iPSC-based modeling of RAG2 severe combined immunodeficiency reveals multiple T cell developmental arrests

RAG2 severe combined immune deficiency (RAG2-SCID) is a lethal disorder caused by the absence of functional T and B cells due to a differentiation block. Here, we generated induced pluripotent stem cells (iPSCs) from a RAG2-SCID patient to study the nature of the T cell developmental blockade. We observed a strongly reduced capacity to differentiate at every investigated stage of T cell development, from early CD7(-)CD5(-) to CD4(+)CD8(+). The impaired differentiation was accompanied by an increase in CD7(-)CD56(+)CD33(+) natural killer (NK) cell-like cells. T cell receptor D rearrangements were completely absent in RAG2SCID cells, whereas the rare T cell receptor B rearrangements were likely the result of illegitimate rearrangements. Repair of RAG2 restored the capacity to induce T cell receptor rearrangements, normalized T cell development, and corrected the NK cell-like phenotype. In conclusion, we succeeded in generating an iPSC-based RAG2-SCID model, which enabled the identification of previously unrecognized disorder-related T cell developmental roadblocks

iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests

RAG2 severe combined immune deficiency (RAG2-SCID) is a lethal disorder caused by the absence of functional T and B cells due to a differentiation block. Here, we generated induced pluripotent stem cells (iPSCs) from a RAG2-SCID patient to study the nature of the T cell developmental blockade. We observed a strongly reduced capacity to differentiate at every investigated stage of T cell development, from early CD7−CD5− to CD4+CD8+. The impaired differentiation was accompanied by an increase in CD7−CD56+CD33+ natural killer (NK) cell-like cells. T cell receptor D rearrangements were completely absent in RAG2SCID cells, whereas the rare T cell receptor B rearrangements were likely the result of illegitimate rearrangements. Repair of RAG2 restored the capacity to induce T cell receptor rearrangements, normalized T cell development, and corrected the NK cell-like phenotype. In conclusion, we succeeded in generating an iPSC-based RAG2-SCID model, which enabled the identification of previously unrecognized disorder-related T cell developmental roadblocks.In this article, Mikkers

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

Association of pulp stones with coronary artery stenosis

Background: Dental pulp stones are discrete calcifications in the pulp chamber which are often seen in deciduous and permanent teeth. It has been hypothesised that atherosclerosis can be associated with their development. Objective: To determine whether a higher prevalence of dental pulp stones is correlated with coronary artery stenosis. Clinical setting: Sixty-one patients aged 20-55 years referred to Afshar Heart Center for invasive coronary angiography were invited to undergo panoramic dental radiography. The panoramic radiographs were independently examined for the presence of pulp stones. Results: Pulp stones were present in 82% (31/38) of patients with at least one clinically significant coronary artery stenosis and in 48% (11/23) of patients with normal coronary angiography. They were present in 13% of the teeth in the former group and in 5% of the teeth in the latter. The findings show a statistically significant association between coronary artery stenosis and presence of pulp stones (odds ratio 4.83, 95% confidence interval 1.5-15.4). Conclusion: Coronary artery stenosis and dental pulp calcification are significantly associated. Dental radiography has the potential to be used as a rapid screening method for the early detection of coronary artery stenosis