New cause for primary immunodeficiency discovered

Our lab has a new study on primary immunodeficiencies out now at Cellular & Molecular Biology! We studied two families with combined immunodeficiency and found mutations in the Calcium channel ITPR3. The mutations reduce the function of the channel, making the channels 100-fold less capable of initiating a Calcium flux after cellular stimulation. T cells from the patient had poor responses throughout the signalling cascade: reduced Calcium flux, poor nuclear localisation of NFAT1 and reduced proliferative burst, explaining the impeded response to infections. The most severe patient required a bone-marrow transplantation to correct the defect, while the other patient is doing well with regular IgIV treatment. The work established ITPR3 as a new cause of primary immunodeficiency, after previously assuming that these Calcium channels had too much redundancy to be a cause of genetic disease. Read the full paper here, or take a look at the illustrated abstract below for a short-cut summary!

Using gene delivery to protect against diabetes

Exciting new paper out from the lab on using gene delivery to protect against diabetes. The work is based on the "fragile beta cell" hypothesis, which postulates that some individuals are prone to diabetes because their beta cells are more prone to fail during stress situations. We previously demonstrated that the Glis3-Manf axis was central to dictacting how robust or fragile beta cells were, during stresses either immunological (type 1 diabetes) or metabolic (type 2 diabetes) in origin. Based on this data, we designed a gene delivery system, which essentially tricks beta cells into making more Manf and becomes robust in the face of stress. NOD mice, treated with this gene delivery of Manf, become resistant to diabetes. As the gene delivery system we use harnesses the endogenous insulin promoter (specific to beta cells, and upregulated during cellular stress), we can use low doses of the gene delivery system delivered intravenously, without altering the rest of the body. This gives the system a high potential for clinical translation. Read the full paper here, or check out our illustrated abstract below.