Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus
Corresponding Author
Jennifer H. Anolik
University of Rochester School of Medicine and Dentistry, Rochester, New York
University of Rochester School of Medicine, Box 695, 601 Elmwood Avenue, Rochester, NY 14642Search for more papers by this authorJennifer Barnard
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorAmedeo Cappione
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorAimee E. Pugh-Bernard
National Jewish Medical and Research Center, Denver, Colorado
Search for more papers by this authorRaymond E. Felgar
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorR. John Looney
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorIñaki Sanz
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorCorresponding Author
Jennifer H. Anolik
University of Rochester School of Medicine and Dentistry, Rochester, New York
University of Rochester School of Medicine, Box 695, 601 Elmwood Avenue, Rochester, NY 14642Search for more papers by this authorJennifer Barnard
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorAmedeo Cappione
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorAimee E. Pugh-Bernard
National Jewish Medical and Research Center, Denver, Colorado
Search for more papers by this authorRaymond E. Felgar
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorR. John Looney
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorIñaki Sanz
University of Rochester School of Medicine and Dentistry, Rochester, New York
Search for more papers by this authorAbstract
Objective
B lymphocyte depletion has recently emerged as a promising approach to the treatment of systemic lupus erythematosus (SLE). As part of a phase I/II dose-ranging trial of rituximab in the treatment of SLE, we evaluated the fate of discrete B cell subsets in the setting of selective depletion by anti-CD20 monoclonal antibody and during the B cell recovery phase.
Methods
B cell depletion and phenotype were examined by flow cytometry of peripheral blood mononuclear cells for CD19, CD20, CD27, IgD, and CD38 expression. Changes in autoreactive B lymphocytes and plasma cells were assessed by determination of serum autoantibody levels (anti–double-stranded DNA and VH4.34) and by direct monitoring of a unique autoreactive B cell population bearing surface antibodies whose heavy chain is encoded by the VH4.34 gene segment.
Results
Compared with normal controls, SLE patients displayed several abnormalities in peripheral B cell homeostasis at baseline, including naive lymphopenia, expansion of a CD27−,IgD− (double negative) population, and expansion of circulating plasmablasts. Remarkably, these abnormalities resolved after effective B cell depletion with rituximab and immune reconstitution. The frequency of autoreactive VH4.34 memory B cells also decreased 1 year posttreatment, despite the presence of low levels of residual memory B cells at the point of maximal B cell depletion and persistently elevated serum autoantibody titers in most patients.
Conclusion
This study is the first to show evidence that in SLE, specific B cell depletion therapy with rituximab dramatically improves abnormalities in B cell homeostasis and tolerance that are characteristic of this disease. The persistence of elevated autoantibody titers may reflect the presence of low levels of residual autoreactive memory B cells and/or long-lived autoreactive plasma cells.
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