Histiocytosis

Abstract

Histiocytoses are a group of pathologies characterized by the pathological accumulation of monocytes and/or dendritic cells. In particular, the best described disease is Langerhansian histiocytosis - associated with the accumulation of a particular category of dendritic cells of partly embryonic origin : Langerhans cells. This disease has been the subject of recent discoveries in the understanding of its pathophysiology. These were described in the lecture and seminar that followed. Langerhansian histiocytosis (LCH) varies in severity - from localized lesions - to multivisceral damage and a particular form of cerebral damage with a much more severe prognosis.

A major advance has been the identification of somatic mutations in certain genes present in Langerhans cells during the course of UC. Characteristic of these mutations is that they involve molecules of the same pathway, known as MAP kinases, which are generally involved in cell activation. These mutations, the most frequent of which affects " BRAF ", are all gain-of-function, i.e. they activate the MAP kinase pathway. As a result, pathological cells - de facto malignant - have a survival advantage, but do not differentiate or migrate normally. As a result, they accumulate in damaged tissues (skin, liver, bone...). It is likely that the severity of the damage depends on the nature of the cell targeted by the mutation. The earlier the mutation occurs in the differentiation stages of Langerhans cells, the more severe the pathology, as a greater number of cells in different tissues are affected. It has even been possible to reproduce the neurological impairment of UC by introducing one of these mutations into an embryonic hematopoietic stem cell which gives rise to microglia cells (cf. lecture 1). Thus, this disease is probably sometimes secondary to a pathological event occurring during embryogenesis ! This improved understanding of the pathophysiology of CCHL has led to the use of drugs that inhibit mutated molecules, and thus the MAP kinase pathway, in the treatment of CCHL and related diseases.