Dataset Information

Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.

ABSTRACT:

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.

SUBMITTER: Szalat R

PROVIDER: S-EPMC4279948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundC3 glomerulonephritis (GN) is a proliferative GN resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. Dysregulation of the alternative pathway of complement may occur as a result of mutations or functional inhibition of complement-regulating proteins. Functional inhibition of the complement-regulating proteins may result from a monoclonal gammopathy.Study designCase series.Setting & participants32 Mayo Clinic patients with C3 GN, 10 (31%) of whom had evidence of a monoclonal immunoglobulin in serum.OutcomesClinical features, hematologic and bone marrow biopsy findings, kidney biopsy findings, kidney measures, complement pathway abnormalities, treatment, and follow-up of patients with C3 GN that was associated with a monoclonal gammopathy.ResultsMean age of patients with C3 GN associated with monoclonal gammopathy was 54.5 years. Bone marrow biopsy done in 9 patients revealed monoclonal gammopathy of undetermined significance in 5 patients, small lymphocytic lymphoma/chronic lymphocytic leukemia in one patient, and no abnormal clones in the other 3 patients. Kidney biopsy showed membranoproliferative GN with bright capillary wall C3 staining in all 10 patients. Evaluation of the alternative pathway of complement showed abnormalities in 7 of 9 patients tested. No mutation in complement-regulating proteins was detected in any patient. As an index case, one patient with C3 GN and chronic lymphocytic leukemia was treated with rituximab, cyclophosphamide, vincristine, and prednisone, and one patient with C3 GN and monoclonal gammopathy of undetermined significance was treated with dexamethasone and bortezomib. Both patients showed significant decreases in hematuria and proteinuria and stabilization of kidney function.LimitationsStudies to show evidence of direct activation of the alternative pathway by monoclonal immunoglobulin were not done.ConclusionsThe study highlights the association of C3 GN and monoclonal gammopathy, in particular in the older population, and the importance of targeting the underlying hematologic malignancy as an approach to treating C3 GN.