The incidence of type 1 diabetes (T1DM) is increasing annually and the disease pathophysiology remains to be completely understood. The current understanding suggests a complex interplay of genetic factors, environmental factors and the immune system that ultimately converge to cause selective destruction of the pancreatic beta cells. As part of this process immune cells (e.g. cytotoxic T-cells), infiltrate the islets and release pro-inflammatory cytokines (e.g. IL-1β, TNF-α and IFN-γ) which cause beta cell dysfunction and cell death. Increasing evidence suggests that there is an imbalance between the levels of pro-inflammatory and anti-inflammatory cytokines at the islet site in T1DM and this may contribute to beta cell death. Anti-inflammatory cytokines (e.g. IL-4, IL-13 and IL-10) are reported to be protective in certain animal models of the disease, but their roles in pancreatic beta cells have been less extensively studied.
The work in this thesis primarily examines the pathway stimulated by the anti-inflammatory cytokines IL-13 and IL-4 and its role in mediating the cytoprotectivity in beta cells. Particularly, we examine whether STAT6 is central to these protective effects.
It was confirmed that STAT6 plays a crucial role in IL-4 and IL-13 mediated protection of beta cells against a range of cytotoxic stimuli (pro-inflammatory cytokines, palmitate and serum withdrawal). Additionally, it was shown that IL-13 and IL-4 induce the upregulation of anti-apoptotic genes such as MCL1, BCLXL and SOCS1, in a STAT6 regulated manner in beta cells. Surprisingly, we observed the STAT6-dependent upregulation of a gene not previously associated with this pathway, SIRPα. This was further investigated as a regulator of beta cell viability and the results revealed that knockdown of SIRPα resulted in beta cell apoptosis, implicating this protein as a novel regulator of beta cell viability.
Taken together, this work shows that loss of STAT6 renders beta cells vulnerable to cell death and suggest that therapeutic targeting of this pathway may offer a potential treatment for T1DM.

AIMS/HYPOTHESIS: in type 1 diabetes, selective beta cell loss occurs within the inflamed milieu of insulitic islets. This milieu is generated via the enhanced secretion of proinflammatory cytokines and by the loss of anti-inflammatory molecules such as IL-4 and IL-13. While the actions of proinflammatory cytokines have been well-studied in beta cells, the effects of their anti-inflammatory counterparts have received relatively little attention and we have addressed this. METHODS: Clonal beta cells, isolated human islets and pancreas sections from control individuals and those with type 1 diabetes were employed. Gene expression was measured using targeted gene arrays and by quantitative RT-PCR. Protein expression was monitored in cell extracts by western blotting and in tissue sections by immunocytochemistry. Target proteins were knocked down selectively with interference RNA. RESULTS: Cytoprotection achieved with IL-4 and IL-13 is mediated by the early activation of signal transducer and activator of transcription 6 (STAT6) in beta cells, leading to the upregulation of anti-apoptotic proteins, including myeloid leukaemia-1 (MCL-1) and B cell lymphoma-extra large (BCLXL). We also report the induction of signal regulatory protein-α (SIRPα), and find that knockdown of SIRPα is associated with reduced beta cell viability. These anti-apoptotic proteins and their attendant cytoprotective effects are lost following siRNA-mediated knockdown of STAT6 in beta cells. Importantly, analysis of human pancreas sections revealed that STAT6 is markedly depleted in the beta cells of individuals with type 1 diabetes, implying the loss of cytoprotective responses. CONCLUSIONS/INTERPRETATION: Selective loss of STAT6 may contribute to beta cell demise during the progression of type 1 diabetes.

Background. Cameroon this last decade continues to present a low contribution of M. africanum and M. bovis in human tuberculosis (TB), while M. bovis was prevalent in cattle but all these pieces of information only concerned West and Center regions. Methods. We carried out the first study in Adamaoua, one of the most rearing regions of Cameroon, on the genetic structure and drug susceptibility of the MTBC strains isolated from newly diagnosed sputum smear-positive patients aged 15 years and above. For that purpose, spoligotyping, a modified 15 standard MIRU/VNTR loci typing, and the proportion method were used. Results. Four hundred and thirty-seven MTBC isolates were analyzed by spoligotyping. of these, 423 were identified as M. tuberculosis, within the Cameroon family being dominant with 278 (65.7%) isolates; twelve (2.75%) isolates were classified as M. africanum and two as M. bovis. MIRU/VNTR typing of the most prevalent sublineage (SIT 61) suggested that this lineage is not a unique clone as thought earlier but could constitute a group of strains implicated to different pocket of TB transmission. Only M. tuberculosis sublineages were associated with antituberculosis drug resistance. Conclusion. These results showed the weak contribution of M. africanum and M. bovis to human active pulmonary tuberculosis in Cameroon even in the rearing region.