title: CD21(-/low) marginal zone B cells highly express Fc receptor-like 5 protein and are killed by anti-Fc receptor-like 5 immunotoxins in hepatitis C virus-associated mixed cryoglobulinemia vasculitis.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) is associated with B cell lymphoproliferative disorders, including mixed cryoglobulinemia (MC) vasculitis and B cell non-Hodgkin's lymphoma. The expansion of clonal and autoreactive rheumatoid factor-bearing CD21(-/low) marginal zone (MZ) B cells was demonstrated in patients with HCV-associated MC vasculitis. Fc receptor-like (FCRL) proteins comprise a family of immunoregulatory proteins preferentially expressed on B lineage cells. The goal of this study was to investigate the expression of FCRL proteins 1-5 on B cells from patients with HCV-associated MC vasculitis.
  
  
  METHODS
  Expression of FCRL proteins 1-5 was assessed by flow cytometry on B cells from 15 HCV-infected patients with type II MC (7 of whom had B cell non-Hodgkin's lymphoma), 20 HCV-infected patients without MC, and 20 healthy donors. To evaluate FCRL-5 as an immunotherapy target in HCV-associated MC vasculitis, 2 anti-FCRL-5 recombinant immunotoxins were produced using anti-FCRL-5 monoclonal antibodies and Pseudomonas exotoxin.
  
  
  RESULTS
  Expression of FCRLs 2, 3, and 5 was markedly increased while expression of FCRL-1 was decreased on clonal CD21(-/low) MZ B cells, as compared with other B cell subsets, from HCV-infected patients and healthy donors. However, there was no difference in the pattern of FCRL expression between HCV-MC patients with lymphoma and those without lymphoma. The anti-FCRL-5 immunotoxins showed specific cytotoxicity against FCRL-5-expressing clonal CD21(-/low) MZ B cells isolated from HCV-infected patients as well as FCRL-5-transfected cell lines. No cytotoxicity against T cells or conventional B cells was observed.
  
  
  CONCLUSIONS
  These findings suggest that FCRL-5-targeting therapies could be a specific treatment for HCV-associated MC vasculitis and other FCRL-5-positive autoimmune B cell disorders.
authors: UMR CNRS 7211, INSERM U959, Groupe Hospitalier Pitié-Salpetrière, and Université Pierre et Marie Curie, Paris 6, Paris, France.
authors: Benjamin
authors: B
authors: Terrier
authors: Satoshi
authors: S
authors: Nagata
authors: Tomoko
authors: T
authors: Ise
authors: Michelle
authors: M
authors: Rosenzwajg
authors: Ira
authors: I
authors: Pastan
authors: David
authors: D
authors: Klatzmann
authors: David
authors: D
authors: Saadoun
authors: Patrice
authors: P
authors: Cacoub
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D015897:Comorbidity; D003449:Cryoglobulinemia / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D005098:Exotoxins / Q000378:metabolism; D005260:Female; D016174:Hepacivirus; D006526:Hepatitis C / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D011549:Pseudomonas / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017464:Receptors, Complement 3d / Q000378:metabolism*; D011961:Receptors, Fc; D011971:Receptors, Immunologic / Q000378:metabolism; D014657:Vasculitis / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology
chemical_list: D005098:Exotoxins; C551993:FCRL1 protein, human; C422179:FCRL2 protein, human; C457775:FCRL3 protein, human; C432367:FCRL5 protein, human; D000922:Immunotoxins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D017464:Receptors, Complement 3d; D011961:Receptors, Fc; D011971:Receptors, Immunologic