Genes And Gene Products As Immunoadjuvants

我们正致力于鉴别、描述和治疗对分枝杆菌和细胞内真菌感染易感性增加的先天性和获得性综合征，包括球孢子菌病。我们感兴趣的综合征主要影响吞噬细胞，最明显的是对非结核分枝杆菌的易感性增加。这些生物被认为仅在免疫功能低下的宿主中是重要的病原体。因此，我们试图确定没有先前认识到的免疫功能低下的感染患者，然后确定其易感性的性质。通过这种方式，我们已经确定并描述了参与控制分枝杆菌和其他细胞内病原体的途径，如沙门氏菌、组织浆菌病、球孢子菌病、隐球菌病以及非结核分枝杆菌。我们已经确定的异常集中在巨噬细胞/淋巴细胞相互作用周围，导致干扰素γ、IL-12、IL-23、IL-17和肿瘤坏死因子的产生或应答。此外，调节对肿瘤坏死因子反应的途径与干扰素γ信号通路重叠，并已被证明在这些感染患者中受损。这些“自然实验”的研究强调了巨噬细胞/淋巴细胞相互作用在控制分枝杆菌和其他细胞内病原体（包括真菌）中的关键作用。这些观察结果引导我们探索细胞因子疗法和细胞因子修饰疗法，这些疗法可能在结核病的治疗中有更广泛的应用。在过去的一年里，我们通过对肺外真菌患者的研究，继续关注分枝杆菌感染中炎症基因调节的重要性。我们已经在组织浆菌病和球孢子菌病以及分枝杆菌患者中发现了细胞因子受体和信号的异常。我们还关注单核细胞减少症和分枝杆菌病（MonoMAC）综合征，这是由于GATA2突变引起的，也容易导致骨髓增生异常和恶性肿瘤。

We are working on the identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to mycobacterial and intracellular fungal infections, including coccidioidomycosis. The syndromes in which we are interested primarily affect the phagocytes, and are most apparent in the increased susceptibility to nontuberculous mycobacteria. These organisms are thought to be important pathogens only in the immunocompromised host. Therefore, we have sought to identify patients without previously recognized forms of immunocompromise who have these infections and then determine the nature of their susceptibility. In this way we have identified and characterized the pathways involved in the control of mycobacteria and other intracellular pathogens, such as Salmonella, histoplasmosis, coccidioidomycosis, and cryptococcosis as well as nontuberculous mycobacteria. The abnormalities we have already identified center around macrophage/lymphocyte interactions leading to the production of or response to interferon gamma, IL-12, IL-23, IL-17 and tumor necrosis factor. In addition, the pathways regulating the response to tumor necrosis factor overlap with the interferon gamma signaling pathways and have been shown to be lesioned in patients with these infections. The study of these "experiments of nature" highlights the critical role of the macrophage/ lymphocyte interaction in control of mycobacteria and other intracellular pathogens, including fungi. These observations have led us to explore cytokine therapies and cytokine modifying therapies that may have broader applications to the treatment of tuberculosis. Over the last year we have continued our focus on the importance of the regulation of inflammatory genes in mycobacterial infections through the study of patients with extrapulmonary fungi. We have identified abnormalities in cytokine receptors and signaling in those with histoplasmosis and coccidioidomycosis as well as mycobacteria. We have also focused on the syndrome of monocytopenia and mycobacterial disease (MonoMAC), which is due to mutations in GATA2 and also predisposes to myelodysplasia and malignancy. The identification of genes in these overlapping pathways has helped us understand the control of intracellular infection and should lead us to the development of more focused and more successful therapeutics. These infections overlap in many ways with those seen in AIDS.