Plasma proteomics identifies a 'chemokine storm' in idiopathic multicentric Castleman disease.

Abstract

Human Herpesvirus-8 (HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving polyclonal lymphoproliferation with dysmorphic germinal centers, constitutional symptoms, and multi-organ failure. Patients can experience thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly, and normal immunoglobulin levels, - iMCD-TAFRO. Others experience thrombocytosis, milder effusions, and hypergammaglobulinemia, -iMCD-Not Otherwise Specified (iMCD-NOS). Though the etiology is unknown in both subtypes, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin-6 (IL-6). However, approximately two-thirds of patients do not respond to anti-IL-6 therapy; alternative drivers and signaling pathways are not known for anti-IL-6 nonresponders. To identify potential mediators of iMCD pathogenesis, we quantified 1129 proteins in 13 plasma samples from six iMCD patients during flare and remission. The acute phase reactant NPS-PLA2 was the only significantly increased protein (P = .017); chemokines and complement were significantly enriched pathways. Chemokines represented the greatest proportion of upregulated cytokines, suggesting that iMCD involves a chemokine storm. The chemokine CXCL13, which is essential in homing B cells to germinal centers, was the most upregulated cytokine across all patients (log2 fold-change = 3.22). Expression of CXCL13 was also significantly increased in iMCD lymph node germinal centers compared to controls in a stromal meshwork pattern. We observed distinct proteomic profiles between the two iMCD-TAFRO patients, who both failed anti-IL-6-therapy, and the four iMCD-NOS patients, in whom all three treated with anti-IL-6-therapy responded, suggesting that differing mechanisms may exist. This study reveals proteomic differences between flare and remission and the potential to molecularly define iMCD subgroups.

• Authors: Sheila K Pierson, Aaron J Stonestrom, Dustin Shilling, Jason Ruth, Christopher S Nabel, Amrit Singh, Yue Ren, Katie Stone, Hongzhe Li, Frits van Rhee, David C Fajgenbaum
• Journal: American journal of hematology (Am J Hematol) Vol. 93 Issue 7 Pg. 902-912 (07 2018) ISSN: 1096-8652 [Electronic] United States
• PMID: 29675946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Antibodies, Monoclonal
• CXCL13 protein, human
• Chemokine CXCL13
• Chemokines
• Interleukin-6

Topics

• Adult
• Antibodies, Monoclonal (therapeutic use)
• Castleman Disease (blood, etiology)
• Chemokine CXCL13 (metabolism)
• Chemokines (metabolism)
• Female
• Humans
• Interleukin-6 (immunology)
• Male
• Middle Aged
• Plasma (chemistry)
• Proteomics (methods)
• Up-Regulation