UNLABELLED: 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. (HEPATOLOGY 2012;56:1602-1610).
UNLABELLED: 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-infectedpatients with MC. HCVpatients with MC (n = 17) also displayed a reduced number and a reduced frequency of naïve B cells compared with HCV-infectedpatients without MC (n = 19), hepatitis B virus-infectedpatients (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. (HEPATOLOGY 2012;56:1602-1610).
Authors: F Loder; B Mutschler; R J Ray; C J Paige; P Sideras; R Torres; M C Lamers; R Carsetti Journal: J Exp Med Date: 1999-07-05 Impact factor: 14.307
Authors: M E Reff; K Carner; K S Chambers; P C Chinn; J E Leonard; R Raab; R A Newman; N Hanna; D R Anderson Journal: Blood Date: 1994-01-15 Impact factor: 22.113
Authors: Angela Malaspina; Susan Moir; Jason Ho; Wei Wang; Melissa L Howell; Marie A O'Shea; Gregg A Roby; Catherine A Rehm; Joann M Mican; Tae-Wook Chun; Anthony S Fauci Journal: Proc Natl Acad Sci U S A Date: 2006-02-06 Impact factor: 11.205
Authors: Thomas Horvatits; Julian Schulze Zur Wiesch; Susanne Polywka; Gustav Buescher; Marc Lütgehetmann; Elaine Hussey; Karoline Horvatits; Sven Peine; Friedrich Haag; Marylyn M Addo; Ansgar W Lohse; Christina Weiler-Normann; Sven Pischke Journal: Pathogens Date: 2020-09-16