Vhsp 65 Antibodies In Atherosclerosis

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Arteriosclerotic lesions can be induced by immunization with hsp 65 in animals. Obviously, hsp 65 may serve as antigen or pathogen to initiate a specific immune reaction in the development of the disease. We therefore wondered whether hsp 65 was also involved as an antigen to stimulate B-cell production of specific antibodies in humans with atherosclerosis. To investigate this issue, we participated in an epidemiological study carried out in Bruneck, a small town in South Tyrol (8). Of 13,534 clinically normal inhabitants, 867 volunteers, aged 40-79 years, were randomly selected for determination of serum antibodies against hsp 65, simultaneous sonographic assessment of carotid atherosclerotic lesions, and evaluation of established risk factors, that is, blood cholesterol, hypertension, smoking, diabetes mellitus, and obesity. Autoantibodies to nuclear antigens, thyroid antigens, and rheumatoid factors were determined for control purposes. Our data showed that serum hsp 65 antibodies were significantly (p < 0.01) increased in subjects with carotid atherosclerosis compared with those without lesions, and this increased antibody level was independent of other established risk factors. On the other hand, the incidence and titers of various autoantibodies (antinuclear antibodies, antibodies to thyroglobulin and thyroid microsomal antigens, and rheumatoid factors) did not correlate with carotid atherosclerotic lesions. These data provided the first strong correlation of hsp 65 antibodies with carotid atherosclerosis, suggesting that hsp 65 may be involved in the pathogenesis of human atherosclerosis (8).

Antibodies to hsp 65/60 can be induced by several different mechanisms: Infection with agents containing hsp proteins homologous to mammalian hsp 60 could induce an antiself response through molecular mimicry in susceptible individuals (45); viral infection might result in hsp 60 incorporation into the budding virus, rendering it immunogenic (46); the protein could become immunogenic owing to structural alteration or posttranslational modification resulting from metabolic changes or viral infection (47); other foreign or self-anti-gens could interact with hsp 60 to form immunogenic complexes in which B cells recognize hsp 60, and T cells direct their response at the associated antigen (48); and finally, a bona fide autoimmune reaction to hsp 60 might occur. We hypothesized that the increased levels of hsp 65 antibodies may be involved in the development of atherosclerosis by a cross-reactive response to lesion proteins or cell components.

On the other hand, increased reactivity to mycobacterial hsp 65 and homologous mammalian hsp 60 antigens was observed previously in several other diseases, such as adjuvant arthritis in rats (49), insulin-dependent diabetes mellitus in mice (51), and in humans with rheumatoid arthritis (50), schizophrenia (52), and systemic sclerosis (53). The hsp 65 molecule containing 573 amino acids could feature multiple lymphocyte and/or antibody epitopes, and it is conceivable that at least one is cross reactive with an antigen in atherosclerotic lesions, whereas another cross reacts with an antigen present in joints. Indeed, the hsp 65 epitope critical for adjuvant arthritis (amino acids 180-188) appears to be homologous to a sequence in the link protein of the cartilage proteoglycan (50). Hence, responses to different hsp 65 epitopes might lead either to arthritis or to atherosclerosis depending on genetically determined recognization of different epitopes. Therapeutically, vaccination with the nonapeptide amino acid sequence 180-188 of hsp 65 was demonstrated to reduce the incidence and severity of adjuvant arthritis in rats (54), and administration of hsp 65 can vaccinate against diabetes in mice (51). If different hsp 65 epitopes are confirmed to play a pathogenic role in different diseases, the use of various peptides may also be considered for therapeutic or preventive purposes in humans in the future. Furthermore, although increased concentrations of serum antibodies to hsp 65 are not specific for atherosclerosis, they may prove to be a new diagnostic marker for this disease (55).

The question arose as to whether human serum antibodies to mycobacterial hsp 65 could react specifically against autologous hsp 60 or another cellullar component of atherosclerotic lesions. We selected human sera with high or low titers to recombinant mycobacterial hsp 65 and investigated their reactivity with human arterial lesion components using immunoblotting and immunofluorescence. All high-titer sera against hsp 65 reacted with a 60-kDa band of atherosclerotic lesion proteins and human recombinant hsp 60 on Western blots (Fig. 1). Pooled sera with a low antibody titer to hsp 65, which was diluted in a manner similar to high-titer sera, showed no reactivity with atherosclerotic lesion and media proteins. Using immunohistochemistry and immunofluorescence with human immunoglobulin (IgG) isolated from different sera, labeled with biotin, and visualized with a streptavidin conjugate, positive staining was observed in sections of fatty streaks and atherosclerotic plaques of carotid arteries and weak staining in normal intima. Double immunofluorescence identified the majority of positively stained cells as macrophages, endothelial cells, and a few smooth muscle cells (9). Therefore, serum antibodies against hsp 65 cross react with the human 60-kDa homologue present in high levels in atherosclerotic lesions mainly associated with macrophages and endothelial cells, supporting our concept of a humorally mediated immune reaction against hsp 60 in atherogenesis.

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