Etiological and clinical studies of Langerhans Cell Histiocytosis (LCH)

Abstract: Langerhans cell histiocytosis (LCH) is a rare disease of unknown origin. LCH may occur at any age but affects mainly children and the most severe forms of the disease are seen in the youngest children. In LCH, granulomatous lesions are formed in various organs. These lesions always contain CD1a+ dendritic cells (LCH DCs), and multinucleated giant cells (MGCs) of unknown origin are also commonly seen in the lesions. The course of LCH is extremely variable ranging from self-healing, solitary lesions in the bone or the skin, to recurrent multiple lesions or progressive disseminated forms of the disease. Recently, a mutation in BRAF, a pivotal kinase in the RAS-RAF-MAPK signaling pathway, important for cell survival and proliferation, was identified in LCH DCs. Still it is, however, not known whether the disease has a neoplastic origin or whether it is triggered by inflammatory stimuli allowing for secondary pro-survival mutations to take place. In terms of survival, the prognosis is usually good except for children with severe disseminated forms of the disease, but long term permanent consequences of LCH are common. One severe complication is a slowly developing neurodegeneration, linked to CNS inflammation, which may develop in around 10-25% of the children. In spite of improved therapies for LCH in general, the cause of the neurodegenerative process and how it can be haltered is still unknown. Once MRI changes are evident, substantial neuronal loss has already occurred. Therefore, it would be valuable to detect signs of ongoing neurodegeneration earlier than with MRI. This would also provide an opportunity to more promptly evaluate treatment interventions. In paper I in this thesis we evaluated the presence of three well-known biomarkers in the cerebrospinal fluid (CSF) of children with radiologically manifest neurodegeneration; NF-L, TAU and GFAp. The results indicate that patients with neurodegenerative LCH have elevated levels of at least one CSF biomarker and that NF-L, TAU and GFAp analyzed together may be useful to detect ongoing neurodegeneration in LCH. NF-L might be of special interest as a marker of progressive neurodegeneration. However, further studies are needed to evaluate this. Previous register studies have indicated an overrepresentation of LCH among Swedish children born after in vitro fertilization (IVF) 1982-2005. By confirming the diagnoses and characterizing the disease in these children, in paper II we verified a, possibly temporary, overrepresentation of LCH in children born after IVF, which was not due to over-diagnosis of mild forms of the disease. The reasons for this finding, that might provide a clue to the origin of LCH, are however, still unknown. The possible correlation between IVF and LCH should also be confirmed in independent studies from other countries. IL-17A is a pro-inflammatory cytokine involved in the pathogenesis of many chronic inflammatory disorders. In papers III, IV and V we investigated how IL-17A affects monocyte-derived immature dendritic cells (mo-DCs) and a possible role for IL-17A in LCH. We found that IL-17A modifies mo-DCs to cells with a mixed macrophage-DC phenotype, spontaneously resistant to apoptosis, associated with up-regulation of the pro-survival protein BCL2A1. IL-17A-treated DCs were prone to undergo cell fusion to form MGCs and expressed a variety of pro-inflammatory molecules, in many ways resembling LCH DCs. We also found that IL-17A was present in LCH lesions and that mo-DCs from LCH patients secreted IL-17A, in contrast to cells from healthy donors. Moreover, Mo-DCs from LCH patients also expressed BCL2A1 and underwent cell fusion spontaneously, a process that was dependent on IL-17A. The significance of IL-17A in the pathogenesis of LCH is under debate. Yet, our findings indicate a role for this cytokine in LCH where IL-17A might contribute to the pro-inflammatory, tissue degrading environment, characteristic for LCH lesions, and an inefficient immune response resulting in the failure of the body to clear the LCH lesions. Moreover, IL-17A may contribute to an increased viability of LCH DCs allowing for formation of MGCs and pro-survival mutations to take place.