Nowak J, Mika-Witkowska R, Mendek-Czajkowska E, Rogatko-Koros M, Graczyk-Pol E, Pyl H, Klimczak A, Wojcik M, Nowak E A, Dlugokecka A, Prochorec M, Zupanska B
Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
Transplant Proc. 2010 Oct;42(8):3266-70. doi: 10.1016/j.transproceed.2010.07.030.
The pathologies of paroxysmal nocturnal hemoglobinuria (PNH) are primarily caused by somatic mutation in the PIG-A gene in hematopoietic stem cells resulting in glycosyl phosphatidylinositol deficiency and accumulation of phosphatidylinositol (PI) in plasma membranes. The mechanism of pathologic clone domination over normal hematopoietic clones in PNH patients is not yet understood. Forty-four PNH patients, including 9 with aplastic anemia traits (AA/PNH), 31 without full aplasia in bone marrow (de novo PNH, or dn/PNH), and 4 with unclassified PNH, and 200 ethnically matched controls were tested for the HLA A, B, C, DRB1, and DQB1 alleles and haplotype associations. The top block association analysis showed the primary association of PNH with 3 haplotype fragments: the class I fragment A2501-Cw1203-B1801 (risk ratio [RR], 6.64; P=.00012), and 2 class II fragments: DRB11501-DQB10602 (RR, 7.09; P=.0000015) and DRB10401-DQB10301 (RR, 6.76, P=.0093). The stratified analysis revealed that the A2501-Cw1203-B1801 haplotype associated preferentially with AA/PNH, and its component HLA molecule showed immunodominant antiapoptotic peptides derived from PI-activated phospholipase D; whereas the DRB11501-DQB10602 haplotype was associated strongly with dn/PNH and presented immunodominant class II-derived autopeptides. We concluded that certain HLA haplotypes were associated with PNH much more strongly than their allelic components. At least 3 HLA haplotype blocks (A2501-Cw1203-B1801, DRB11501-DQB10602, and DRB10401-DQB1*0301) were primarily associated with PNH. Our results supported the hypothesis of the roles in AA/PNH of antiapoptotic and in dn/PNH of autoimmune mechanisms.
阵发性睡眠性血红蛋白尿（PNH）的病理主要是由造血干细胞中PIG-A基因的体细胞突变引起的，导致糖基磷脂酰肌醇缺乏和磷脂酰肌醇（PI）在质膜中蓄积。目前尚不清楚PNH患者中病理性克隆优于正常造血克隆的机制。对44例PNH患者进行了检测，其中包括9例具有再生障碍性贫血特征（AA/PNH）的患者、31例骨髓无完全再生障碍的患者（初发性PNH，或dn/PNH）、4例未分类的PNH患者，以及200例种族匹配的对照，检测了他们的HLA A、B、C、DRB1和DQB1等位基因及单倍型关联。顶级模块关联分析显示PNH与3个单倍型片段主要相关：I类片段A2501-Cw1203-B1801（风险比[RR]，6.64；P = 0.00012），以及2个II类片段：DRB11501-DQB10602（RR，7.09；P = 0.0000015）和DRB10401-DQB10301（RR，6.76，P = 0.0093）。分层分析显示，A2501-Cw1203-B1801单倍型优先与AA/PNH相关，其组成的HLA分子显示出源自PI激活的磷脂酶D的免疫显性抗凋亡肽；而DRB11501-DQB10602单倍型与dn/PNH强烈相关，并呈现免疫显性的II类衍生自身肽。我们得出结论，某些HLA单倍型与PNH的关联比其等位基因成分更强。至少3个HLA单倍型模块（A2501-Cw1203-B1801、DRB11501-DQB10602和DRB10401-DQB1*0301）主要与PNH相关。我们的结果支持了抗凋亡机制在AA/PNH中起作用以及自身免疫机制在dn/PNH中起作用的假说。
