title: Delayed memory B cell recovery in peripheral blood and lymphoid tissue in systemic lupus erythematosus after B cell depletion therapy.
abstract: OBJECTIVE
  Recent data suggest that the reconstituting peripheral B cell compartment after B cell depletion therapy may be functionally immature, with a preponderance of transitional B cells and a paucity of memory B cells. This study was undertaken to determine the magnitude, duration, and cause of these defects in rituximab-treated systemic lupus erythematosus (SLE) patients.
  
  
  METHODS
  Fifteen patients with SLE previously treated with rituximab as part of a phase I/II dose-escalation study were evaluated during a long-term followup (mean followup period 41 months). B cells from peripheral blood and tonsils were assessed using multicolor flow cytometry, and their developmental pathway was classified based on the expression of defined surface markers.
  
  
  RESULTS
  Reconstitution of peripheral blood CD27+ memory B cells was delayed for several years after B cell depletion therapy in a subset of patients with prolonged clinical responses and autoantibody normalization. This delay correlated with the degree of expansion of B cells of a transitional phenotype during the B cell reconstitution phase (P = 0.005) and the absence of baseline autoantibodies directed against extractable nuclear antigens (RNP, Sm, Ro antigen, La antigen). Despite the paucity of peripheral blood memory cells and the prolonged expansion of functionally immature transitional B cells, tonsil biopsy tissues revealed active germinal center (GC) reactions, but with decreased Fc receptor homolog 4-positive memory B cells.
  
  
  CONCLUSIONS
  These results suggest heterogeneity in the B cell depletion and reconstitution process that impacts clinical and immunologic outcomes in SLE. The presence of GC reactions, but with altered memory B cell subpopulations in tonsils, suggests that peripheral blood memory cell reconstitution lags behind a slow secondary lymphoid tissue recovery, with important implications for immunologic competence and tolerance.
authors.affiliation: University of Rochester, Rochester, New York 14642, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Anolik
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barnard
authors.forename: Teresa
authors.initials: T
authors.lastname: Owen
authors.forename: Bo
authors.initials: B
authors.lastname: Zheng
authors.forename: Sunil
authors.initials: S
authors.lastname: Kemshetti
authors.forename: R John
authors.initials: RJ
authors.lastname: Looney
authors.forename: Iñaki
authors.initials: I
authors.lastname: Sanz
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes / Q000502:physiology*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007156:Immunologic Memory; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology* / Q000628:therapy*; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab