Differences in the concentration and correlation of cervical immune markers among HPV positive and negative perimenopausal women

Abstract

Introduction Women ≥45 years of age with persistent HPV infections have distinct peripheral circulating immune profiles. Few studies have comprehensively evaluated the cervical immunologic microenvironment in HPV-positive and HPV-negative perimenopausal women. Methods We collected cervical secretion specimens from 34 high risk HPV (HR-HPV) positive and 44 HR-HPV negative women enrolled in an ongoing prospective cohort assessing the natural history of HPV across the menopausal transition. We used these specimens to quantify concentrations of 27 different immune markers using multiplexed bead-based immunoassays. Results HR-HPV positive women had significantly higher median concentrations of IL-5 (0.11 ng/mgtotal protein vs. 0.08 ng/mgtotal protein), IL-9 (2.7 ng/mgtotal protein vs. 2.1 ng/mgtotal protein), IL-13 (2.1 ng/mgtotal protein vs. 0.9 ng/mgtotal protein), IL-17 (2.9 ng/mgtotal protein vs. 1.1 ng/mgtotal protein), EOTAXIN (4.1 ng/mgtotal protein vs. 1.1 ng/mgtotal protein), GM-CSF (4.3 ng/mgtotal protein vs. 3.3 ng/mgtotal protein), and MIP-1α (3.5 ng/mgtotal protein vs. 1.9 ng/mgtotal protein) compared to HR-HPV negative women. A shift in the correlation of T-cell and pro-inflammatory cytokines (IFN-γ, IL-5, IL-9, IL-10, IL-12, IL-13, IL-15, and TNF-α) from IL-2 to EOTAXIN was observed between HR-HPV negative and positive women. Conclusions Higher local concentrations of anti-inflammatory and allergy associated markers, with a shift in T-cell associated cytokine correlation from IL-2 to EOTAXIN, are associated with HPV infection among older women.

IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia

“…Recently, increased IL-17 production has been associated with persistent HPV16/18 infection and cervical epithelial neoplasia and transformation (15, 16). However, the function of IL-17 in viral persistence and premalignant epithelial disease is unknown.…”

Serum levels of soluble interleukin-2 receptor in association with oxidative stress index in patients with different types of HPV

“…Many of the authors have evaluated immune markers that were locally secreted in the cervix, tissue-based immune markers or immune response by patient-derived peripheral blood mononuclear cells (PBMCs) [27][28][29][30]. However, data concerning infection-related immune response in either plasma or serum is limited.…”

Cytokines and Markers of Immune Response to HPV Infection

“…Of the seven cervical secretion studies included in this review, two collected cervical secretions through cervicovaginal lavage (Tjiong, van der Vange et al 2001;Guha and Chatterjee 2009), four used Weck-cel® (Crowley-Nowick, Ellenberg et al 2000; or Merocel® (Lieberman, Moscicki et al 2008;Marks, Viscidi et al 2011) ophthalmic sponges, and one used cytobrush sample suspensions (Scott, Stites et al 1999). Cervicovaginal lavages may not be specific enough to the cervix and may overly dilute the specimen.…”

“…Currently, seven studies that met our inclusion criteria have measured immune responses in cervical secretions (Table 2). Unlike the studies of circulating cytokines above, most of these studies have tested for a broad range of HPV types, although one (Guha and Chatterjee, 2009) only tested for carcinogenic HPV types using the Hybrid Capture 2 assay, and another only analyzed results for women with carcinogenic HPV infection compared to women without carcinogenic HPV infection (Marks, Viscidi et al 2011). Scott et al (Scott, Stites et al 1999) found no statistical differences in IL-10 and IL-12 concentrations by HPV-positivity versus HPV-negativity in women selected from a population-based cohort study in Guanacaste, Costa Rica, after adjusting for stage of menstrual cycle, recent oral contraceptive use secretion volume, and pH.…”

“…This study also evaluated cytokine levels by abnormal versus normal cervical cytology and found that only IL-6 was related to abnormal cytology (P = 0.03). Finally, a recent study by Marks et al (Marks, Viscidi et al 2011) evaluated 27 different cytokines in a multiplex assay in cervical secretions from 35-60-year-old women attending outpatient obstetrics and gynecology clinics for routine examination. Similar to Gravitt et al and Lieberman et al (Lieberman, Moscicki et al 2008), this study found no association between IL-12p70 and HPV status.…”