Understanding DOCK8 Function in Health and Human Disease

多年来，在研究NIH临床中心评估的dock8缺陷患者时，我们观察到他们在疾病谱系和疾病严重程度上经常彼此不同。详细的遗传评估显示，一些患者的表型变异与体细胞逆转的存在和程度有关。由于涉及同源重组的机制，这种情况在我们没有纯合或重叠大缺失的患者群体中发生的频率很高。我们开发了一种细胞内流式细胞术方法来快速诊断DOCK8缺陷并评估体细胞逆转，结果表明逆转主要发生在T细胞中，有时发生在NK细胞中。我们的结果表明，在大多数患者中，体细胞逆转可能会改善，但不足以治愈疾病。然而，临床表现良好且逆转程度高的罕见患者可能受益于持续监测，这可能影响有关造血细胞移植治疗的决定。

Over many years, while studying DOCK8-deficient patients who were evaluated at the NIH Clinical Center, we observed that they often differed from each other in their spectrum of disease and disease severity. Detailed genetic evaluations revealed that the phenotypic variability in some patients was associated with the presence and degree of somatic reversion. This occurred to a high frequency among our patient population who did not have homozygous or overlapping large deletions, due to mechanisms involving homologous recombination. We developed an intracellular flow cytometric method to rapidly diagnose DOCK8 deficiency and assess for somatic reversion, which showed that reversion occurs mostly in T cells and sometimes NK cells. Our results indicate that in most patients somatic reversion may improve but is inadequate to cure disease. However, rare patients who are clinically doing well and have high levels of reversion might benefit from ongoing monitoring, which could influence decisions regarding treatment with hematopoietic cell transplantation. In FY2014, we also participated in two collaborative studies related to DOCK8 deficiency. In the first, we helped to show that the neurological symptoms in DOCK8-deficient patients, which are often attributed to vasculitis, can result from viral reactivation after vaccination with varicella-zoster virus. However, this occurred in the additional setting of immunodeficiency and additional immunosuppressant medications. In the second collaborative study, we helped to show that DOCK8-deficient patients and mice have impaired NKT cell development, which could contribute to the patients' immunodeficiency.