Langerhans’ cell count and HLA class II profile in cervical intraepithelial neoplasia in the presence or absence of HIV infection

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Abstract

Objectives: The progression of immunosuppression in human immunodeficiency virus (HIV)+ women has been correlated with elevated incidence of squamous intraepithelial lesions (SIL), probably indicating the role of local immune milieu. In this study, we analysed S100, and HLA class II molecule expression in cervical biopsies according to HIV status, to the severity of SIL and to human papillomavirus (HPV) type. Methods: Biopsies from 34 HIV+ and 44 HIV− patients with normal cervix or low- or high-grade SIL were studied. Langerhans’ cells (LC) (S100), HLA class II and HLA-DQ molecules were evaluated by immunohistochemistry. HPV detection was performed using polymerase chain reaction (PCR). For statistical analysis Mann–Whitney (P≤0.05) and Spearman test were used. Results: Epithelial S100 and HLA class II density were significantly increased with the severity of lesion (P=0.032; P=0.005). Epithelial S100+ increased in HPV+ (P=0.038), and HLA class II density decreased in HPV 16+ (P=0.035) or 18+ (P<0.0001) samples. HIV infection was associated with increased stromal S100+ (P=0.0005) and decreased HLA class II densities (P=0.0001). Decreased stromal S100+ was observed in women with CD4<500 cells/μl (P=0.050). Among HIV+ patients with SIL, the lowest S100 and epithelial HLA class II densities were detected in women with CD4<200 cells/μl (P=0.045). Conclusions: After the establishment of AIDS, increased numbers of immature LCs and a reduction in HLA class II occurred, possibly turning the cervical milieu more favourable to HPV persistence. HPV 16 and 18 infections may interfere with the antigen presenting activity, possibly as an evasion mechanism.

Introduction

Langerhans’ cells (LC) are the primary cells responsible for antigen processing and peptide presentation to T cells in the uterine cervix, being strategically located in lower strata of the epithelium of vulva, vagina and cervix [1], [2]. These cells represent a small population of bone marrow-derived cells, which can be histologically stained by ATPase, T6, CD1a, S100, MHC class II molecules, co-stimulatory/adhesion molecules and other markers [3]. In contrast, keratinocytes represent 95% of the cervical epithelium cells, may also present MHC class II molecules during inflammation and may provide some accessory co-stimulatory signals to T cells [3], [4].

The mean number of Langerhans’ cells is reported to be reduced in the cervix of women presenting with cervical intraepithelial neoplasia (CIN), harbouring human papillomavirus (HPV) or human immunodeficiency virus (HIV), or both [5], [6], [7]. Overall, most Langerhans’ cells constitutively express HLA class II molecules, and the expression of HLA-DQ molecules by these professional antigen-presenting cells (APCs) has been reported to be upregulated in patients presenting with high-grade squamous intraepithelial lesions (HG-SIL) related to HPV, suggesting that the increased expression of HLA-DQ molecules may be functionally related to the progression of neoplasia [8]. On the other hand, the severity of CIN has also been associated with several immunosuppressive conditions, particularly with HIV-related diseases [9], [10]. HIV-positive women without CIN exhibit increased expression of HLA-DR molecules in epithelial cervix macrophages and a decreased proportion of dendritic cells in the cervical stroma [11].

HIV-positive women have an increased risk of persistent HPV infection and genital lesions; however, the natural history of cervical neoplasia in these patients remains unclear. An inverse correlation between CD4+ cell counts and severity of cervical neoplasia has been reported in these patients, indicating the importance of these cells in local immunomodulation [12]. Despite the studies, documenting the local immune profile in SIL in the general population [13], [14], only few studies were published regarding the features of immune cells in HIV-positive women presenting with CIN, most of them evaluating the S100 protein of Langerhans’ cells [7], [15]. However, no studies have been conducted regarding the evaluation of HLA class II molecules in HPV-related cervical lesions of HIV-positive patients.

In the present study, we analysed the histological pattern of S100, and HLA class II molecule expression in cervical biopsies stratified according to HIV status, to the severity of CIN and to HPV type.

Section snippets

Sample selection

A total of 78 non-pregnant premenopausal patients, colposcopically and cytologically screened for HPV and CIN, seen at four Gynaecological Reference Outpatient Services of the State of São Paulo, Brazil, from 1996 to 2001 were studied. Forty-four HIV-negative women aged 19–50 years (median=36 years), and 34 HIV-positive women aged 19–47 years (median=29 years) were enrolled. According to CDC 1993 classification criteria [16], HIV-positive women were assigned to category 1 when their peripheral

Histopathological features

Cervical specimens collected from HIV-negative patients (n=44) showed normal histology in four cases, LG-SIL in 12 and HG-SIL in 28. Cervical biopsies from HIV-positive women (n=34) showed normal histology in six cases, LG-SIL in 17, and HG-SIL in 11.

Human papillomavirus detection and typing

Among HIV-negative women, HPV DNA was identified in 36/44 (81.8%) cases. HPV 16 was detected in 23/36 (63.9%) of these patients, nine of them (39.1%) presented LG-SIL and 14 (60.8%) HG-SIL. HPV 18 was detected in 14/23 (60.8%) of these patients,

Discussion

A higher prevalence (30–50%) of HPV DNA has been previously reported for HIV-positive women included in category 2 and 3 of CDC classification when compared to HIV-positive category 1 and HIV-negative patients [26]. The increased frequency of HPV DNA in HIV-positive women has been explained by the immunosuppression to which HIV-positive women are submitted, resulting in a more persistent HPV infection in relation to HIV-negative women. Irrespective of HIV status, HPV clearance is deficient in

Condensation

Langerhans’ cells and HLA molecules were evaluated in cervical biopsies from HIV+ and HIV− patients.

Acknowledgements

To Mrs. Ana Maria Anselmi Dorigan for excellent technical assistance. Financial support: FAPESP (97/04490-8 and 01/02908-2-MA Gonçalves).

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