Abstract
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 K409A recombinant Hsp65 of M. leprae in an animal model of Systemic Lupus Erythematosus [SLE] was evaluated in vivo using the genetically homogeneous [NZBxNZW]F1 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 F1 serum from WT treated mice resulted in acute cell necrosis; treatment of these cells with serum from K409A 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 K409A 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.
Highlights
The Hsp60 guides essential activities for cell homeostasis being highly conserved among organisms; in stress or inflammation conditions, they increase 4 to 5-fold in the cell subsequently undergoing autolysis returning to basal levels [1]
WT rHsp65 treatment accelerates death in SLE To determine the effect of M. leprae rHsp65 on the development of autoimmunity, 45 days-old [NZBxNZW]F1 mice were injected with a single dose of the WT rHsp65 or with the point mutated K409A rHsp65, and monitored until death, and compared to untreated mice
Untreated and K409A-treated animals presented the typical clinical signs of murine lupus: anemia, proteinuria, including progressive ascites starting at day 180
Summary
The Hsp guides essential activities for cell homeostasis being highly conserved among organisms; in stress or inflammation conditions, they increase 4 to 5-fold in the cell subsequently undergoing autolysis returning to basal levels [1]. Published data show that Hsp is one of the major target for the immune response to pathogens [6,7]. The major sequence similarity among species renders the Hsp a potential inducer of immune responses to host self molecules that may lead to autoimmune phenomena. Due to high similarity inter-species in their sequence, it is suggested from a process of molecular mimicry, the participation of the Hsp in the modulation and etiology or pathogenesis of autoimmunities [8,9,10,11]. Pockley et al [12] indicated the presence of antibodies for Hsp family in healthy individuals, such as that of Stephanou et al [13] showing significant increase of anti-Hsp antibody titers in patients with SLE compared to healthy individuals. High anti-Hsp60/65 antibody titers were not restricted to disease patients and could be detected during aging [12,14,15,16]
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