Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado, United States of America.
PLoS One. 2010 Feb 26;5(2):e9441. doi: 10.1371/journal.pone.0009441.
Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory clinical syndrome associated with neoplastic disorders especially lymphoma, autoimmune conditions, and infectious agents including bacteria, viruses, protozoa and fungi. In both human and veterinary medicine, hemophagocytic histiocytic disorders are clinically important and frequently fatal. HLH in humans can be a primary (familial, autosomal recessive) or secondary (acquired) condition, with both types generally precipitated by an infectious agent. Previously, no mouse model for secondary HLH has been reported. Using Salmonella enterica serotype Typhimurium by oral gavage to mimic naturally-occurring infection in Sv129S6 mice, we characterized the clinical, hematologic and morphologic host responses to disease thereby describing an animal model with the clinico-pathologic features of secondary HLH as set forth by the Histiocyte Society: fever, splenomegaly, cytopenias (anemia, thrombocytopenia), hemophagocytosis in bone marrow and spleen, hyperferritinemia, and hypofibrinogenemia. Disease severity correlates with high splenic and hepatic bacterial load, and we show disease course can be monitored and tracked in live animals. Whereby secondary HLH is known to occur in human patients with typhoid fever and other infectious diseases, our characterization of a viable natural disease model of secondary HLH offers an important means to elucidate pathogenesis of poorly understood mechanisms of secondary HLH and investigation of novel therapies. We characterize previously unreported secondary HLH in a chronic mouse model of typhoid fever, and novel changes in hematology including decreased tissue ferric iron storage that differs from classically described anemia of chronic disease. Our studies demonstrate S. Typhimurium infection of mice is a natural infectious disease model of secondary HLH that may have utility for elucidating disease pathogenesis and developing novel therapies.
噬血细胞性淋巴组织细胞增生症（HLH）是一种与肿瘤性疾病相关的炎症过度活跃的临床综合征，特别是淋巴瘤、自身免疫性疾病以及感染因子，包括细菌、病毒、原生动物和真菌。在人类和兽医医学中，噬血细胞性组织细胞疾病具有重要的临床意义，并且经常是致命的。人类 HLH 可以是原发性（家族性、常染色体隐性）或继发性（获得性）疾病，这两种类型通常都由感染因子引发。以前，尚未有报道过继发性 HLH 的小鼠模型。我们通过口服灌胃沙门氏菌 Typhimurium 来模拟 Sv129S6 小鼠中自然发生的感染，从而描述了一种继发性 HLH 的临床、血液学和形态学宿主反应特征，该疾病模型具有组织细胞协会规定的继发性 HLH 的临床病理特征：发热、脾肿大、细胞减少症（贫血、血小板减少症）、骨髓和脾脏中的噬血细胞现象、高铁蛋白血症和低纤维蛋白原血症。疾病严重程度与高脾脏和肝脏细菌负荷相关，我们证明可以在活动物中监测和跟踪疾病进程。已知继发性 HLH 发生在伤寒和其他传染病的人类患者中，我们对继发性 HLH 的可行天然疾病模型的特征描述为阐明继发性 HLH 的发病机制以及研究新疗法提供了重要手段。我们在慢性伤寒小鼠模型中描述了以前未报道过的继发性 HLH，以及血液学中的新变化，包括组织铁储存减少，这与经典描述的慢性疾病性贫血不同。我们的研究表明，鼠伤寒沙门氏菌感染是继发性 HLH 的一种天然传染性疾病模型，可能有助于阐明疾病发病机制并开发新疗法。
