Broad spectrum of autoantibodies in patients with Wiskott-Aldrich syndrome and X-linked thrombocytopenia

TH1and TH17-induced inflammation, inhibition of nuclear factor kappa b, and upregulation of IL-10. As such, PPARg agonists are being trialed for a number of inflammatory diseases (www.clinicaltrials.gov). We have shown that PPARg activation occurs downstream of the activated NADPH oxidase and is lacking in CGD phagocytes, but can be restored by pioglitazone. PPARg agonism restores efferocytosis by macrophages in murine CGD, and, as shown here, in human CGD monocytes as well. This was demonstrated after both ex vivo treatment of human CGD monocytes and treatment of 2 patients with CGD with pioglitazone. As in our earlier studies, PPARg agonism was also accompanied by enhanced phagocyte mitochondrial ROS production. Whether mitochondrial ROS contributes to efferocytic capability is an area for future study. Whether pioglitazone will decrease inflammation in CGD and whether pioglitazone-enhanced mitochondrial ROS will bolster host defense in human CGD, as it did in murine models, are key unanswered questions. If human data are similar to preclinical models, pioglitazone, an on-the-shelf therapy, may ameliorate both immunodeficiency and inflammatory aspects of CGD. Ruby F. Fernandez-Boyanapalli, PhD Emilia Liana Falcone, MD Christa S. Zerbe, MD Beatriz E. Marciano, MD S. Courtney Frasch, PhD Peter M. Henson, DVD, PhD Steven M. Holland, MD* Donna L. Bratton, MD* From the Department of Pediatrics, National Jewish Health, Denver, Colo, and the Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. E-mail: brattond@njhealth.org. *These authors contributed equally to this work as senior authors. The Chronic Granulomatous Disorder Society (UK) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant nos. NIH AI110408, HL114381, and AI058228) supported this study. Disclosure of potential conflict of interest: P. M. Henson has received grants from the National Institutes of Health (NIH). D. L. Bratton has received grants from the NIH and the Chronic Granulomatous Disorder Society, has received travel support from the NIH, and is employed by National Jewish Health. The rest of the authors declare that they have no relevant conflicts of interest.