Reduced CD4+T cell activation in children with type 1 diabetes carrying the PTPN22/Lyp 620Trp variant

The 620Trp variant of the LYP protein, encoded by the lymphoid tyrosine phosphatase 22 gene (PTPN22), is associated with autoimmunity. In this study we aimed at characterising the role of this variant on lymphocyte activation. We analysed cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) and CD4(+)T cells in a cohort of clinically non-diabetic, multiple autoantibody-positive children, healthy controls and in children with type 1 diabetes (T1D). We found a decreased proliferation and IL-2 production of CD4(+)T cells after anti-CD3/anti-CD28 stimulation (p=0.04 for IL-2) among T1D patients. In addition, a profoundly decreased intracellular calcium flux in CD4(+)T cells after PHA stimulus was detected among 620Trp carriers. In contrast, no effect of this polymorphism on tuberculin and tetanus toxoid induced PBMC proliferation and cytokine secretion was observed in autoantibody positive children, healthy controls and children with newly-diagnosed T1D. In conclusion, the LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients. In accordance with our previous findings on the key role of this variant on disease progression, this mechanism is likely to contribute to the development of beta-cell specific autoimmunity.     

Factors influencing accuracy of cortical thickness in the diagnosis of Alzheimer's disease

There is great value to use of structural neuroimaging in the assessment of Alzheimer's disease (AD). However, to date, predictive value of structural imaging tend to range between 80% and 90% in accuracy and it is unclear why this is the case given that structural imaging should parallel the pathologic processes of AD. There is a possibility that clinical misdiagnosis relative to the gold standard pathologic diagnosis and/or additional brain pathologies are confounding factors contributing to reduced structural imaging classification accuracy. We examined potential factors contributing to misclassification of individuals with clinically diagnosed AD purely from cortical thickness measures. Correctly classified and incorrectly classified groups were compared across a range of demographic, biological, and neuropsychological data including cerebrospinal fluid biomarkers, amyloid imaging, white matter hyperintensity (WMH) volume, cognitive, and genetic factors. Individual subject analyses suggested that at least a portion of the control individuals misclassified as AD from structural imaging additionally harbor substantial AD biomarker pathology and risk, yet are relatively resistant to cognitive symptoms, likely due to “cognitive reserve,” and therefore clinically unimpaired. In contrast, certain clinical control individuals misclassified as AD from cortical thickness had increased WMH volume relative to other controls in the sample, suggesting that vascular conditions may contribute to classification accuracy from cortical thickness measures. These results provide examples of factors that contribute to the accuracy of structural imaging in predicting a clinical diagnosis of AD, and provide important information about considerations for future work aimed at optimizing structural based diagnostic classifiers for AD.