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

Annels NE, Da Costa CE, Prins FA, Willemze A, Hogendoorn PC, Egeler RM - J. Exp. Med. (2003)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Leiden University Medical Center, Department of Pediatrics, Division of Immunology, Hematology, Oncology, BMT and Autoimmune Diseases, PO Box 9600, 2300 RC Leiden, Netherlands.

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.

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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×.
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fig4: 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×.

Mentions: One other predominant cell type that infiltrates LCH lesions is the T cell. To characterize these cells further and to try to determine which of the prominently expressed chemoattractants could explain their presence, double and triple immunofluorescent staining was performed. All LCH lesions studied showed a predominance of CD4+ T cells which also displayed a memory/activated type as indicated by their CD45RO+ expression (unpublished data). In addition, a large majority of these T cells expressed CXCR3, a chemokine receptor specific for CXCL11/I-TAC, which is commonly expressed on activated T cells (unpublished data). Due to the enhanced expression of CCL20/MIP-3α in the LCH lesions, expression of its cognate receptor CCR6, on the infiltrating T cells was also investigated. Triple immunofluorescent staining of LCH lesions for CD3, CD4 and CCR6 clearly showed positive staining of CCR6 on the T cell infiltrate (Fig. 4) . Thus, both CXCR3 and CCR6 may explain the presence and retention of the lesional T cells through the aberrant up-regulation of CCL20/MIP-3α and CXCL11/I-TAC by the CD1a+ cells.


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

Annels NE, Da Costa CE, Prins FA, Willemze A, Hogendoorn PC, Egeler RM - J. Exp. Med. (2003)

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×.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193776&req=5

fig4: 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×.
Mentions: One other predominant cell type that infiltrates LCH lesions is the T cell. To characterize these cells further and to try to determine which of the prominently expressed chemoattractants could explain their presence, double and triple immunofluorescent staining was performed. All LCH lesions studied showed a predominance of CD4+ T cells which also displayed a memory/activated type as indicated by their CD45RO+ expression (unpublished data). In addition, a large majority of these T cells expressed CXCR3, a chemokine receptor specific for CXCL11/I-TAC, which is commonly expressed on activated T cells (unpublished data). Due to the enhanced expression of CCL20/MIP-3α in the LCH lesions, expression of its cognate receptor CCR6, on the infiltrating T cells was also investigated. Triple immunofluorescent staining of LCH lesions for CD3, CD4 and CCR6 clearly showed positive staining of CCR6 on the T cell infiltrate (Fig. 4) . Thus, both CXCR3 and CCR6 may explain the presence and retention of the lesional T cells through the aberrant up-regulation of CCL20/MIP-3α and CXCL11/I-TAC by the CD1a+ cells.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Leiden University Medical Center, Department of Pediatrics, Division of Immunology, Hematology, Oncology, BMT and Autoimmune Diseases, PO Box 9600, 2300 RC Leiden, Netherlands.

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.

Show MeSH
Related in: MedlinePlus