title: B cell homeostasis in chronic hepatitis C virus-related mixed cryoglobulinemia is maintained through naïve B cell apoptosis.
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.
  
  
  CONCLUSIONS
  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. (HEPATOLOGY 2012;56:1602-1610).
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Holz
authors.forename: Joo Chun
authors.initials: JC
authors.lastname: Yoon
authors.forename: Sukanya
authors.initials: S
authors.lastname: Raghuraman
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sneller
authors.forename: Barbara
authors.initials: B
authors.lastname: Rehermann
mesh_terms: D000328:Adult; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology / Q000627:therapeutic use; D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D003449:Cryoglobulinemia / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D003450:Cryoglobulins / Q000378:metabolism; D005260:Female; D019698:Hepatitis C, Chronic / Q000150:complications / Q000276:immunology*; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D015260:Neprilysin / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000069283:Rituximab; D018709:Statistics, Nonparametric
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018941:Antigens, CD19; D003450:Cryoglobulins; D007155:Immunologic Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D000069283:Rituximab; D053148:Caspase 3; D053181:Caspase 8; D015260:Neprilysin