Immune recognition of the 60kD heat shock protein: Implications for subsequent fertility

Abstract

The 60kD heat shock protein (hsp60) is a highly conserved protein and a dominant antigen of most pathogenic bacteria. In some women, chronic or repeated upper genital tract infections with Chlamydia trachomatis, and possibly with other microorganisms, induces immune sensitization to epitopes of hsp60 that are present in both the microbial and human hsp60. Once a woman becomes sensitized to these conserved epitopes, any subsequent induction of human or bacterial hsp60 expression will reactivate hsp60‐sensitized lymphocytes and initiate a pro‐inflammatory immune response. Hsp60 is expressed during the early stages of pregnancy, by both the embryo and the maternal decidua. We examined, therefore, whether women who were sensitized to hsp60 experienced less successful pregnancy outcomes compared to women who were not sensitized to this antigen. In women undergoing in vitro fertilization (IVF), the presence of cervical IgA antibodies reactive with the C. trachomatis hsp60 correlated with implantation failure after embryo transfer. Further analysis revealed that an immunodominant epitope for these IgA antibodies was an hsp60 epitope shared between C. trachomatis and man. In subsequent studies of women not undergoing IVF, cervical IgA antibodies to the human hsp60 were identified in 13 of 91 reproductive age women. This antibody was most prevalent in those women with a history of primary infertility (p = 0.003). In addition, cervical anti‐hsp60 IgA correlated with the detection of the pro‐inflammatory cytokines interferon‐γ (p = 0.001) and tumor necrosis factor‐α (p = 0.02) in the cervix. Conversely, women with proven fertility had the highest prevalence of the anti‐inflammatory cytokine, interleukin 10, in their cervices (p = 0.001). In an analysis of serum samples in a third study, women with a history of two or more consecutive first trimester spontaneous abortions had a higher prevalence (p = 0.01) of IgG antibodies to the human hsp60 (36.8%) than did age matched fertile women (11.1%) or women with primary infertility (11.8%). Immune sensitization to epitopes expressed by the human hsp60 may reduce the probability of a successful pregnancy outcome due to reactivation of hsp60‐reactive lymphocytes, induction of a pro‐inflammatory cytokine response and interference with early embryo development and/or implantation. © 1996 Wiley‐Liss, Inc.

Circulating anti-heat-shock-protein antibodies in normal pregnancy and preeclampsia

“…Cross-reactive anti-heat-shock-protein antibodies and T cells can damage vascular tissues overexpressing heat shock proteins, contributing to the development of atherosclerosis (Mandal et al 2004). Additionally, immune sensitization to human Hsp60, possibly developed as a consequence of infection, may adversely affect pregnancy outcome (Witkin et al 1994(Witkin et al , 1996. Furthermore, the presence of anti-Hsp60 and anti-Hsp70 antibodies in the serum and formation of Hsp60-and Hsp70-immune complexes in the placenta were associated with preterm birth (Ziegert et al 1999).…”

Heat Shock Protein Expression During Gametogenesis and Embryogenesis

“…36 In addition, it could be demonstrated that systemic immunity to human hsp60 was associated with firsttrimester spontaneous abortion. 37 In many IVF culture systems, the in vitro fertilized embryos are cultured in medium containing maternal serum. Preexisting hsp antibodies in these sera at high titers could thus compromise the growth potential of developing embryos.…”

Stored of Hsp72/Hsp73 in Germinal Vesicle‐stage Mouse Oocytes

“…1994). Even a high spontaneous abortion at first trimester during the pregnancy was also found in antibody‐positive women (Witkin et al. 1996).…”

“…Improving pregnancy rate during in vitro fertilization (IVF) sometime remains a challenge task. An increased failure rate in women undergoing IVF was found when local and systemic immunity to the human Hsp60 was demonstrated (Witkin et al. 1996).…”