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Functional Attributes of Mucosal Immunity in Cervical Intraepithelial Neoplasia and Effects of HIV Infection

¹ The Cancer Research Institute and Department of Obstetrics, Gynecology, and Reproductive Sciences, ² the Department of Medicine, ³ the Department of Pathology, and ⁴ the Comprehensive Cancer Center at University of California at San Francisco, San Francisco, California; ⁵ the Connie Wofsy Study Consortium of Northern California, University of California, San Francisco; ⁶ New York City/Bronx Consortium, Bronx-Lebanon Hospital/Montefiore Medical Center, Bronx, New York; ⁷ Maimonides Medical Center, Brooklyn, New York; ⁸ Southern Illinois University School of Medicine, Springfield, Illinois; ⁹ Washington DC Metropolitan Consortium, Washington DC; ¹⁰ University of Southern California Consortium, Los Angeles, California

The role of mucosal immunity in human papillomavirus (HPV)-related cervical diseases is poorly understood. To characterize the local immune microenvironment in cervical intraepithelial neoplasia (CIN) 2/3 and determine the effects of HIV infection, we compared samples from three groups: normal cervix, CIN 2/3 from immunocompetent women (HIV^– CIN 2/3), and CIN 2/3 from HIV seropositive women (HIV⁺ CIN 2/3). CIN 2/3 lesions contained increased numbers of immune cells from both the acquired and innate arms of the immune response in stroma [CD4+ and CD8+ T cells, macrophages, mast cells, B cells, neutrophils, and natural killer (NK) cells] and dysplastic epithelium (CD4+ T cells, macrophages, and NK cells). Immune cells in CIN 2/3 expressed activation markers, as measured by interleukin-2 receptor (IL-2R) and transcription factor T bet. Interferon- production was significantly up-regulated in CIN lesions and was expressed by CD4+ and CD8+ T cells and NK cells, indicating the activation of immune cells. Abundant presence of transforming growth factor-ß+ CD25+ cells in the infiltrates associated with CIN lesions, and of immature CD1a+ dendritic cells expressing IL-10 and transforming growth factor-ß, indicate that CIN is associated with an influx of immune cells that produce a mixture of proinflammatory and regulatory cytokines. In HIV⁺ CIN, immune cell densities (CD4+ T cells, macrophages, neutrophils, and NK cells) and expression of interferon- were significantly decreased compared with HIV^– CIN. Regulatory cytokines were also down-regulated in this group. Therefore, both pro- and anti-inflammatory responses present in CIN 2/3 lesions are suppressed in HIV-seropositive women.

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