Understanding DOCK8 Function in Health and Human Disease

DOCK 8缺乏症是一种联合免疫缺陷疾病，具有不寻常的功能：患者具有复发性和持续性皮肤感染的严重问题。他们的皮肤感染是由各种各样的微生物引起的。这些微生物包括导致腹泻的细菌，有时也包括念珠菌。然而，患者最大的问题是控制感染皮肤的常见病毒，如单纯疱疹病毒、人乳头瘤病毒、传染性软疣病毒和水痘带状疱疹病毒。如果患者不接受骨髓移植治疗，这些病毒会导致毁容、无法愈合的皮疹。患者还患有其他皮肤疾病，如过敏性炎症引起的湿疹，以及与病毒性皮肤感染范围有关的皮肤癌。 我们计划的一个主要目标是了解为什么免疫细胞中DOCK8的丢失会导致皮肤免疫缺陷。为此，在2015财年的工作中，我们研究了在NIH临床中心接受随访的患者的T细胞和NK细胞。已知这些细胞对于抗病毒免疫特别重要。通过在显微镜下观察细胞，我们发现当它们穿过皮肤或类似皮肤的人工环境时，它们会变得畸形并死亡。通过研究在皮肤实验性单纯疱疹病毒感染期间DOCK 8缺陷的小鼠模型，我们还发现通常驻留在皮肤中的记忆T细胞也会死亡。我们的研究结果现在解释了皮肤免疫的一个重要方面：免疫细胞在穿过构成皮肤的紧密网络时必须保持其形状的完整性。这个过程是免疫细胞生存和正常运作所必需的，其关键调节因子是DOCK 8。了解这一点对于免疫细胞在其他皮肤疾病中的功能具有重要意义。 在2015财政年度，我们还参与了一项与DOCK 8缺乏症的自身免疫相关的合作研究，DOCK 8缺乏症很少发生，但可能很严重，例如影响大脑中的大血管。该研究表明，DOCK 8的缺失导致外周B细胞耐受性和调节性T细胞的缺陷，这可能有助于自身免疫。我们还参与了一项正在进行的合作研究，重点是改善DOCK8缺乏症的造血干细胞移植。

DOCK8 deficiency is a combined immunodeficiency disease that has an unusual feature: patients have severe problems with recurrent and persistent infections of the skin. Their skin infections are caused by a wide variety of microbes. The microbes include bacteria that cause abscesses, and sometimes candida. However, the patients have the greatest problem controlling common viruses that infect the skin, such as herpes simplex virus, human papilloma virus, molluscum contagiosum virus, and varicella-zoster virus. These viruses can cause disfiguring, non-healing rashes if the patients are not treated with bone marrow transplantation. The patients also have other diseases of the skin, such as eczema caused by allergic inflammation, and skin cancers that are related to how extensive the viral skin infections are. A major goal of our program is to understand why the loss of DOCK8 in immune cells causes defective skin immunity. To do so, in work culminating in FY2015, we have studied T cells and NK cells from patients who are followed at the NIH Clinical Center. These cells are known to be especially important for antiviral immunity. By looking at the cells under the microscope, we discovered that they become misshapen and die when they move through skin or artificial environments that resemble skin. By studying a mouse model of DOCK8-deficiency during experimental herpes simplex virus infections of the skin, we also found that the memory T cells that normally reside in the skin where they patrol against viral infections, also die off. Our findings now explain an important aspect of skin immunity: that the immune cells must maintain their shape integrity when they travel through the tight meshwork that makes up the skin. This process is needed for the immune cells to survive and function properly, and its critical regulator is DOCK8. Understanding this has important implications for how immune cells function in other skin conditions. In FY2015, we also participated in a collaborative study related to autoimmunity in DOCK8 deficiency, which occurs infrequently but can be severe, for example affecting the large blood vessels in the brain. This study showed that the loss of DOCK8 results in defects in B cell tolerance in the periphery and in regulatory T cells, which could contribute to the autoimmunity. We also participated in an ongoing collaborative study focusing on improving hematopoietic stem cell transplantation for DOCK8 deficiency.