Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.

RATIONALE: 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. CONCLUSION: 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.

Bilateral necrobiotic xanthogranuloma of the eyelids followed by a diagnosis of multiple myeloma 20 years later.

A uniquely indolent case of necrobiotic xanthogranuloma with bilateral, periorbital involvement was presented. This patient presented with cutaneous eyelid lesions of 20 years' duration. Although symptomless, the patient underwent testing for hematologic malignancy, which led to a diagnosis of multiple myeloma. A review of the literature revealed that this is the longest interval between the onset of the skin manifestations and the diagnosis of the systemic malignancy in this rare disease.

TIMP-1 Mediates Inflammatory and Immune Response to IL-6 in Adult Orbital Xanthogranulomatous Disease.

Purpose: To explore the pathogenesis that TIMP-1 mediated in adult orbital xanthogranulomatous disease (AOXGD), a rare type of non-Langerhans histiocytosis that damages the appearance and quality of life of patientsMethods: We reviewed 22 patients diagnosed with AOXGD based on clinical manifestations and histological analysis, and then investigated the expression of TIMP-1 and IL-6 with q-PCR and IHC in AOXGD tissues and the possible mechanism involved in the induction of TIMP-1 by IL-6.Results: IL-6 and TIMP-1 were significantly increased in AOXGD tissues. IL-6 promoted TIMP-1 production by M1 macrophages by stimulating the phosphorylation of JAK2 and STAT3. Moreover, IL-17 and IFN-γ, the classical markers of Th1 and Th17 cells, were increased in AOXGD.Conclusion: These data implied that the IL6~JAK2/STAT3-TIMP-1 signalling pathway is activated in AOXGD and that adaptive Th1 and Th17 responses are involved in the development of AOXGD.

Expression of stabilin-1 in M2 macrophages in human granulomatous disease and melanocytic lesions.

Stabilin-1 is an endocytotic scavenger receptor, specifically expressed by non-continuous sinusoidal endothelial cells in the liver, spleen and lymph nodes and by M2 or alternatively activated macrophages in human malignancies. We analysed paraffin-embedded tissue of melanocytic lesions and granulomatous diseases for stabilin-1 expression, using the human/murine RS1 antibody. The specificity of the RS1 staining was confirmed in a knockout model, as only M2-like tumor-associated macrophages and vessels of a B16F10 melanoma in wild type mice stained positive; while staining of tumor-associated macrophages and vessels originating from stabilin-1 deficient mice remained negative for stabilin-1 specific antibody RS1. In human specimens, the RS1 antibody stained tumor-associated macrophages in all pathological stages of melanoma. In addition, five cases of juvenile xanthogranulomas and one case of necrobiotic xanthogranuloma were strongly stabilin-1 positive, while Th-1 cytokine dominated granulomatous diseases such as sarcoidosis and granulomatous leprosy were negative. Stabilin-1 positive vessels were found in all analysed non-Langerhans cell histiocytoses and melanocytic lesions. No stabilin-1 positive vessels were present in any other granulomatous diseases.