Cell of Origin and Biologic Correlates
Modern classification of the histiocytic diseases subdivides them into dendritic cell-related, monocyte/macrophage-related, or true malignancies. Langerhans cell histiocytosis (LCH) is a dendritic cell disease.[1,2] The Langerhans cells (LCH cells) in LCH lesions are immature dendritic cells making up less than 10% of the cells present in LCH lesions.[3,4] Comprehensive gene expression array data analysis on LCH cells is consistent with the concept that the skin LC is not the cell of origin for LCH. Rather it is likely to be a myeloid dendritic cell, which expresses the same antigens (CD1a and CD207) as the skin LC. This concept was further supported by a study reporting that the transcription profile of LCH cells was distinct from myeloid and plasmacytoid dendritic cells, as well as epidermal LCs.[6,7]
LCH lesions also contain lymphocytes, macrophages, neutrophils, eosinophils, fibroblasts, and sometimes multinucleated giant cells. In the brain, the following three types of histopathologic findings have been described in LCH:
- Mass lesions in meninges or choroid plexus with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes.
- Mass lesions in connective tissue spaces with CD1a-positive LCH cells and predominantly CD8-positive lymphocytes causing an inflammatory response and neuronal loss.
- Predominantly CD8+ lymphocyte infiltration with neuronal degeneration, microglial activation, and gliosis.
Normally, the LC is a primary presenter of antigen to naïve T-lymphocytes. However, in LCH, the pathologic dendritic cell does not efficiently stimulate primary T-lymphocyte responses. Antibody staining for the dendritic cell markers, CD80, CD86, and class II antigens, has been used to show that in LCH, the abnormal cells are immature dendritic cells that present antigen poorly and are proliferating at a low rate.[3,9,10] Transforming growth factor-beta (TGF-beta) and interleukin (IL)-10 are possibly responsible for preventing LCH cell maturation in LCH. The expansion of regulatory T cells in patients with LCH has been reported. The population of CD4-positive CD25(high) FoxP3(high) cells was reported to comprise 20% of T cells and appeared to be in contact with LCH cells in the lesions. These T cells were present in higher numbers in the peripheral blood of patients with LCH than in controls and returned to a normal level when patients were in remission.