A block in the road to fertility: autoantibodies to heat-shock protein 90-β in human ovarian autoimmunity

Objective To report autoantibodies to human heat-shock protein 90-β (HSP90β) in sera of women with infertility. Design Prospective, controlled observations. Setting Major urban infertility referral center and research institution. Patient(s) Fifty women with premature ovarian failure, 65 infertile women enrolled in the in vitro fertilization–embryo transfer program, and 60 normally menstruating fertile women as controls. Intervention(s) None. Main Outcome Measure(s) Identification and complete characterization of a 90-kd protein, the most immunodominant autoantigen. Result(s) Our previous studies employing a novel blocking demonstrated several cellular and molecular ovarian antigenic targets using patient's serum. Of all these antigens, the 90-kd protein designated as EP90 was found to be conserved across species, was serine–threonine phosphorylated, and was expressed from the primordial stage to the graafian-stage ooplasm of the oocytes during follicular development. Using high-throughput proteomic technologies like liquid chromatography/mass spectrometry, matrix-assisted laser desorption/ionization time-of-flight/time-of-flight (MALDI-TOF/TOF), and tandem mass spectrometry analysis revealed the identity of this protein to be HSP90β. Commercially available recombinant protein immunoreacted with the sera from patients with antiovarian antibodies against the 90-kd antigen. In parallel, using monoclonal antibody to human HSP90, we found that it reacts with the eluted protein from a crude ovarian extract. Conclusion(s) This is the first report to show the presence of ovarian autoantibodies to human HSP90 in sera of women with infertility. This protein could be involved in human ovarian autoimmunity and thereby be a causative factor in early ovarian failure.