The association between the pathogenesis of benign prostatic hyperplasia (BPH) and inflammation has recently received attention. We previously showed that not only the inflammation response pathway, but also the classical complement pathway is activated in BPH tissue from model rats with stroma-dominant BPH. The classical complement pathway is activated by autoantigens that recognize immunocomplexes and it is responsible for various diseases via a mechanism that amplifies inflammation. We postulated that immunocomplexes amplify inflammation through complement activation, which leads to prostatic proliferation. Therefore, we expressed complement factors, analyzed their functions, and identified autoantigens to understand the pathogenic mechanism of BPH.

Fetal urogenital sinus (UGS) isolated from male 20-day-old rat embryos was implanted into the ventral prostate of pubertal male rats to create rat models of BPH. Complement factors were expressed and functionally analyzed in BPH tissues, and then serum concentrations of IgG and the expression of complement factors in BPH tissues were assessed. We immunoprecipitated BPH protein using an anti-IgG antibody to identify antigens, and analyzed the protein by mass spectrometry after SDS-PAGE separation. The expression of complement factors in human BPH tissue was also analyzed.

The expression of complement factors C1q, C3, MBL, Factor B, and MAC was significantly up-regulated in tissues from BPH rats compared with those from normal rats (Fig 1. p<0.01). The classical complement pathway was initially activated, followed by an alternative complement pathway activated in BPH. These complement factors were also up-regulated mostly in stromal areas of human BPH. The serum IgG concentration was significantly increased (398.1 ng/mL, p<0.01) in rat BPH and IgG was deposited in stromal areas of the BPH. Mass spectrometry of IgG binding protein identified Annexin, Hsp90, α-SMA, and β-actin as antigens of immunocomplexes.

Annexin, Hsp90, and β-actin are known to present in various cells. It has also been reported that these molecules are exposed as antigen on the cell surface due to cytotoxicity by stimulation such as ischemia. On the other hand, α-SMA is reported as a marker of myofibroblast in BPH and is thought to be involved in the BPH growth process. In this present study, antigen-antibody reaction recognizing these molecules as autoantigen is occurring in BPH growth processs. Subsequently, immunocomplexes activates classical complement pathway through binding to C1q , and then, lectin pathway, alternative pathway is activated. Complement system activation was thought to be responsible for the proliferation process of BPH by various inflammatory cell proliferation and tissue remodeling. In other words, the autoimmune reaction has possibilities to be involved in the growth process of BPH.

We clarified that the immune system is responsible for the development of BPH. Complement pathway activation by immunocomplexes recognizing Annexin, Hsp90, α-SMA, and β-actin as autoantigens might be responsible for the pathogenesis of BPH.