B cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naïve B cell apoptosis

Lauren E. Holz, Joo Chun Yoon, Sukanya Raghuraman, Susan Moir, Michael C. Sneller, Barbara Rehermann

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. Although the formation of inflammation-triggering immune complexes is driven by clonal expansions of autoreactive B cells, we found total B cell numbers paradoxically reduced in HCV-infected patients with MC. HCV patients with MC (n = 17) also displayed a reduced number and a reduced frequency of naïve B cells compared with HCV-infected patients without MC (n = 19), hepatitis B virus-infected patients (n = 10), and uninfected controls (n = 50). This was due to an increased sensitivity of naïve B cells to apoptosis resulting in a reduction in the size of the naïve B cell subset. In addition, 4-fold expansion and skewing (lower T1/T2-ratio) of the immature B cell subset was noted in MC patients, suggesting that apoptosis of naïve B cells triggered the release of B cell precursors from bone marrow in an attempt to maintain normal B cell numbers. Following treatment of MC with the B cell-depleting antibody rituximab, the size of all B cell subsets, the T1/T2-ratio, and the cyroglobulin levels all normalized. Cryoglobulin levels correlated with in vivo proliferation of T2 B cells, suggesting a link between the skewing of the T1/T2 ratio and the formation of immune complexes. Conclusion: This study provides insight into the mechanisms maintaining B cell homeostasis in HCV-induced MC and the ability of rituximab therapy to restore normal B cell compartments.

Original languageEnglish
Pages (from-to)1602-1610
Number of pages9
JournalHepatology
Volume56
Issue number5
DOIs
StatePublished - Nov 2012

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