Marengo Eliana B, de Moraes Luciana V, Faria Marcella, Fernandes Beatriz L, Carvalho Luciana V, Tambourgi Denise V, Rizzo Luiz V, Portaro Fernanda C V, Camargo Antônio Carlos M, Sant'anna Osvaldo A
Immunochemistry Laboratory, Instituto Butantan, São Paulo, Brazil.
PLoS One. 2008 Aug 21;3(8):e3025. doi: 10.1371/journal.pone.0003025.
The heat shock protein [Hsp] family guides several steps during protein synthesis, are abundant in prokaryotic and eukaryotic cells, and are highly conserved during evolution. The Hsp60 family is involved in assembly and transport of proteins, and is expressed at very high levels during autoimmunity or autoinflammatory phenomena. Here, the pathophysiological role of the wild type [WT] and the point mutated K(409)A recombinant Hsp65 of M. leprae in an animal model of Systemic Lupus Erythematosus [SLE] was evaluated in vivo using the genetically homogeneous [NZBxNZW]F(1) mice. Anti-DNA and anti-Hsp65 antibodies responsiveness was individually measured during the animal's life span, and the mean survival time [MST] was determined. The treatment with WT abbreviates the MST in 46%, when compared to non-treated mice [p<0.001]. An increase in the IgG2a/IgG1 anti-DNA antibodies ratio was also observed in animals injected with the WT Hsp65. Incubation of BALB/c macrophages with F(1) serum from WT treated mice resulted in acute cell necrosis; treatment of these cells with serum from K(409)A treated mice did not cause any toxic effect. Moreover, the involvement of WT correlates with age and is dose-dependent. Our data suggest that Hsp65 may be a central molecule intervening in the progression of the SLE, and that the point mutated K(409)A recombinant immunogenic molecule, that counteracts the deleterious effect of WT, may act mitigating and delaying the development of SLE in treated mice. This study gives new insights into the general biological role of Hsp and the significant impact of environmental factors during the pathogenesis of this autoimmune process.
热休克蛋白（Hsp）家族在蛋白质合成过程中指导多个步骤，在原核细胞和真核细胞中含量丰富，且在进化过程中高度保守。Hsp60家族参与蛋白质的组装和运输，在自身免疫或自身炎症现象期间高水平表达。在此，利用基因同源的（NZBxNZW）F1小鼠在体内评估了野生型（WT）和麻风分枝杆菌点突变K（409）A重组Hsp65在系统性红斑狼疮（SLE）动物模型中的病理生理作用。在动物的寿命期间分别测量抗DNA和抗Hsp65抗体反应性，并确定平均存活时间（MST）。与未治疗的小鼠相比，WT治疗使MST缩短了46%（p<0.001）。在注射WT Hsp65的动物中也观察到IgG2a/IgG1抗DNA抗体比率增加。用来自WT治疗小鼠的F1血清孵育BALB/c巨噬细胞导致急性细胞坏死；用来自K（409）A治疗小鼠的血清处理这些细胞未引起任何毒性作用。此外，WT的参与与年龄相关且呈剂量依赖性。我们的数据表明，Hsp65可能是干预SLE进展的核心分子，而点突变K（409）A重组免疫原性分子可抵消WT的有害作用，可能在治疗小鼠中减轻和延缓SLE的发展。这项研究为Hsp的一般生物学作用以及环境因素在这种自身免疫过程发病机制中的重大影响提供了新的见解。
