Inverse modulation of intraepithelial Langerhans' cells and stromal macrophage/dendrocyte populations in human papillomavirus-associated squamous intraepithelial lesions of the cervix

Abstract

Ninety-four cervical biopsies from normal tissue to high-grade squamous intraepithelial lesion (SILs) were examined for the presence of intraepithelial Langerhans' cells and subpopulations of stromal macrophages/dendrocytes by immunohistochemistry using anti-S100, -L1, -CD68 and -factor XIIIa antibodies. Human papillomavirus (HPV) detection was performed in all cases by using first a mixture of DNA probes for 14 HPV types commonly found in anogenital biopsies at low stringency conditions (Tm -40 degrees C) and by reanalyzing the tissues at high stringency (Tm -10 degrees C) with HPV 6/11, 16/18 and 31/33/35 biotinylated probe cocktails and individual digoxigenin-labelled probes. SILs and metaplastic tissues were significantly associated with a depletion of S100-positive intraepithelial Langerhans' cells when compared with normal epithelium. In contrast, there was a significant increase in L1-positive stromal macrophages in SIL biopsies compared with normal or metaplastic cervix. A significantly higher density of CD68-positive macrophages was also observed in high-grade SILs compared with normal or metaplastic biopsies and with low-grade SILs. The density of factor XIIIa-positive dendrocytes was found to be higher in SILs compared with metaplastic tissues and in high-grade SILs when compared with normal cervical biopsies. No specific relationship was found between the densities of these cells and the HPV type detected in SILs separated into low grade and high grade. The significance of this inverse modulation of intraepithelial Langerhans' cells and stromal macrophages/dendrocytes in normal and SIL biopsies is discussed in relation to HPV infection and malignant transformation.

Influence of the mucosal epithelium microenvironment on Langerhans cells: Implications for the development of squamous intraepithelial lesions of the cervix

“…Nevertheless, we and others have suggested that other factors may contribute to the sensitivity of the TZ to SIL development. 6,17,18 For example, we have observed that the density of LC is significantly reduced and the immunosuppressive cytokine IL10 is more frequently expressed in the microenvironment of TZ in comparison to the exocervix. 5,6,17 To the contrary, other groups have reported that the density of LC in the TZ is equal to that of the exocervix.…”

“…6,17,18 For example, we have observed that the density of LC is significantly reduced and the immunosuppressive cytokine IL10 is more frequently expressed in the microenvironment of TZ in comparison to the exocervix. 5,6,17 To the contrary, other groups have reported that the density of LC in the TZ is equal to that of the exocervix. 19,20 As an approach to understanding the factors involved in the initiation and progression of SILs, we sought to use a variety of methods to assess the differential density and the antigen presenting function of LC derived from TZ and SILs.…”

In vitro propagated dendritic cells from patients with human-papilloma virus-associated preneoplastic lesions of the uterine cervix: use of Flt3 ligand

“…Moreover, previous studies have reported a depletion and qualitative alterations of Langerhans cells in SIL compared to a normal squamous mucosa during the HPV-associated cervical carcinogenesis [1,45]. This ®nding might be due to an altered generation of DC or to a lack of maturation/migration of DC in relation to a decreased production of chemotactic factors by epithelial cells in the presence of HPV [14].…”

“…Several explanations have been proposed to explain the changes of Langerhans cells locally in SIL [16,21,29]. These lesions develop in the transformation zone of the cervix, where there is a low density of Langerhans cells, even in the absence of HPV infection [1,2,8]. Other authors have suggested that these changes might be due to the cytopathic e ect of the virus [38].…”

Role of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix

“…The squamous epithelium of the cervix is composed not only of keratinocytes (the primary target of HPV) but also of a type of immature dendritic cell (DC), the Langerhans cells (LC), which are important for the immunosurveillance of the squamous epithelium (Romani et al, 2003). Interestingly, the density of LC and their function are significantly reduced in the TZ compared to the ectocervix (Al- Saleh et al, 1995;Giannini et al, 2002), suggesting that keratinocyte/DC interactions could play a role in the establishment of SIL in this region. The production of cytokines/chemokines is necessary to maintain a balanced turnover of LC (Griffiths et al, 2005) and is most likely influenced by the complex differentiation state of keratinocytes, which is altered in metaplastic areas of the TZ and during cervical carcinogenesis (Hubert et al, 1999;Smedts et al, 1992).…”