title: Expansion of functionally anergic CD21-/low marginal zone-like B cell clones in hepatitis C virus infection-related autoimmunity.
abstract: Homeostasis of peripheral B cell subsets is disturbed during chronic hepatitis C virus (HCV) infection, leading to the occurrence of autoimmunity and B cell lymphoproliferation. However, mechanisms by which HCV causes lymphoproliferation remain controversial. We report in this article on the elevated number of clonal CD21(-/low)IgM(+)CD27(+) marginal zone (MZ)-like B cells, which correlates with autoimmunity and lymphoproliferation in HCV patients. We found an increase in autoreactive BCRs using V(H)1-69 and V(H)4-34 genes in CD21(-/low) MZ B cells. CD21(-/low) MZ B cells showed impaired calcium-mediated signaling, did not upregulate activation markers, and did not proliferate in response to BCR triggering. CD21(-/low) MZ B cells also were prone to dying faster than their CD21(+) counterparts, suggesting that these B cells were anergic. CD21(-/low) MZ B cells, in contrast, remained responsive to TLR9 stimulation. Gene array analyses revealed the critical role of Early growth response 2 and Cbl-b in the induction of anergy. Therefore, HCV patients who display high frequencies of unresponsive CD21(-/low) MZ B cells are more susceptible to developing autoimmunity and/or lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.
authors.affiliation: Laboratoire I3 Immunologie, Immunopathologie, Immunothérapeutique, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7211 et INSERM U959, Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie, F-75013 Paris, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Terrier
authors.forename: Florence
authors.initials: F
authors.lastname: Joly
authors.forename: Thomas
authors.initials: T
authors.lastname: Vazquez
authors.forename: Philippe
authors.initials: P
authors.lastname: Benech
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Marlène
authors.initials: M
authors.lastname: Garrido
authors.forename: Pascale
authors.initials: P
authors.lastname: Ghillani-Dalbin
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.forename: Patrice
authors.initials: P
authors.lastname: Cacoub
authors.forename: David
authors.initials: D
authors.lastname: Saadoun
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology*; D002999:Clone Cells; D003449:Cryoglobulinemia / Q000276:immunology / Q000473:pathology / Q000821:virology; D005260:Female; D020022:Genetic Predisposition to Disease; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000096:biosynthesis; D017464:Receptors, Complement 3d / Q000096:biosynthesis / Q000378:metabolism*; D013154:Spleen / Q000276:immunology* / Q000473:pathology / Q000821:virology
chemical_list: D011947:Receptors, Antigen, B-Cell; D017464:Receptors, Complement 3d