A population-based study of interactions between high-risk human papillomavirus infection and vaginal local cytokines CD4 CD8 IL-10 with cervical intraepithelial neoplasia

Ruoxi Zhu¹Aimin Yang^2,3Wenhao Wang¹Weihong Zhao¹Wei Wang¹Zhilian Wang¹Jintao Wang⁴Yongli Hou¹Xiaoqiang Su¹Lili Zhang¹Bo Feng¹Jing Yang¹Zhe Wang¹Xiaofen Niu¹Weiguo Lv⁵Zhican Qu¹Min Hao^1*

• ¹Departments of Obstetrics and Gynecology, Second Hospital of Shanxi Medical University, Taiyuan, China
• ²Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, Hong Kong, SAR China
• ³Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong, Hong Kong, SAR China
• ⁴Department of Epidemiology, School of Public Health, Shanxi Medical University, Taiyuan, China
• ⁵Department of Gynecologic Oncology,Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, China

Background: Cluster of Differentiation-4(CD4) ,CD8, and interleukin-10 (IL-10) have long been considered to be related to cervical cancer, but the exact relationship remains unclear. Few studies investigated the relationship between CD4,CD8,IL-10, and high-risk human papillomavirus (HPV) with risk of cervical intraepithelial neoplasia (CIN). Objective: Our aim is to evaluate the relationship between CD4, CD8, IL-10, and high-risk HPV infection with the risk of CIN, as well as their interactions on CIN. Design: In 2014-2015, a cross-sectional study of screening data was conducted among 2285 women aged 19-65 years who participated in an ongoing community-based cohort of 40,000 women in Shanxi, China. Using categorical and spline analyses to evaluate the relationship between local vaginal fluids of CD4,CD8,CD4/CD8,IL-10, and CIN risk. A total of 1,503 controls were followed up until January 31, 2019. A nested case-control study was used to assess the relationship between vaginal lavage CD4, CD8, CD4/CD8, and IL-10 levels and the risk of CIN progression. Results: After adjusting for possible confounding factors,CD4 and CD8 levels were positively related to CIN risk (the 1st versus 4th quartile CD4,CD8 OR=0.45[0.34, 0.60] and 0.34[0.26, 0.45] for CIN1, 0.32 [0.21, 0.48] and 0.24 [0.16, 0.38] for CIN2/3). Increased CD4 and CD8 levels were positively related to the occurrence of CIN(P-overall<0.01).CD4/CD8 levels and the risk of CIN1 followed a nonlinear "U-shape" (P-nonlinear <0.01). IL-10 levels and the risk of CIN1 followed a nonlinear "n-shape"(P-nonlinear <0.01).IL-10 levels were inversely related to the occurrence of CIN2/3(OR=3.87, [2.49, 6.00],P-overall<0.01). The highest risk of CIN was observed in women with high-risk HPV, whose CD4 and CD8 levels were the highest(P-interaction < 0.01).Patients with the lowest IL-10 levels( IL-10≤53.17pg/ml) who are positive for high-risk HPV infection have the highest risk of CIN2/3(OR=18.46,[9.33-36.51]). Nested case-control analysis observed a positive relationship between CD4,CD8 levels, and risk of CIN progression (CD4 OR=0.34,[ 0.13, 0.94];CD8 OR=0.27, [0.09, 0.79]),and an opposite relationship between IL-10 levels and risk of CIN progression (OR=2.92, [1.09, 7.84]). Conclusions: Local vaginal CD4 and CD8 levels were positively correlated with CIN risk, and IL-10 levels were inversely correlated with CIN2/3, whether or not with high-risk HPV infection in Chinese women.