title: Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.
abstract: BACKGROUND
  Xanthomatosis associated with monoclonal gammopathy includes hyperlipidaemic xanthoma (HX), normolipidaemic xanthoma (NX) and necrobiotic xanthogranuloma (NXG). All three pathologies are characterized by skin or visceral lesions related to cholesterol accumulation, monoclonal immunoglobulin (MIg) and hypocomplementemia. The pathophysiology underlying NXG remains unknown although the involvement of MIg is suspected.
  
  
  OBJECTIVE
  To provide further insights into the pathophysiology of NXG, we evaluated the plasma lipid phenotype, mechanisms involved in cellular cholesterol accumulation and role of MIg in an analysis of blood and plasma markers of inflammation in 16 patients with xanthomatosis [NXG (n = 8) and NX (n = 8)] associated with monoclonal IgG relative to the relevant controls.
  
  
  RESULTS
  The lipid profile of patients with NXG was characterized by a low HDL-C phenotype and an abnormal distribution of HDL particles. Sera from patients with NXG induced cholesterol accumulation in human macrophages. This accumulation was due in part to a significant reduction in the HDL capacity to promote cholesterol efflux from macrophages, which was not found in the case of NX. The MIg of NXG and NX patients was tested positively by ELISA to recognize a large spectrum of lipoproteins. High plasma levels of pro-inflammatory cytokines (TNFα and IL-6), soluble cytokine receptors (sIL-6R, sTNFRI and sTNFRII), adhesion molecules (VCAM-1 and ICAM-1) and chemokines (MCP-1, IL-8 and MIP-1α) were observed in both patients with NXG and NX, revealing a specific xanthoma inflammatory signature which was inversely correlated with plasma levels of anti-inflammatory HDL. However, patients with NXG were distinguished by elevated levels of IL-15 and a marked increase in the rate of intermediate CD14++CD16+ monocytes.
  
  
  CONCLUSIONS
  This study revealed that NXG is characterized by impaired macrophage lipid homeostasis associated with a systemic inflammatory profile that may result from the interaction of MIg and lipoproteins.
authors.affiliation: Département d'immunologie Clinique, Hôpital Saint Louis, Paris, France; EA3963, Université Paris 7 Denis Diderot, INSERM, IFR105, Institut Universitaire d'Hématologie, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Szalat
authors.forename: J
authors.initials: J
authors.lastname: Pirault
authors.forename: J-P
authors.initials: JP
authors.lastname: Fermand
authors.forename: A
authors.initials: A
authors.lastname: Carrié
authors.forename: F
authors.initials: F
authors.lastname: Saint-Charles
authors.forename: M
authors.initials: M
authors.lastname: Olivier
authors.forename: P
authors.initials: P
authors.lastname: Robillard
authors.forename: E
authors.initials: E
authors.lastname: Frisdal
authors.forename: E F
authors.initials: EF
authors.lastname: Villard
authors.forename: P
authors.initials: P
authors.lastname: Cathébras
authors.forename: E
authors.initials: E
authors.lastname: Bruckert
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.forename: P
authors.initials: P
authors.lastname: Giral
authors.forename: M
authors.initials: M
authors.lastname: Guerin
authors.forename: P
authors.initials: P
authors.lastname: Lesnik
authors.forename: W
authors.initials: W
authors.lastname: Le Goff
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058252:Necrobiotic Xanthogranuloma / Q000209:etiology* / Q000378:metabolism; D010265:Paraproteinemias / Q000209:etiology* / Q000378:metabolism; D010641:Phenotype
chemical_list: D008076:Cholesterol, HDL; D016207:Cytokines; D007074:Immunoglobulin G
keywords: HDL; histiocytes; immune complex; monoclonal immunoglobulin; monocyte; necrobiotic xanthogranuloma