Pathogenesis of histiocytoses

Langerhans cell histiocytosis (LCH) is a disease of unknown etiology showing clonal proliferation of Langerhans-like cells or their precursors [1, 16]. Pathologic LCH cells appear to be in an immature state of activation and/or differentiation [1]. They accumulate in peripheral tissue and express inflammatory cytokines resulting in their own recruitment and retention [21]. Moreover, activated CD40 ligand expressing T helper cells are found to be the predominant source of cytokines and growth factors in LCH lesions [3]. The “cytokine storm” seems to be further enhanced by the interaction of CD40 expressing LCH cells and CD40 ligand expressing T-cells [3]. High levels of granulocyte-macrophage colony-stimulating factor, tumor-necrosis factor alpha, interleukin-3, and other cytokines are potential chemoattractants for recruiting eosinophils, neutrophils, marcrophages, and CD34+ Langerhans cell precursors into the LCH lesion [3, 7]. These cytokines are known to contribute directly to the development of fibrosis, necrosis, and osteolysis [11]. They are also supposed to play a role in the presence of several other myeloid cell types; the multinucleated giant cell (MGC), amongst others, was found in LCH lesions [8]. MGCs are believed to play a major role in tissue destruction, as they are express osteoclast markers [8]. Remarkably, though various inflammatory cytokines are present in LCH lesions, LCH cells remain immature and do not maturate [3]. Lesional microenvironment seems to play a role in the maintenance of the phenotype of LCH cells [3]