Drs. Raphael Szalat and John Pirault contributed equally to this work.
Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy
Version of Record online: 10 FEB 2014
© 2014 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of The Association for the Publication of the Journal of Internal Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Journal of Internal Medicine
Volume 276, Issue 3, pages 269–284, September 2014
How to Cite
Hôpital Saint Louis; EA3963, Université Paris 7 Denis Diderot, INSERM, IFR105, Institut Universitaire d'Hématologie; INSERM, UMR_S939, Dyslipidemia, Inflammation and Atherosclerosis in Metabolic Diseases; UPMC Univ Paris 06, UMR_S939; Institute of Cardiometabolism and Nutrition (ICAN); Assistance-Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris; Service de médecine interne hôpital Nord, Saint-Etienne Cedex 2, France. Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy. J Intern Med 2014; 276: 269–284., , , , , , , , , , , , , , ,
- Issue online: 12 AUG 2014
- Version of Record online: 10 FEB 2014
- Accepted manuscript online: 16 JAN 2014 01:00AM EST
- Fondation de France
- Région Ile-de-France CODDIM
- immune complex;
- monoclonal immunoglobulin;
- necrobiotic xanthogranuloma
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.
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.
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.
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.