title: Regulatory B cells are numerically but not functionally deficient in anti-neutrophil cytoplasm antibody-associated vasculitis.
abstract: OBJECTIVE
  B cells are central to the pathology of ANCA-associated vasculitis (AAV), a disease characterized by autoantibodies and effectively treated by rituximab. In addition to promoting inflammation, a subset of B cells act to suppress harmful autoimmune responses (Breg). The balance of effector and regulatory B cell subsets in AAV is not known. This study was conducted to assess the relative frequency of these subsets during different states of disease activity.
  
  
  METHODS
  B memory (Bmem), naive (Bnaive) and regulatory (Breg) subsets were defined by their relative expression of CD24 and CD38. Function was assessed by cytokine production and suppressive action on CD4(+) Th1 activation evaluated in a co-culture system.
  
  
  RESULTS
  Compared with healthy controls, the frequency of Breg (CD24(hi)CD38(hi)) was significantly reduced during disease remission in both proteinase 3 (PR3)- and MPO-ANCA patients and during acute disease in PR3-ANCA patients, while the frequency of memory cells (CD24(hi)CD38(lo)) was reduced during active disease and restored during remission. Breg cell frequency showed a positive correlation, while Bmem had an inverse correlation with IL-10 production in vitro. B and T cell co-cultures revealed that memory and naive B cell subsets augmented Th1 activation in vitro, which was prevented by Breg, and this pattern did not differ between remission AAV patients and controls.
  
  
  CONCLUSIONS
  In remission there is a numerical, but not functional, deficiency in Breg and preservation of Bmem associated with reduced IL-10 production and increased Th1 activation in vitro. This imbalance may contribute to the high rate of relapse observed in AAV, especially in PR3-ANCA patients.
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK.
authors.forename: Sarah Katrina
authors.initials: SK
authors.lastname: Todd
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Pepper
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK.
authors.forename: Juliana
authors.initials: J
authors.lastname: Draibe
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK.
authors.forename: Anisha
authors.initials: A
authors.lastname: Tanna
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mauri
authors.affiliation: UCL Centre for Nephrology, Royal Free Hospital, Renal and Vascular Inflammation Group, Imperial College London, Hammersmith Hospital and Centre for Rheumatology, University College London, London, UK. a.salama@ucl.ac.uk.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
mesh_terms: D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000188:drug therapy / Q000276:immunology*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D016175:B-Lymphocyte Subsets / Q000276:immunology; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D016022:Case-Control Studies; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D000069283:Rituximab; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000069283:Rituximab
keywords: ANCA-associated vasculitis; B lymphocyte subsets; B regulatory cells
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