Serum Immunoglobulin G Antibodies to Chlamydial Heat Shock Protein 60 but Not to Human and Bacterial Homologs Are Associated With Coronary Artery Disease

Abstract

Background— Evidence for an association between Chlamydia pneumoniae infection and coronary artery disease (CAD) has been reported by numerous studies, cross-reactive heat shock protein (Hsp) antibody responses have been causally linked to CAD, and the severity of chlamydial disease pathogenesis correlates with Hsp serology. Our aim was to determine if chlamydial Hsp (cHsp) antibody responses are predictive of CAD. Methods and Results— Patients were recruited in a case-control study: 250 cases had angiographically significant CAD (stenosis ≥70%), and 250 controls had normal coronary arteries (stenosis <10%). Serum immunoglobulin G reactivity to Hsp10 and Hsp60 antigens (chlamydial, Escherichia coli , and human), and C pneumoniae whole organisms were measured by ELISA. Univariate analysis confirmed that classical CAD risk factors were predictors of CAD. Univariate analysis showed that cHsp60 ( P = 0.001, OR 3.9), cHsp10 ( P =0.045, OR 3.8), E coli Hsp60 ( P =0.04, OR 1.5) and C pneumoniae ( P =0.03, OR 1.8) ELISA optical density (OD) values were significantly different between cases and controls. Multivariate analysis found that only upper-quintile cHsp60 seroreactivity remained a significant predictor of CAD after controlling for classical CAD risk factors and seroreactivity to the other antigens (cHsp60 OD, P =0.005, OR 3.9 per OD unit; cHsp60 quintile, 5 versus 1 to 4; P =0.01, OR 2.1). Conclusions— The presence of elevated anti-cHsp60 immunoglobulin G antibodies, but not anti-human or anti– E coli homologs, was independently associated with CAD. This finding argues against previous suggestions that cross-reactive or autoimmune Hsp60 responses may contribute to disease progression. High anti-cHsp60 antibody response appears to identify the subset of patients with chlamydial infection and significant CAD.

Chlamydia pneumoniaeInfection and Risk for Lung Cancer

“…Therefore, it is likely that CHSP-60 antibodies identify a subset of individuals with severe or persistent infections. Crossreactivity of the CHSP-60 assay with C. trachomatis or human HSP antibodies could theoretically have led to poor correlation with C. pneumoniae MIF results (23). However, our observations that neither C. trachomatis nor human HSP-70 antibodies were related to CHSP-60 seropositivity argue against this explanation.…”

“…Studies on C. trachomatisrelated diseases, such as pelvic inflammatory disease, tubal infertility, and ectopic pregnancy (16,20,21), as well as those addressing the C. pneumoniae-atherosclerosis relationship (23,24,(30)(31)(32), indicate that CHSP-60 antibodies reflect a process of Chlamydia-induced inflammatory damage in tissues. Furthermore, these studies show that CHSP-60 antibodies are better markers than IgA antibodies for identifying chronic Chlamydia infections (16,(18)(19)(20)(21)(22).…”

“…We used the MIF assay using the method of Wang et al (27) The CHSP-60 ELISA assay uses a recombinant C. trachomatis HSP-60 antigen, which shares a high degree of homology (>90%) with HSP-60 antigens across other Chlamydia species (16). CHSPs also share homology (∼50%) with human heat shock proteins (23), and elevated levels of human HSP-70 antibodies have been associated with increased lung cancer risk (28). Therefore, given the possibility that the CHSP-60 ELISA would detect cross-reacting antibodies, we conducted additional testing on a subset of 99 subjects (50 negative and 49 positive for CHSP-60 antibodies).…”

“…Antibodies to the Chlamydia heat shock protein-60 (CHSP-60) could be one such marker for identifying chronic C. pneumoniae infections. CHSP-60 is consistently expressed during the chronic/persistent phase of chlamydial infection and is the major immunodominant protein responsible for Chlamydia-induced inflammatory tissue damage (6,(16)(17)(18)(19)(20)(21)(22)(23)(24). No study to date has evaluated the relationship of CHSP-60 antibodies with lung cancer.…”

B7-1/B7-2 Costimulation Regulates Plaque Antigen–Specific T-Cell Responses and Atherogenesis in Low-Density Lipoprotein Receptor–Deficient Mice

“…6 Levels of serum antibodies against HSP65 and HSP60 correlate with the progression of carotid atherosclerotic disease in humans. 7,8 Furthermore, immunization of mice prone to atherosclerosis due to a lack of LDL receptor (LDLR) with HSP65 promotes cholesterol dietinduced atherosclerosis, 9 and mucosal administration of HSP60 to LDLR-null mice leads to immunologic tolerance to this protein and decreased cholesterol diet-induced atherogenesis. 10 The two closely related costimulatory molecules B7-1 (CD80) and B7-2 (CD86) are expressed on antigen-presenting cells and provide signals, in addition to antigen, essential for the full activation of T cells.…”