Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis.
Mutations of complement factor I and potential mechanisms of neuroinflammation in acute hemorrhagic leukoencephalitis.
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DOI：
10.1007/s10875-012-9767-z
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发表时间：
2013-01
影响因子：
9.1
通讯作者：
Bastian, John F.
中科院分区：
文献类型：
--
作者：
Broderick, Lori;Gandhi, Chhavi;Mueller, James L.;Putnam, Christopher D.;Shayan, Katayoon;Giclas, Patricia C.;Peterson, Karin S.;Aceves, Seema S.;Sheets, Robert M.;Peterson, Bradley M.;Newbury, Robert O.;Hoffman, Hal M.;Bastian, John F.
急性出血性脑白质炎（AHLE）是一种罕见的脱髓鞘疾病，发病急，恶化快，发病率和死亡率高。最常被描述为上呼吸道疾病的感染后并发症，其确切的病理生理学尚不清楚。我们描述了两名患有部分补体因子I （FI）缺乏症的AHLE患儿，他们的成功治疗包括白细胞介素1 （IL-1）受体拮抗剂阿那金那，这暗示了FI和IL-1在这种疾病中的作用。两名AHLE患者的广泛临床检查显示补体异常，特别是与替代途径及其调节因子FI相关。类固醇、免疫球蛋白和阿那白的积极治疗最终改善了两例患者的临床状况，并接近恢复到神经系统基线。对患者及其家属的FI编码区进行基因测序。采用体外蛋白表达研究和固定脑组织免疫组化研究致病机制。在我们的患者中发现了两种新的FI突变，导致无法分泌FI。脑组织免疫组化评价显示C3、膜攻击复合物（MAC）和IL-1染色阳性。我们认为AHLE是部分FI缺乏的一种未报道的罕见表型。C3、MAC和IL-1的上调以及随后的脱髓鞘支持补体激活在AHLE中的病理作用，并提示阿那白那作为该疾病的重要辅助治疗。
Acute Hemorrhagic Leukoencephalitis (AHLE) is a rare demyelinating disorder of acute onset, rapid deterioration and significant morbidity and mortality. Most often described as a post-infectious complication of an upper respiratory illness, its precise pathophysiology remains unclear. We describe two pediatric patients with AHLE with partial complement factor I (FI) deficiency whose successful treatment included the interleukin-1 (IL-1) receptor antagonist, anakinra, implicating a role for FI and IL-1 in this disorder. Extensive clinical workup of two patients presenting with AHLE revealed complement abnormalities, specifically related to the alternative pathway and its regulator, FI. Aggressive management with steroids, immunoglobulin, and anakinra ultimately led to improvement of clinical status and near return to neurologic baseline in both patients. Genetic sequencing of the FI coding regions of the patients and their families was performed. In vitro protein expression studies and immunohistochemistry of fixed brain tissue was used to investigate pathogenic mechanisms. Two novel mutations in FI were identified in our patients, which result in failure to secrete FI. Immunohistochemical evaluation of brain tissue demonstrated positive staining for C3, membrane attack complex (MAC) and IL-1. We propose AHLE is an unreported, rare phenotype for partial FI deficiency. The upregulation of C3, MAC and IL-1 with subsequent demyelination support a pathologic role for complement activation in AHLE, and suggest anakinra as an important adjunctive therapy in this disease.
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DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
5.4
作者：
Nilsson, Sara C.;Trouw, Leendert A.;Blom, Anna M.
通讯作者：
Blom, Anna M.
影响因子：
2.5
作者：
BARNUM, SR;JONES, JL
通讯作者：
JONES, JL
影响因子：
3.6
作者：
Maria Ponce-Castro, Isabel;Gonzalez-Rubio, Carolina;Lopez-Trascasa, Margarita
通讯作者：
Lopez-Trascasa, Margarita
影响因子：
3.3
作者：
Palin, K;Verrier, D;Lestage, J
通讯作者：
Lestage, J