liver fibrosis, cirrhosis and potentially liver cancer. Kupffer cells modulate hepatic stellate cells by secreting immunologically active proteins as TGF-beta. TGF-beta promotes liver fibrosis via the activation of Sma- and Mad-related protein 3. IL-37 broadly suppresses innate and adaptive immune responses. Intracellular IL-37 interacts with Smad3. We hypothesize that IL-37 downregulates the activation of hepatic Kupffer and stellate cells and interferes with the TGF-beta signaling cascade to modulate liver fibrogenesis. Methods: The role of IL-37 on liver inflammation and fibrogenesis was assessed in three mouse models as well as isolated Kupffer- and stellate cells. Serum IL-37 was tested by ELISA in a clinical cohort and correlated with liver disease severity. Results: Transgene expression of IL-37 in mice extends survival, reduces hepatic damage, expression of early markers of fibrosis and histologically assessed liver fibrosis after bile duct ligation. IL-37tg mice were protected against CCl4-induced liver inflammation. Colitis-associated liver inflammation and fibrosis was less severe in IL-10 knockout IL-37tg mice. Spontaneous and LPS/TGF-beta-induced cytokine release and profibrogenic gene expression was lower in HSC and KC isolated from IL-37tg mice and IL-37 overexpressing, IL-1 beta stimulated human LX-2 stellate cells. However, administration of recombinant human IL-37 did not modulate fibrosis pathways after BDL in mice, LX2 cells or murine HSCs. In a large clinical cohort, we observed a positive correlation of serum IL-37 levels with disease severity in liver cirrhosis. Conclusions: Predominantly intracellular IL-37 downregulates liver inflammation and fibrosis. The correlation of serum IL-37 with disease severity in cirrhosis suggests its potential as a novel target modulating the course of liver fibrosis

Correlation and differences of patient-reported outcomes vs. Likert-Rating of MS symptoms in a real-world cohort using a digital patient app

Background Multiple Sclerosis (MS) is a chronic and progressive neurological autoimmune disease currently affecting 250,000 individuals in Germany. Patients suffering from the disease can be severely impaired in their day-to-day activities. BRISA is a digital app specifically designed to help MS patients monitor their disease by regularly tracking symptoms. Lengthy and time-consuming questionnaires for patient-reported outcomes (PRO) are the standard method to assess the patients’ current condition. Here, we examine whether simplified versions of these questionnaires can provide comparable information regarding individual symptom presentations in BRISA users. Methods 828 users were included in the analysis. Patients who provided onboarding information and answered at least one questionnaire and the corresponding simplified smiley symptoms assessment were included. Correlation of questionnaire and symptom scores was calculated using Pearson's correlation. Results Our analysis cohort predominantly consisted of female, 26–55-year-olds. Relapsing-remitting MS (RRMS) was the most common MS type recorded. Most patients were diagnosed 2–5 years ago. Questionnaires regarding fatigue and vision impairment were among the most answered, those regarding bowel movement and sexual satisfaction received fewest responses. Overall, the scores from questionnaires and symptoms correlated positively. Scoring correlation could also be shown across the subgroups divided by gender, age groups, type of MS, and time since diagnosis of the disease. Conclusion Scores recorded from traditional PRO questionnaires can be reflected more easily as a trend in a simplified scale using smileys. Nevertheless, traditional questionnaires are needed to also maintain a more objective assessment. In conclusion, the patient will benefit most from an adaptive combination of regular traditional PRO questionnaire assessments and simplified symptom recording

Characterization of MENX-associated pituitary tumours

Aims: The aim of this study is to evaluate the pathological features, serum hormone levels and ex-vivo cultures of pituitary adenomas that occur in rats affected by MENX syndrome. MENX is multiple endocrine neoplasia syndrome caused by a germline mutation in the cell cycle inhibitor p27. Characterisation of MENX adenomas is a prerequisite to exploit this animal model for molecular and translational studies of pituitary adenomas. Methods: We investigated MENX pituitary adenomas with immunohistochemistry, double immunofluorescence, electron microscopy, RT-PCR, measurement of serum hormone levels and ex-vivo cultures. Results: Adenomas in MENX rats belong to the gonadotroph lineage. They start from 4 months of age as multiple neoplastic nodules and progress to become large lesions that efface the gland. Adenomas are composed of chromophobic cells predominantly expressing the glycoprotein alpha-subunit (αGSU). They show mitotic activity and high Ki67 labelling. A few neoplastic cells co-express gonadotrophins and the transcription factor SF1, together with growth hormone or prolactin and Pit-1, suggesting that they are not fully committed to one cell lineage. Ex vivo cultures show features similar to the primary tumour. Conclusions: Our results suggest that p27 function is critical in regulating gonadotroph cells growth. The MENX syndrome represents a unique model to elucidate the physiological and molecular mechanisms mediating the pathogenesis of gonadotroph adenomas. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society