背景:据报道,在多囊卵巢综合征(PCOS)中,补体系统因子的上调增加,可能是由于肥胖和胰岛素抵抗,而不是由于PCOS本身。我们直接比较了肥胖患者的补体因子,胰岛素抵抗PCOS人群与非肥胖人群,非胰岛素抵抗PCOS人群的蛋白质组学分析对此进行了研究。
方法:从生物库队列中收集234名女性(137名PCOS患者和97名对照)的血浆,并与非肥胖患者进行比较,非胰岛素抵抗人群(24名PCOS患者和24名对照)。对以下补体系统蛋白进行慢解离速率修饰的适体(SOMA)扫描血浆蛋白测量:C1q,C1r,C2,C3,C3a,iC3b,C3b,C3d,C3adesArg,C4、C4a、C4b,C5、C5a、C5b-6复杂,C8,properdin,因素B,因子D,系数H,因子I,甘露糖结合蛋白C(MBL),补体衰减加速因子(DAF)和补体因子H相关蛋白5(CFHR5)。
结果:补体系统的替代途径在肥胖和非肥胖PCOS中均过表达,C3(p<0.05)和备解素(p<0.01)增加;此外,肥胖PCOS患者B因子增加(p<0.01)。对于这种途径的抑制剂,在苗条和肥胖的PCOS中,因子I均增加(p<0.01),肥胖PCOS患者CFHR5和H因子增加(p<0.01)。补体因子iC3b,C3d和C5a,与增强的B细胞反应和炎性细胞因子释放相关,苗条和肥胖的PCOS均增加(p<0.05)。C3a及其产品,C3adesArg,在非肥胖型PCOS中两者均显著升高(<0.01),但在肥胖型PCOS中未改变。在肥胖PCOS中,高雄激素血症与备解素和iC3b呈正相关(p<0.05),而在非肥胖PCOS中没有。与胰岛素抵抗无关。两组BMI与B因子呈正相关,因子H和C5a。此外,在肥胖的PCOS中,BMI与C3d相关,因子D,因子I,CFHR5和C5a(p<0.05),在非肥胖的PCOS中,BMI与备解素相关,iC3b,C3,C3adesArg,C3a,C4、C5、C5a和C1q。在肥胖对照组中,BMI与C3,C3desArg,C3a,C3d,C4,因子I,因素B,C5a和C5,而在非肥胖对照组中,BMI仅与C1q呈负相关。非肥胖和肥胖PCOS的比较表明,备解素,C3b,iC3b,C4A,因子D,因子H和MBL不同。
结论:替代补体途径的上调见于非肥胖型PCOS,在肥胖型PCOS中进一步加剧,这表明这是PCOS病理生理学的固有特征,肥胖会使其恶化,并反映在非肥胖和肥胖PCOS表型之间的差异上.然而,补体抑制剂的上调抵消了与激活相关的补体蛋白的增加;这在两个PCOS组中都很明显,暗示侮辱,如心血管事件或感染,导致补体途径激活的可能在PCOS中扩增。
BACKGROUND: Upregulation of complement system factors are reported to be increased in polycystic ovary syndrome (PCOS) and may be due to obesity and insulin resistance rather than inherently due to PCOS. We directly compared complement factors from an obese, insulin-resistant PCOS population to a nonobese, non-insulin-resistant PCOS population in a proteomic analysis to investigate this.
METHODS: Plasma was collected from 234 women (137 with PCOS and 97 controls) from a biobank cohort and compared to a nonobese, non-insulin-resistant population (24 with PCOS and 24 controls). Slow off-rate modified aptamer (SOMA) scan plasma protein measurement was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8,
properdin, factor B, factor D, factor H, factor I, Mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5).
RESULTS: The alternative pathway of the complement system was overexpressed in both obese and nonobese PCOS, with increased C3 (p < 0.05) and
properdin (p < 0.01); additionally, factor B increased in obese PCOS (p < 0.01). For inhibitors of this pathway, factor I was increased (p < 0.01) in both slim and obese PCOS, with an increase in CFHR5 and factor H in obese PCOS (p < 0.01). Complement factors iC3b, C3d and C5a, associated with an enhanced B cell response and inflammatory cytokine release, were increased in both slim and obese PCOS (p < 0.05). C3a and its product, C3adesArg, were both significantly elevated in nonobese PCOS (<0.01) but not altered in obese PCOS. Hyperandrogenemia correlated positively with
properdin and iC3b in obese PCOS (p < 0.05) but not in nonobese PCOS. There was no association with insulin resistance. BMI correlated positively in both groups with factor B, factor H and C5a. Additionally, in obese PCOS, BMI correlated with C3d, factor D, factor I, CFHR5 and C5a (p < 0.05), and in nonobese PCOS, BMI correlated with
properdin, iC3b, C3, C3adesArg, C3a, C4, C5, C5a and C1q. In obese controls, BMI correlated with C3, C3desArg, C3a, C3d, C4, factor I, factor B, C5a and C5, whilst in nonobese controls, BMI only correlated negatively with C1q. Comparison of nonobese and obese PCOS showed that
properdin, C3b, iC3b, C4A, factor D, factor H and MBL differed.
CONCLUSIONS: The upregulation of the alternative complement pathway was seen in nonobese PCOS and was further exacerbated in obese PCOS, indicating that this is an inherent feature of the pathophysiology of PCOS that is worsened by obesity and is reflected in the differences between the nonobese and obese PCOS phenotypes. However, the increase in the complement proteins associated with activation was counterbalanced by upregulation of complement inhibitors; this was evident in both PCOS groups, suggesting that insults, such as a cardiovascular event or infection, that cause activation of complement pathways may be amplified in PCOS.