We propose
Langerhans cell histiocytosis (LCH) is an inflammatory process that is prolonged by mutations. We hypothesize that Merkel cell polyomavirus (MCPyV)
infection triggers an
interleukin-1 (IL-1) activation loop that underlies the pathogenesis of LCH. Langerhans cells (LCs) are antigen presenting cells in the skin. When LCs encounter exogenous
antigens, they migrate from the epidermis into draining lymphoid tissues to initiate T-cell activity. It has been proposed that LC migration-related factors, including
E-cadherin,
matrix metalloproteinase, and Notch
ligand induce LCH activity. We found that the
tyrosine phosphatase SHP-1, which binds
IL-1 receptor-associated kinase 1, is expressed at a significantly higher level in LCH affecting multiple organ systems (MS-LCH) than in LCH affecting a single organ system (SS-LCH).
IL-1 stimulates T helper 17 cells and their signature
cytokine IL-17 had been a matter of controversy. We detected higher levels of
IL-17A receptor expression in MS-LCH than in SS-LCH and proposed an
IL-17 endocrine model that could settle the controversy.
IL-1 is the first
cytokine secreted in response to sensitizers and promotes LC migration from sentinel tissues. Myeloid differentiation primary response 88 (MyD88), downstream of the
IL-1 receptor, has functions in both RAS signaling and
inflammation, leading to human cell transformation. In 2010, an activating mutation in the B-rapidly accelerated
fibrosarcoma gene (BRAF) V600E was found in LCH. This BRAF mutation induces phosphorylation of the
extracellular signal-regulated kinase (ERK) that may play an important role with MyD88 in LCH pathogenesis. However, phosphorylated ERK (pERK) is rapidly dephosphorylated by
dual specificity phosphatase 6 (DUSP6), and limited proliferation is predicted in BRAF mutant cells. MyD88 binds pERK via its D-domain, thereby preventing pERK-DUSP6 interaction and maintaining ERK in an active, phosphorylated state. We detected MCPyV-
DNA in the peripheral blood cells of two out of three patients with LCH in high-risk organs but not in those of patients with LCH in non-high-risk organs (0/12; P = .029). MCPyV
infection can trigger precursor LCH cells with BRAF mutation to produce IL-1; the
IL-1 loop is amplified in all LCH subclasses. Our model indicates both BRAF mutation and
IL-1 loop regulation as potential therapeutic targets.