Immunohistochemical Detection of the Apoptosis-Related Proteins FADD, FLICE, and FLIP in Langerhans Cell Histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in various organs. The etiology of LCH remains enigmatic. Fas/APO-1/CD95 belongs to the "death receptor" family of apoptosis regulators and has been implicated in the downregulation of immune responses. The authors examined the expression of three proteins that are engaged in the Fas signaling cascade-FADD/Fas-associated death domain-containing protein, FLICE/FADD-like interleukin-1beta-converting enzyme (both pro-apoptotic), and FLIP/FLICE-inhibitory protein (anti-apoptotic)-in lesions from LCH patients. Immunohistochemistry was performed on paraffin-embedded tissue specimens from 43 children with LCH. The infiltrates were scored according to the amount of positive pathologic Langerhans cells (pLCs). In all investigated specimens, the majority of the pLCs expressed FADD, active FLICE, and FLIP. The clinical outcome of the disease could not be correlated to the expression of the investigated proteins. This study shows a high expression of the apoptosis-related proteins FADD, active FLICE, and FLIP in pLCs. The authors previously showed that pLCs express Fas and Fas ligand. Taken together, these findings suggest that the Fas signaling pathway may be involved in the pathogenesis of LCH.

Cell-Specific Gene Expression in Langerhans Cell Histiocytosis Lesions Reveals a Distinct Profile Compared with Epidermal Langerhans Cells

“…BCL2L1 (48,49), CASP3 (48), CASP8 (50), CCL2 (10), CCL20/MIP-3α (51), CD44 (52), CCL22 (10,53,54), CCR6 (51), CCR7 (55), CD11b/ITGAM (25,52,56–58), CD11c/ITGAX (25,38,52,57), CD14 (39), CD1a (Reviewed in 3,4,10), CD2 (25,52,58,59), CD36 (60), CD40 (39,61), CD49d/ITGA4 (25), CD54/ICAM1 (25,52), CD58 (25,52), CD68 (57), CD80 (39), CD83 (39,62), CD86 (39), cdc2a/p16 (49), CD-SIGN/CD209 (63), CFLAR (50), CLA/SELPLG (64), c-myc (65), CXCL11/I-TAC (51), CXCL8/IL-8 (10), DC-LAMP/CD208 (39), E-cadherin/CDH1 (25,26), FADD (50), FAS (66), Fascin/FSCN1 (67,68), FASLG (66), FLT3LG (38), GMCSF/CSF2 (10,69,70), GM-CSFR/CSF2RA (70), H-ras (65), hTERT (71,72), IFNγ (10,23,24), IL-10 (10,32,39), IL-17A (22), IL1R1 (73), IL-1α (10,23,24), IL-1β (10,23,24), IL-2 (10,24), IL-22 (22), IL2Rα/CD25 (58,74,75), IL-3 (10,24), IL-4 (10,23,24), IL-6 (10), Ki67 (…”

PET/CT in nononcological lung diseases: current applications and future perspectives

“…Although pro-inflammatory cytokines IL-17A was found in LCH lesions, the association has yet to be validated [97]. Studies suggest the involvement of vascular endothelial growth factor in LCH development while others found evidence of abnormal apoptosis proteins [98][99][100].…”

Bone metabolism in Langerhans cell histiocytosis

“…The identification of these genomic changes has led to the introduction of agents, such as vemurafenib and trametinib, which target the proteins encoded by these genes, as new treatment options ( 23 , 24 ). In addition, some studies have implicated the expression of vascular endothelial growth factor (VEGF), Bcl-2 family proteins, Fas-signaling and E-cadherin-beta-catenin-Wnt signaling pathways in the pathogenesis of LCH ( 25 , 26 , 27 ).…”