The role of class IA P13Kơ in experimental autoimmune encephalomyelitis.

Through its role in cells of haematopoietic origin, the class IA phosphoinositide 3-kinase delta (PI3Kδ) has a significant impact on both the cell-mediated and innate arms of the immune system. The catalytic protein subunit of PI3Kδ, p110δ, has been implicated in leukocyte activation and survival, Th1 and Th2 differentiation as well as the development of autoimmunity in a model of rheumatoid arthritis. While the impact of p110δ inactivation in vitro is becoming clearer, the precise role that p110δ plays in vivo remains poorly understood, particularly in regard to Th17 differentiation and models of autoimmunity. Here, using mice that express a catalytically inactive form of p110δ (p110δD910A/D910A mice) it is shown that functional p110δ is required for full expression of experimental autoimmune encephalomyelitis (EAE), a Th17-dependent model of the human autoimmune disease multiple sclerosis (MS). In p110δ-inactivated mice, T and B cell activation and function during EAE were markedly reduced, and fewer T and B cells were observed in the central nervous system (CNS) throughout disease. Th17 cell generation was demonstrably more dependent on p110δ than was the Th1 response. The decrease in T cell activation was not due to a defect in dendritic cell (DC) function because p110δ-inactivated DCs migrated, became activated and presented antigen normally. However, there was a significant increase in the proportion of T and B lymphocytes undergoing apoptosis at early stages of EAE. Due to the promising findings observed in the p110δD910A/D910A mice, the ability of the p110δ inhibitor, IC87114, to reduce EAE pathogenesis was investigated. While IC87114 was shown to be a potent inhibitor of Th1 and Th17 activation and differentiation in vitro, administration of this compound failed to reduce EAE disease under the dosing regimen used. Despite this, these findings indicate that p110δ plays an important role in the development of IL-17-dependent inflammation and suggest that small molecule inhibitors for p110δ may be useful therapeutics for the treatment of IL-17-driven pathologies.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 201

Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA)

Background: Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. Methods: In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses. Results: This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1–60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (−) (<LLOQ), 190 (22.5%) had qHBsAg 1–100, 91 (10.8%) had qHBsAg 100–500, 54 (6.4%) had qHBsAg 500–1000, and 272 (32.2%) had qHBsAg >1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (−). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89–143.39, p = 0.01) or HCC (8.23, 95% CI 1.01–67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001). Conclusion: In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance