Lindsley AW, Saal HM, Burrow TA, Hopkin RJ, Shchelochkov O, Khandelwal P, Xie C, Bleesing J, Filipovich L, Risma K, Assa'ad AH, Roehrs PA, Bernstein JA. Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome. J Allergy Clin Immunol. 2016 Jan;137(1):179-87.e10.

Kabuki syndrome is a rare developmental disorder that affects many systems of the body. It's associated with mutations in genes encoding histone-modifying proteins. This study, led by Andrew W. Lindsley, MD, PhD, characterizes the humoral immune defects of this understudied condition in patients with mutations in lysine methyltransferase 2D (KMT2D). The research showed that mutations in KMT2D associate with dysregulation of terminal B-cell differentiation. This dysregulation is what leads to the humoral immune deficiency observed in Kabuki syndrome and the autoimmunity that sometimes develops. These findings support the importance of a change in clinical practice in that patients with Kabuki syndrome would benefit from undergoing serial clinical immune evaluations.

Morris DW, Stucke EM, Martin LJ, Abonia JP, Mukkada VA, Putnam PE, Rothenberg ME, Fulkerson PC. Eosinophil progenitor levels are increased in patients with active pediatric eosinophilic esophagitis. J Allergy Clin Immunol. 2016 Sep;138(3):915-918.e5.

Eosinophilic esophagitis (EoE) is a lifelong, severe and often painful food allergic disease whose activity is monitored, even after an effective treatment with restricted diets and steroids is in place. The disease activity of EoE is currently monitored using peak esophageal eosinophil count, which requires invasive endoscopy to collect esophageal tissue biopsies for assessment. Treatment changes, such as reintroducing a single food, requires additional endoscopic exams to assess for disease flare-ups. In searching for a less invasive marker of disease activity, researchers led by Patricia C. Fulkerson, MD, PhD, investigated a precursor cell to eosinophils, a lineage-committed eosinophil progenitor (EoP), as a potential marker. They found elevated EoP levels in the blood of pediatric patients with active EoE disease, suggesting a promising, blood-based marker. Measuring EoP blood levels to monitor disease activity has the potential to reduce discomfort, costs and side effects for patients; however, additional research will work to validate the EoP-based marker before its routine use in clinical settings.

Vrazo AC, Hontz AE, Figueira SK, Butler BL, Ferrell JM, Binkowski BF, Li J, Risma KA. Live cell evaluation of granzyme delivery and death receptor signaling in tumor cells targeted by human natural killer cells. Blood. 2015 Aug 20;126(8):e1-e10.

Natural killer (NK) cells are cytotoxic lymphocytes and first responders of the human immune system in identifying and eliminating tumor cells and virally infected cells. As we consider using natural killer (NK) cell–based therapy for treating human cancer, developing new tools to measure early events in cell death is critical. After recently demonstrating that protease-cleavable luciferase biosensors detect granzyme B and pro-apoptotic caspase activation within minutes of target cell recognition by murine cytotoxic lymphocytes, researchers led by Kimberly A. Risma, MD, PhD, successfully adapted the biosensor technology to assess perforin-dependent and -independent induction of death pathways in tumor cells recognized by human NK cell lines and primary cells and also developed biosensors for granzyme A and K, for which no other functional reporters are available. These studies establish the sensitivity of protease-cleaved luciferase biosensors to measure previously undetectable events in live cells in real time. Further development of caspase and granzyme biosensors will allow interrogation of additional features of granzyme activity in live cells including localization, timing, and specificity, which will inform NK cell–based therapy development.

Kartashov AV, Barski A. BioWardrobe: an integrated platform for analysis of epigenomics and transcriptomics data. Genome Biol. 2015 Aug 7;16:158.

High-throughput sequencing has revolutionized biology by enhancing our ability to perform genome-wide studies. However, due to lack of bioinformatics expertise, modern technologies are still beyond the capabilities of many laboratories. Andrey Kartashov, MSc and Artem Barski, PhD developed the BioWardrobe platform, which allows users to store, visualize and analyze epigenomics and transcriptomics data using a biologist-friendly web interface, without the need for programming expertise. Predefined pipelines allow users to download data, visualize results on a genome browser, calculate RPKMs (reads per kilobase per million) and identify peaks. Advanced capabilities include differential gene expression and binding analysis and creation of average tag-density profiles and heatmaps. Find more about BioWardrobe.

Sledd J, Wu D, Ahrens R, Lee J, Waggoner L, Tsai YT, Wang YH, Hogan SP. Loss of IL-4R⍺-mediated PI3K signaling accelerates the progression of IgE/mast cell-mediated reactions. Immun Inflamm Dis. 2015 Sep 17;3(4):420-30.

This study, led by Simon P. Hogan, MD, PhD, demonstrates that loss of the phosphatidylinositol 3-kinase (PI3K) activating signal triggered by interleukin 4 receptor alpha (IL-4R⍺) does not alter susceptibility to food-induced experimental anaphylaxis. Symptoms of experimental anaphylaxis, namely diarrhea, antigen-specific IgE and intestinal mastocytosis, are comparable between mice with and without functional IL-4R⍺ and PI3K signaling. However, mice without functional IL-4R⍺-mediated PI3K signaling have accelerated disease progression. Histamine causes this quickened anaphylactic response associated with a more rapid decrease in blood volume. Notably, endothelial IL-4R⍺ PI3K signaling negatively regulates the histamine-induced endothelial leak response. These results define an unanticipated role for IL-4R⍺-mediated PI3K signaling in putting the brakes on IgE-mediated anaphylactic reactions.