INTRODUCTION H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). AIM The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. PATIENT AND METHODS Mitochondrial dysfunction, lysosomal integrity, cytokine response in response to stimulation with different pattern recognition receptor ligands, and circulating cell-free mitochondrial-DNA(ccf-mtDNA) level in plasma were analyzed compared to controls to understand the cellular triggers of autoinflammation. RNA sequencing (RS) analyses were also performed in monocytes before/after culture with lipopolysaccharide. RESULTS Patient had progressive destructive arthropathy in addition to clinical findings due to combined immunodeficiency. Pure red cell aplasia (PRCA), vitiligo, diabetes, multiple autoantibody positivity, lymphopenia, increased acute phase reactants were present. Recent thymic emigrants (RTE), naïve T cells were decreased, effector memory CD4 + T cells, nonclassical inflammatory monocytes were increased. Patient's peripheral blood mononuclear cells secreted more IL-1β and IL-6, showed lysosomal disruption and significant mitochondrial dysfunction compared to healthy controls. Plasma ccf-mtDNA level was significantly elevated compared to age-matched controls (p < 0.05). RNA sequencing studies revealed decreased expression of NLR Family Caspase Recrument-Domain Containing 4(NLRC4), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4(PFKFB4), serine dehydratase(SDS), heparan sulfate(Glucosamine) 3-O-sulfotransferase 1(HS3ST1), neutral cholesterol ester hydrolase 1 (NCEH1), and interleukin-8 (IL-8) in patient's monocytes compared to controls. Longstanding PRCA, which is possibly autoimmune, resolved after initiating monthly intravenous immunoglobulins (IVIG) and low dose steroids to the patient. CONCLUSION Although autoinflammation and autoimmunity are reported in HS, by functional analyses we here show in the present patient that over-active inflammasome pathway in HS might be related with mitochondrial and lysosomal dysfunction. Increased plasma ccf-mtDNA may be used as a biomarker of inflammasomopathy in HS. HS should be included in the classification of primary immunodeficiency diseases.

中文翻译：

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除联合免疫缺陷外，自身炎症：SLC29A3基因缺陷。

引言H综合征是由SLCA29A3基因缺陷引起的常染色体隐性遗传（AR）疾病。该基因编码平衡的核苷转运蛋白，该蛋白在脾脏，淋巴结和骨髓中高表达。自身炎症和自身免疫性伴随H综合征（HS）。目的目的是通过分子研究进一步阐明患有SLC29A3基因缺陷的患者的疾病机制。患者和方法分析了线粒体功能障碍，溶酶体完整性，细胞因子对不同模式识别受体配体刺激的反应，以及血浆中循环的线粒体DNA（ccf-mtDNA）水平与对照组的关系，以了解自身炎症的细胞触发因素。在用脂多糖培养之前/之后，还在单核细胞中进行了RNA测序（RS）分析。结果患者由于综合免疫缺陷，除了临床表现外还患有进行性破坏性关节炎。存在纯红细胞发育不全（PRCA），白癜风，糖尿病，多种自身抗体阳性，淋巴细胞减少，急性期反应物增加。最近的胸腺迁徙者（RTE），幼稚T细胞减少，效应记忆CD4 + T细胞，非经典炎症单核细胞增加。与健康对照组相比，患者的外周血单核细胞分泌更多的IL-1β和IL-6，表现出溶酶体破坏和明显的线粒体功能障碍。与年龄匹配的对照组相比，血浆ccf-mtDNA水平显着升高（p <0.05）。RNA测序研究显示，含4（NLRC4），6-磷酸果糖-2-激酶/果糖2，患者单核细胞中的6-双磷酸酶4（PFKFB4），丝氨酸脱水酶（SDS），硫酸乙酰肝素（葡萄糖胺）3-O-磺基转移酶1（HS3ST1），中性胆固醇酯水解酶1（NCEH1）和白介素8（IL-8）与控件相比。长期的PRCA，可能是自身免疫性的，在向患者启动每月静脉注射免疫球蛋白（IVIG）和低剂量类固醇后解决。结论尽管在HS中报告了自发炎症和自身免疫性，但通过功能分析，我们在本患者中显示，HS中过活跃的炎性体途径可能与线粒体和溶酶体功能障碍有关。血浆ccf-mtDNA升高可作为HS中炎症性肌病的生物标志物。HS应包括在原发性免疫缺陷疾病的分类中。与对照组相比，患者单核细胞中的硫酸乙酰肝素（葡萄糖胺）3-O-磺基转移酶1（HS3ST1），中性胆固醇酯水解酶1（NCEH1）和白细胞介素8（IL-8）。长期的PRCA，可能是自身免疫性的，在向患者启动每月静脉注射免疫球蛋白（IVIG）和低剂量类固醇后解决。结论尽管在HS中报告了自发炎症和自身免疫性，但通过功能分析，我们在本患者中显示，HS中过活跃的炎性体途径可能与线粒体和溶酶体功能障碍有关。血浆ccf-mtDNA升高可作为HS中炎症性肌病的生物标志物。HS应包括在原发性免疫缺陷疾病的分类中。与对照组相比，患者单核细胞中的硫酸乙酰肝素（葡萄糖胺）3-O-磺基转移酶1（HS3ST1），中性胆固醇酯水解酶1（NCEH1）和白细胞介素8（IL-8）。长期的PRCA，可能是自身免疫性的，在向患者启动每月静脉注射免疫球蛋白（IVIG）和低剂量类固醇后解决。结论尽管在HS中报告了自发炎症和自身免疫性，但通过功能分析，我们在本患者中显示，HS中过活跃的炎性体途径可能与线粒体和溶酶体功能障碍有关。血浆ccf-mtDNA升高可作为HS中炎症性肌病的生物标志物。HS应包括在原发性免疫缺陷疾病的分类中。单核细胞与对照相比。长期的PRCA，可能是自身免疫性的，在向患者启动每月静脉注射免疫球蛋白（IVIG）和低剂量类固醇后解决。结论尽管在HS中报告了自发炎症和自身免疫性，但通过功能分析，我们在本患者中显示，HS中过活跃的炎性体途径可能与线粒体和溶酶体功能障碍有关。血浆ccf-mtDNA升高可作为HS中炎症性肌病的生物标志物。HS应包括在原发性免疫缺陷疾病的分类中。单核细胞与对照相比。长期的PRCA，可能是自身免疫性的，在向患者启动每月静脉注射免疫球蛋白（IVIG）和低剂量类固醇后解决。结论尽管在HS中报告了自发炎症和自身免疫性，但通过功能分析，我们在本患者中显示，HS中过活跃的炎性体途径可能与线粒体和溶酶体功能障碍有关。血浆ccf-mtDNA升高可作为HS中炎症性肌病的生物标志物。HS应包括在原发性免疫缺陷疾病的分类中。通过功能分析，我们在本患者中显示，HS中炎性体通路过度活跃可能与线粒体和溶酶体功能障碍有关。血浆ccf-mtDNA升高可作为HS中炎症性肌病的生物标志物。HS应包括在原发性免疫缺陷疾病的分类中。通过功能分析，我们在本患者中显示，HS中炎性体通路过度活跃可能与线粒体和溶酶体功能障碍有关。血浆ccf-mtDNA升高可作为HS中炎症性肌病的生物标志物。HS应包括在原发性免疫缺陷疾病的分类中。