title: Persistence of a large population of exhausted monoclonal B cells in mixed cryoglobuliemia after the eradication of hepatitis C virus infection.
abstract: OBJECTIVE
  Functionally exhausted and mostly autoreactive B-cells with a peculiar CD21(low)CD11c(+) phenotype accumulate in several human immunological disorders including common variable immunodeficiency, HIV infection and rheumatoid arthritis. In HCV-associated mixed cryoglobulinemia (MC) there is accumulation of exhausted clonal B cells expressing a V(H)1-69-encoded cross-reactive idiotype; these cells are phenotypically heterogeneous, displaying either a CD21(low)CD11c(+) or a marginal zone (MZ)-like (IgM(+)CD27(+)CD21(+)CD11c(-)) phenotype. Irrespective of their phenotype, V(H)1-69(+) B-cells are unresponsive to the stimulation of Toll-like receptor 9 (TLR9). We investigated the fate of these cells after the eradication of HCV.
  
  
  METHODS
  Fourteen MC patients were studied before and after antiviral therapy. V(H)1-69(+) B-cells were identified using the G6 monoclonal antibody and their phenotype and responsiveness to the stimulation of TLR9 were investigated.
  
  
  RESULTS
  In seven virological non-responders, cryoglobulin levels and the number and phenotype of V(H)1-69(+) B cells remained substantially unchanged. By contrast, in sustained viral responders cryoglobulinemia subsided and the number of V(H)1-69(+) B cells declined. However, high proportions of MZ-like V(H)1-69(+) B cells retaining unresponsiveness to TLR9 stimulation persisted for several months in these patients.
  
  
  CONCLUSIONS
  Clonal expansion of CD21(low) V(H)1-69(+) B cells may depend on continual stimulation by HCV, whereas their MZ-like counterparts may persist for years after the eradication of infection. Prolonged survival of exhausted MZ-like B cells after withdrawal of the initial inciting stimulus may contribute to the accumulation of autoreactive B cells in immunological disorders.
authors.affiliation: Department of Clinical Immunology, Sapienza University of Rome, Viale dell'Università 37, 00185, Rome, Italy. marcella.visentini@uniroma1.it
authors.forename: Marcella
authors.initials: M
authors.lastname: Visentini
authors.forename: Valentina
authors.initials: V
authors.lastname: Conti
authors.forename: Maria
authors.initials: M
authors.lastname: Cagliuso
authors.forename: Giulia
authors.initials: G
authors.lastname: Siciliano
authors.forename: Carolina
authors.initials: C
authors.lastname: Scagnolari
authors.forename: Milvia
authors.initials: M
authors.lastname: Casato
authors.forename: Massimo
authors.initials: M
authors.lastname: Fiorilli
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000097:blood*; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D039521:CD11c Antigen / Q000032:analysis; D003449:Cryoglobulinemia / Q000276:immunology* / Q000821:virology; D003450:Cryoglobulins / Q000032:analysis; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology* / Q000628:therapy; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D017464:Receptors, Complement 3d / Q000032:analysis; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D003450:Cryoglobulins; D007130:Immunoglobulin Idiotypes; D012367:RNA, Viral; D017464:Receptors, Complement 3d; D051217:Toll-Like Receptor 9