Administration of M. leprae Hsp65 Interferes with the Murine Lupus Progression

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.

Mycobacterium leprae Hsp65 administration reduces the lifespan of aged high antibody producer mice

“…Based on the immune alterations observed in the aging process, the reports of higher incidence of chronic-degenerative processes in elders [14,43] and the deleterious effect of M. leprae Hsp65 administration on murine lupus and autoimmune uveitis [35,38], we evaluated the interference of WT Hsp65 administration on survival time and correlation with antibody production in H III and L III mice. The animals from Selection III are a well-established model to understand the humoral immune response and its influences over the susceptibility to infections [44], autoimmunity [45] and tumorigenesis [46]; they also differ in the response to antigens not related to those used for the selection procedure [47] and present different susceptibility to autoimmune disease [48].…”

A Mycobacterium leprae Hsp65 Mutant as a Candidate for Mitigating Lupus Aggravation in Mice

“…Following our previously concepted system based on the addition of Hsp to imbalance the endogenous equilibrium of the immunobiological system [16], the Leader and K 409 A peptides were passively administered to these F 1 mice. Here the primary sequence of synthetic peptides derived from M. leprae Hsp65 and their effects in this model are presented.…”

Autoimmune uveitis: study of treatment therapies

“…Source: Toscano MA et al (35) In the above mentioned results, it was evidenced the significant impact of environmental factors prevailing during this autoimmunity process. As recently hypothesized, the immunological history of an individual is unique and irreversible being cumulative, that is, the continued aggravation of an autoimmune process results in inability of tissue regeneration by affected systems (7) . In this context, the use of α4 inhibitors, rGal-1 and LMVp may contribute as an alternative therapeutic approach in the control of autoimmune ocular diseases.…”

“…Under variable and constant environmental pressures along life, the organism expresses several molecular targets that could be susceptible to a series of autoimmune episodes that are surmountable due to homeostasis. However, unbalances in the relations between cells and molecules with expressions increased of multifunctional proteins, such as IL-6, Hsp, and TNF, can trigger chronic, cumulative and irreversible processes of autoimmunity that are influenced by a combination of genetic and environmental factors (7) .…”