Defining New Human Immunodeficiency and Immunodysregulation Disorders

除了缺乏已知诊断的独特免疫缺陷和免疫调节障碍患者外，我们接受的治疗还包括联合免疫缺陷患者、高IgE综合征变异体、自身免疫淋巴增殖性综合征(Alps)或caspase-8缺陷状态变异体(CEDS)、常见变量免疫缺陷(CVID)、X连锁镁缺陷并EBV感染和新生血管病变(XMEN)、Pasli变异体(p110 Delta激活突变导致T细胞衰老、淋巴结病和免疫缺陷)疾病以及Evans综合征。我们的评估包括功能筛选和基因测序，还使用生化分析、基因表达微阵列、流式细胞仪分析、体外功能测试和其他技术对部分患者进行了深入研究。这些实验为以前与疾病无关的新候选基因的测序提供了线索。此外，我们正在使用比较基因组杂交(CGH)阵列、整个外显子组测序和其他技术，以公正的方式确定新的免疫性疾病的遗传原因。 在2014财年，使用这些方法，我们从我们的高免疫球蛋白血症E队列中发现了一种新疾病。这种疾病的特点是免疫缺陷，反复发生肺部和其他感染，严重的特应性皮炎和皮肤血管炎，自身免疫包括肾小球肾炎和细胞减少，运动和神经认知障碍，以及淋巴瘤。我们发现该病是由常染色体隐性遗传的磷酸葡萄糖变位酶3(PGM3)基因亚型突变引起的，这使其成为一种新的先天性糖基化障碍。糖基化缺陷会影响多种免疫功能，包括CTLA4的表达，CTLA4是一种调节因子，通常会抑制适应性免疫反应，以防止自身免疫。我们的发现将改善诊断，为糖基化如何调节免疫系统预防过敏和感染提供新的见解，并提出潜在的治疗方法。

Besides unique patients with immunodeficiency and immunodysregulation disorders lacking known diagnoses, our intake includes patients with combined immunodeficiency, variants of hyper-IgE syndrome, variants of autoimmune lymphoproliferative syndrome (ALPS) or caspase-8-deficiency state (CEDS), common variable immunodeficiency (CVID), X-linked Magnesium defect with EBV infection and Neoplasia (XMEN), variants of PASLI (p110 delta activation mutation causing senescent T cells, lymphadenopathy, and immunodeficiency) disease, and Evans syndrome. Our evaluation includes functional screening and gene sequencing, and a subset of patients is also being intensively studied using biochemical analyses, gene expression microarrays, flow cytometric analyses, in vitro functional tests, and other technologies. These experiments have provided leads for sequencing of new candidate genes not previously associated with disease. Additionally, we are using comparative genomic hybridization (CGH) arrays, whole exome sequencing, and other technologies to determine genetic causes of new immunological diseases in an unbiased manner. In FY2014, using these approaches, we identified from our hyperimmunoglobulinemia E cohort a new disease. This disease is characterized by immune deficiency with recurrent pulmonary and other infections, severe atopic dermatitis and cutaneous vasculitis, autoimmunity including glomerulonephritis and cytopenias, motor and neurocognitive impairment, and lymphoma. We found that this disease is caused by autosomal recessive hypomorphic mutations in the phosphoglucomutase 3 (PGM3) gene, making this a new congenital disorder of glycosylation. The defect in glycolylation affects various immune functions, including the expression of CTLA4, a regulator that normally dampens adaptive immune responses to prevent autoimmunity. Our findings will improve diagnosis, provide new insight into how glycosylation regulates the immune system works to prevent allergy and infection, and also suggest potential therapeutic approaches.