Understanding DOCK8 Function in Health and Human Disease

了解 DOCK8 在健康和人类疾病中的功能

• 批准号: 8946555
• 负责人: Helen Su
• 金额: $ 78.73万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8946555
• 关键词: Affect; Allergic Disease; Atopic Dermatitis; Cells; Clinical; Development; Diagnosis; Disease; Evaluation; Food Hypersensitivity; Frequencies; General Population; Genetic; Goals; Health; Herpesvirus Type 3; Human Papillomavirus; Immune; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infection; Infectious Skin Diseases; Knowledge; Lymphocyte; Lymphoma; Malignant Neoplasms; Methods; Molluscum contagiosum virus; Monitor; Mus; Mutation; Natural Killer Cells; Neurologic; Patients; Pharmaceutical Preparations; Recurrence; Severity of illness; Simplexvirus; Skin; Squamous cell carcinoma; Symptoms; Syndrome; T-Lymphocyte; United States National Institutes of Health; Vaccination; Vasculitis; Viral; Virus Diseases; hematopoietic cell transplantation; homologous recombination; human disease; improved; interest; patient population

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.

多年来，在研究在NIH临床中心接受评估的DOCK 8缺陷患者时，我们观察到他们的疾病谱和疾病严重程度往往彼此不同。详细的遗传评估显示，在一些患者的表型变异与体细胞逆转的存在和程度。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人群中发生的频率很高。我们开发了一种细胞内流式细胞术方法来快速诊断DOCK 8缺陷并评估体细胞逆转，这表明逆转主要发生在T细胞中，有时也发生在NK细胞中。我们的研究结果表明，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水平高的罕见患者可能会受益于持续监测，这可能会影响造血细胞移植治疗的决定。 在2014财政年度，我们还参与了两项与DOCK 8缺陷相关的合作研究。在第一项研究中，我们帮助证明了DOCK 8缺陷患者的神经系统症状，通常归因于血管炎，可能是由于接种水痘-带状疱疹病毒后的病毒再激活引起的。然而，这发生在免疫缺陷和额外的免疫抑制剂药物的额外设置。在第二项合作研究中，我们帮助证明DOCK 8缺陷患者和小鼠的NKT细胞发育受损，这可能导致患者的免疫缺陷。