Fibrosis is the production of excessive amounts of connective tissue, i.e., scar formation, in the course of reactive and reparative processes. Fibrosis develops as a consequence of various underlying diseases and presents a major diagnostically and therapeutically unsolved problem. In this review, we postulate that fibrosis is always a sequela of inflammatory processes and that the many different causes of fibrosis all channel into the same final stereotypical pathways. During the inflammatory phase, both innate and adaptive immune mechanisms are operative. This concept is exemplified by fibrotic diseases that develop as a consequence of tissue damage, primary inflammatory diseases, fibrotic alterations induced by foreign body implants, "spontaneous" fibrosis, and tumor-associated fibrotic changes.

The authors' results indicate that silicone implants trigger a specific, antigen-driven local immune response through activated TH1/TH17 cells, suggesting that ensuing fibrosis is promoted by the production of profibrotic cytokines as a consequence of faltering function of local T regulatory cells.

Objective-Growing evidence suggests that immune reactions to heat shock protein 60 (HSP60) are involved in atherogenesis. Because of the high phylogenetic conservation between microbial and human HSP60, bacterial infections might be responsible for breaking the tolerance to self-HSP60, which is expressed on the surface of stressed arterial endothelial cells. Methods and Results-We purified serum antibodies to Escherichia coli HSP60 (GroEL), the 60-kD chlamydial HSP, and HSP65 of Mycobacterium tuberculosis by affinity chromatography from clinically healthy subjects with sonographically proven carotid atherosclerosis. Reactivity of the purified antibodies with overlapping human HSP60 peptides was measured, and 8 shared common epitopes, recognized by all anti-bacterial HSP60/65 antibodies, were identified. Antisera specific for these cross-reactive epitopes were produced by immunizing rabbits with peptides derived from human HSP60. By immunohistochemistry, the epitopes were found to be present in the arterial wall of young subjects during the earliest stages of the disease. Conclusions-Antibodies to microbial HSP60/65 recognize specific epitopes on human HSP60. These cross-reactive epitopes were shown to serve as autoimmune targets in incipient atherosclerosis and might provide further insights into the mechanisms of early atherogenesis. Key Words: epitopes Ⅲ autoimmunity Ⅲ atherosclerosis Ⅲ heat shock protein 60 Ⅲ aging T he current theory of atherosclerosis suggests that the first stages can be described as an inflammatory process in the arterial wall. 1 However, the initial triggering event and the involved (auto)antigens still remain controversial. Heat shock proteins of the 60-kDa family (HSP60) are among 1 of the most highly conserved families of proteins. 2 Prokaryotic HSP60s have homology Ͼ97% at their protein levels, whereas prokaryotic and human HSP60 (hHSP60) have Ͼ70% amino acid sequence homology. Although microbial HSP60s serve as major antigens in protection from and pathogenesis of infectious diseases, several autoimmune disorders, like rheumatoid arthritis, systemic sclerosis, psoriasis, Kawasaki disease, and Behcet's disease, are believed to be triggered by shared B-and T-cell epitopes that are crossreactive between eukaryotic and prokaryotic HSP60. 3 HSP60 can be found not only in mitochondria but also on the surface of stressed eukaryotic cells. 4 -6 Because chronic bacterial infections are known to be a risk factor for atherosclerosis, 7,8 immunologic cross-reactions between bacterial HSP60 and hHSP60, which is expressed on the surface of stressed arterial cells, might be involved in atherogenesis. In a prospective, longitudinal study, we demonstrated that elevated levels of anti-mycobacterial HSP65 (mHSP65) antibodies, crossreacting with hHSP60, served as a prognostic marker for the incidence, prevalence, severity, and progression of carotid atherosclerosis in a clinically healthy population. 9,10 Those results have subsequently been confirmed by others. 11,12 Recent evidence corroborates that...