Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is characterized by a clonal proliferation and retention of cells with a Langerhans cell (LC)-like phenotype at various sites within the body. The present study set out to elucidate whether aberrant expression of chemokine receptors or dysregulation of chemokine production in LCH lesions could explain abnormal retention of these cells. Immunohistochemical analysis on 13 LCH biopsies of bone, skin, and lymph node all expressed the immature dendritic cell (DC) marker CCR6 on the lesional LCs and absence of the mature DC marker CCR7. Furthermore, regardless of the tissue site, LCH lesions markedly overexpressed CCL20/MIP-3alpha, the ligand for CCR6. The lesional LCs appeared to be the source of this CCL20/MIP-3alpha production as well as other inflammatory chemokines such as CCL5/RANTES and CXCL11/I-TAC. These may explain the recruitment of eosinophils and CD4+CD45RO+ T cells commonly found in LCH lesions. The findings of this study emphasize that, despite abundant TNF-alpha, lesional LCs remain in an immature state and are induced to produce chemokines, which via autocrine and paracrine mechanisms cause not only the retention of the lesional LCs but also the recruitment and retention of other lesional cells. We postulate that the lesional LCs themselves control the persistence and progression of LCH.

Figure 1.

Expression of CCR6 but not CCR7 by LCH CD1a⁺ cells. Immunofluorescence staining of a representative LCH bone lesion using antibodies specific for CD1a (green), CCR6 (red), and CCR7 (red). Double immunofluorescent staining shows that all the CD1a⁺ cells are positive for CCR6, which appear yellow in the merged image (A). In contrast CCR7 is negative on the CD1a⁺ cells (B). Original magnification 400×.

Figure 2.

High expression level of CCL20/MIP-3α in LCH lesions. Immunohistochemistry was performed with an anti-hCCL20/MIP-3α monoclonal antibody and NovaRed detection. CCL20/MIP-3α was weakly expressed by epidermal keratinocytes in normal skin (A) in contrast to LCH skin lesions where CCL20/MIP-3α expression was greatly up-regulated both in the epidermis and by cells infiltrating the dermis (B). Similarly a high expression level of CCL20/MIP-3α was found in LCH bone and lymph node lesions (C and D, respectively). Original magnification 250×.

Figure 3.

Expression of CCL20/MIP-3α by CD1a⁺ cells in LCH lesions. Immunohistochemistry was performed using antibodies specific for CD1a and CCL20/MIP-3α. The CD1a was detected by an immunogold/silver method (black) and the CCL20/MIP-3α by immunofluorescence (green). The merged image shows the same cells positive for CD1a and CCL20/MIP-3α. Note: the arrow points to endothelial cells expressing CCL20/MIP-3α. Original magnification 400×.

Figure 4.

Lesional CD4⁺ T cells express CCR6. Triple immunofluorescent staining on a representative LCH bone lesion for CD3 (red), CD4 (blue), and CCR6 (green). The intensity profile measured between the arrows demonstrates on two representative cells the three different fluorescent labels. Original magnification 500×.