Strain Differences and the Role for HSP47 and HSP70 in Adjuvant Arthritis in Rats

Abstract

Because of high sequence homology between microbial and endogenous heat shock proteins (HSP), immunological cross‐reactivity to microbial HSP has been suggested as a possible cause of the development of autoimmune diseases, such as rheumatoid arthritis. The present study aimed to determine a potential role of HSP47, a molecular chaperone involved in the synthesis and assembly of collagen molecules, and microbial HSP71 (mHSP71) in adjuvant arthritis (AA) in two rat strains: Dark Agouti (DA), susceptible to AA induction and Albino Oxford (AO), which is resistant to AA induction. Immunization with complete Freund's adjuvant (CFA) induced an increased expression of HSP47 in joints of DA rats, which exhibited severe clinical signs of AA at the time of disease peak, while this protein was not detectable in joints of AO rats. In contrast, no strain differences in HSP72 (rat analogue of mHSP71) expressions in joints were observed. The increased levels of anti‐HSP47 antibodies were detected in sera of DA rats during the AA peak, while the immunization with CFA increased levels of anti‐mHSP71 antibodies in sera of AO rats. HSP47 and mHSP71 reduced proliferation of draining inguinal lymph node cells (LNC) in resistant AO rat strain, leading to a hypothesis that both HSP participated in AA control. Finally, mHSP71 potentiated the apoptotic response of LNC in susceptible DA rat strain. In conclusion, our findings indicate involvement of HSP47 in the development of AA in the rat, and point out to the regulatory role for both HSP47 and mHSP71.

Reactive oxygen species (ROS), but not nitric oxide (NO), contribute to strain differences in the susceptibility to experimental arthritis in rats

“…Our findings parallel these results: a decreased capacity to produce ROS by DA macrophages could provide a reducing milieu required for optimal T cell proliferation, and therefore promote susceptibility and potentiate arthritis severity in DA rats. Similarly, the increased ROS production upon in vitro stimulation with HSP47 by macrophages of AO rats immunized with CFA could contribute to lower T cell activity levels, which is in agreement with our previous findings (Miletic´et al, 2006) that this stress protein reduces T and B cell proliferation in AO rats following AA induction. The increased oxidation status in AO rats could affect the depletion of potentially autoreactive T cells or alter their activation threshold, resulting in effective control of autoreactivity in these rats.…”

“…The increased NO production as a consequence of macrophage activation by interferon-g during the BCG infection was reported to mediate increased apoptosis of CD4 + T cells, returning the number of activated CD4 + T cells to normal levels and maintaining their homeostasis (Dalton et al, 2000). Our earlier research has revealed the increased apoptosis of CD3+ cells in DA rats at the time of maximum clinical score of AA (Miletic´et al, 2006). No stimulatory or inhibitory effect of mHSP71 on NO production by macrophages was detected, giving rise to a possibility this molecule is not the element of the mycobacterial cell responsible for the stimulatory effect observed with whole BCG cell stimulation.…”

“…The increased NO production upon in vitro stimulation with HSP47 of DA rats in comparison to AO rat macrophages was recorded only in rats immunized with CFA. This may be a reflection of non-specific stimulation with CFA and may mirror the effects of the increased expression of HSP47 found in DA rat joints at the time of maximum clinical signs (Miletic´et al, 2006).…”

The Involvement of Heat-Shock Proteins in the Pathogenesis of Autoimmune Arthritis: A Critical Appraisal

“…Immune reactivity to HSP65 is observed in rodents with adjuvant arthritis (AA) 9-12 , streptococcal cell wall induced arthritis (SCWIA) 14 , pristine-induced arthritis (PIA) 13,28 , dimethyl dioctadecyl ammonium bromide-induced arthritis (DIA) 15 and avridin-induced arthritis (AvIA) 30 . Other HSPs targeted in 1 or more of these disease models include HSP70 31-33 , HSP40 23 and HSP10 34,35 . It is noteworthy that although Mtb is used as an arthritogen only for AA, the disease induced by several other arthritogenic stimuli (Table 2) can be experimentally modulated by treatment with certain HSPs.…”

“…Heat-shock proteins (HSPs) 4-7 (Table 1) are implicated in the pathogenesis of experimental arthritis in rodents 8-15 as well as human RA 16-18 . The T cells and antibodies from arthritic animals and RA patients are directed against different HSPs 15,19-23 . Various HSPs share a common characteristic of inducibility by heat-shock or other stressful stimuli, and these HSPs can be categorized into 9 protein families (Table 1).…”