Cervical Intraepithelial Neoplasia Is Associated With Genital Tract Mucosal Inflammation

Abstract

Background Clinical studies demonstrate increased prevalence of human papillomavirus (HPV)-associated disease in HIV-infected individuals and an increased risk of HIV acquisition in HPV-infected individuals. The mechanisms underlying this synergy are not defined. We hypothesize that women with cervical intraepithelial neoplasia (CIN) will exhibit changes in soluble mucosal immunity that may promote HPV persistence and facilitate HIV infection. Methods The concentrations of immune mediators and endogenous anti-Escherichia coli activity in genital tract secretions collected by cervicovaginal lavage were compared in HIV-negative women with high-risk HPV-positive (HRHPV+) CIN-3 (n = 37), HRHPV+ CIN-1 (n = 12), or PAP-negative control subjects (n = 57). Results Compared with control subjects, women with CIN-3 or CIN-1 displayed significantly higher levels of proinflammatory cytokines including interleukin (IL)-1α, IL-1β, and IL-8 (P < 0.002) and significantly lower levels of anti-inflammatory mediators and antimicrobial peptides, including IL-1 receptor antagonist, secretory leukocyte protease inhibitor (P < 0.01), and human β defensins 2 and 3 (P < 0.02). There was no significant difference in endogenous anti-E. coli activity after controlling for age and sample storage time. Conclusion HRHPV+ CIN is characterized by changes in soluble mucosal immunity that could contribute to HPV persistence. The observed mucosal inflammation suggests a mechanism that may also contribute to the epidemiologic link between persistent HPV and HIV.

Role of Cytokines in Genesis, Progression and Prognosis of Cervical Cancer

“…These are secreted as pro-cytokines and are subsequently cleaved to form the smaller cytokine units of about 25 to 33 kDa depending on the exact product. Increased levels of IL-1 α/β and IL-10 were observed in cervicovaginal secretions of women with CIN, HPV and HIV indicating the adverse effect of Sexually transmitted infections on cytokine profile (Mhatre et al, 2012). Both IL-1 α/β act via IL-1RI and the polymorphism of IL-1 as well as its receptor are associated with risk of cancer.…”

“…However biopsy is an invasive procedure and is particularly non-desirable in the younger women desirous of conserving menstrual and childbearing functions. Hence further studies were carried out by authors who have observed that the higher local or circulatory peripheral concentrations of some cytokines are indicative of a higher risk of progression from CIN 1 to CIN 2 or 3 and further to invasive cancer and metastasis (Adam et al, 1999;Fugimoto et al, 2000;Pardo-Govea et al, 2005;Bais et al, 2007;Sharma et al, 2007;Hong et al, 2010;Kemp et al, 2010;Ali et al, 2012;Mhatre et al, 2012;Peghini et al, 2012;Lazarenko et al, 2014). Souza et al (2013) recently demonstrated higher serum concentrations of IL-17, mean-pg/ml: 22.50 in HSIL vs 12.20 in LSIL, and of IL-22, mean pg/ml 168.2 vs 61.48, p<0.05 respectively.…”

Early Defensive Mechanisms against Human Papillomavirus Infection

“…The amounts of Th1-promoting cytokines (IFN-␥, TNF) and Th2-promoting cytokines (IL-6, IL-10) were inversely correlated in HPV-positive samples without dysplasia and CIN1, but these correlations decreased with progressive disease grades, suggesting a role for an impaired immune response in disease progression. Mhatre et al (24) reported that women with negative Papanicolaou test results secreted higher levels of anti-inflammatory markers (IL-1 receptor antagonist, ␤-defensins 1, 2, and 3) and lower levels of proinflammatory cytokines (IL-1␣/␤, CCL5, and CXCL8) than did women with CIN1 and CIN3. IL-1 receptor antagonist and ␤-defensins are normally increased with inflammation and infection (24), so this reciprocal modulation with proinflammatory cytokines suggests dysregulation of the normal cytokine-defensin network.…”

“…Mhatre et al (24) reported that women with negative Papanicolaou test results secreted higher levels of anti-inflammatory markers (IL-1 receptor antagonist, ␤-defensins 1, 2, and 3) and lower levels of proinflammatory cytokines (IL-1␣/␤, CCL5, and CXCL8) than did women with CIN1 and CIN3. IL-1 receptor antagonist and ␤-defensins are normally increased with inflammation and infection (24), so this reciprocal modulation with proinflammatory cytokines suggests dysregulation of the normal cytokine-defensin network.…”

Diagnostic Challenge of Cervical Intraepithelial Neoplasia with Concurrent Follicular Cervicitis: Histomorphological Features and P16 Immunostaining as a Diagnostic Adjunct

“…Conversely strong and diffuse (so-called "block-positive" staining) p16 immunoreactivity strongly favours an interpretation of high grade CIN (CIN2 and CIN3). [1][2][3][4][5][6][7] Consensus recommendations from the Lower Anogenital Squamous Terminology (LAST) project from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology advise pathologists to consider using p16 IHC for equivocal lesions only; when the H&E morphologic differential diagnosis is between a high grade disease and either a high grade mimic, such as immature squamous metaplasia or low grade disease. They state that although the grade of CIN should be based on the H&E histomorphology of the lesion, if a biomarker such as p16 IHC is used, the results may override the original H&E interpretation.…”