Toll Receptors and Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis is a clonal proliferative disease of antigen presenting cells. Clinically, it is associated with aberrant secretion of cytokines from both Langerhans cells (LCs) themselves and immune cells associated with the disease. Toll-like receptors (TLRs) are membranous and cytoplasmic proteins involved in pattern-based recognition of bacterial and viral products. Activation of TLRs results in production of pro-inflammatory cytokines, modulation of the immune response, and maturation of LCs. TLRs activate signal transduction pathways involving IRFs (interferon regulatory factors), NFkB (Nuclear Factor-k-B) and MAPK (mitogen activated protein kinases).

In this study, we have examined LCH samples for their expression of TLRs and downstream effector proteins.

We examined archived samples from 42 LCH patients. Paraffin embedded samples were sectioned and stained for immunohistochemistry (IHC) using antibodies directed against TLR1-9; IRF3, 7 and 8; MEK1/2 and ERK1/2. RNA was isolated from the same samples using laser-capture microdissection, and the expression of TLR receptors, effectors and downstream targets was analyzed using qRT-PCR. These data were compared with gene expression data published in Gene Expression Omnibus using data set GSE16395.

IHC results showed upregulation in pathologic LCs compared to normal LCs of TLR 1, 3, 5, 7, 8 and 9, but not TLR 4 and 6. Moreover, upregulation of downstream pathways involving MEK1/2 and ERK1/2 and IRF8 in was also observed in pathologic LCs. Gene expression analysis showed up-regulation of the effectors of TLRs including CASP8, MAP3K7, and PPARA as well as genes in the NFKB pathway (CCL2, NFKb1, NFKB2, NFKBIL1, NFRKB, and REL), the JNK/p-38 pathway (ELK1, c-FOS, MAP3K1 and MAP3K8), and the interferon regulatory factor pathway (CXCL10, IRF7, IRF8 and TBK1). Comparison with the gene expression data base confirmed the results obtained from qRT-PCR for the gene expression of TLRs, their effectors, and downstream.

Upregulation of TLRs and the pathways they control occurs commonly in LCH. Therapies directed toward inhibition of TLRs and their downstream targets may provide a means of modulating the adverse inflammatory aspects of LCH.

No relevant conflicts of interest to declare.