Abstract
Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of IgM+CD27+ B cells. These cells display both the features of anergy induced by continual engagement of the B-cell receptor (BCR), such as high expression of phosphorylated extracellular signal-regulated kinase (pERK) and reduced lifespan, and of virus-specific exhaustion, such as CD21low phenotype and a defective response to ligation of BCR and Toll-like receptor 9 (TLR9). MC usually regresses after eradication of HCV with interferon, whose immunomodulatory activity might contribute to this effect. We investigated the phenotypic and functional changes in clonal B cells of MC patients with sustained virologic responses to direct-acting antivirals (DAAs), which lack immunomodulatory properties. We found that high pERK expression and accelerated apoptosis revert within 4 weeks after beginning therapy, whereas clonal B cells unresponsive to TLR9 stimulation persist for at least 24 weeks, although they may partially rescue normal CD21 expression. Thus, similar to mouse models, features of anergy in MC B cells rapidly revert after disengagement from HCV, whereas virus-specific exhaustion imparts a durable inhibitory imprint on cell function. Trea...Continue Reading
References
May 13, 2003·Nature Immunology·Lixin RuiChristopher C Goodnow
May 10, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Maurizio CarbonariMassimo Fiorilli
Oct 4, 2005·Nature Immunology·Stephen B GauldJohn C Cambier
Dec 31, 2005·Nature·Daniel L BarberRafi Ahmed
Jul 21, 2007·Nature Reviews. Immunology·John C CambierBarbara J Vilen
Oct 19, 2007·Blood·Edgar D CharlesLynn B Dustin
Jul 16, 2008·The Journal of Experimental Medicine·Susan MoirAnthony S Fauci
Mar 23, 2011·Blood·Edgar D CharlesLynn B Dustin
May 6, 2011·Blood·Anatoly V RubtsovPhilippa Marrack
May 13, 2011·Blood·Yi HaoMichael P Cancro
Sep 24, 2011·Blood·Marcella VisentiniMassimo Fiorilli
Nov 16, 2011·The Journal of Immunology : Official Journal of the American Association of Immunologists·Benjamin TerrierDavid Saadoun
Mar 3, 2012·Journal of Clinical Immunology·Marcella VisentiniMassimo Fiorilli
Jun 9, 2012·European Journal of Immunology·Marcella VisentiniMassimo Fiorilli
Sep 4, 2012·Autoimmunity Reviews·Marcella VisentiniMassimo Fiorilli
Jan 23, 2014·Blood·Patrick P NgShoshana Levy
May 6, 2014·The Journal of Allergy and Clinical Immunology·Marcella VisentiniMassimo Fiorilli
Dec 20, 2015·Immunological Reviews·Martin S NaradikianMichael P Cancro
Oct 22, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Laura GragnaniAnna Linda Zignego
Dec 8, 2016·Journal of Viral Hepatitis·L-Y ChangD E Kaplan
Citations
Jul 5, 2017·Expert Review of Hematology·Marcella VisentiniMilvia Casato
Jan 29, 2019·Liver International : Official Journal of the International Association for the Study of the Liver·Marcella VisentiniMilvia Casato
May 16, 2019·Current Opinion in Rheumatology·Dario RoccatelloSavino Sciascia
Dec 7, 2018·Cancer·Rashmi Kanagal-ShamannaL Jeffrey Medeiros
Feb 19, 2020·Genes and Immunity·Ylenia A MinafòMarcella Visentini
Aug 2, 2020·Digestive Diseases and Sciences·Ming-Ling ChangRong-Nan Chien
Jul 8, 2017·Blood·David E Kaplan
Oct 17, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Stefania ColantuonoMilvia Casato
Jun 24, 2019·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·Y-T ChengM-L Chang