Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks

Anolik, Jennifer H.; Ravikumar, Rajan; Barnard, Jennifer; Owen, Teresa; Almudevar, Anthony; Milner, Eric C. B.; Miller, Chase H.; Dutcher, Paul O.; Hadley, James A.; Sanz, Iñaki

doi:10.4049/jimmunol.180.2.688

Cited by 147 publications

(136 citation statements)

References 28 publications

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“…Both cytokines independently or complementarily enhanced the immune responses and augmented inflammation by targeting various immune cells. Particularly, TNF-a has been established as a central player in the pathogenesis of RA (41), TNF-b is required for the formation of germinal center-like structures within the inflamed synovium (42), and our unpublished data suggest that the CD137 expression on peripheral B cells is elevated in autoimmunity (e.g., RA). Therefore, our data suggest that CD137-mediated B cell stimulation might be involved in the pathogenesis of RA.…”

Section: Discussionmentioning

confidence: 99%

CD137 Promotes Proliferation and Survival of Human B Cells

Zhang

Voskens²,

Sallin³

et al. 2009

The Journal of Immunology

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CD137 (4-1BB)-mediated costimulation plays an important role in directing the fate of Ag-stimulated T cells and NK cells, yet the role of CD137 in mediating B cell function is unknown. We found that CD137 is expressed in vitro on anti-Ig–stimulated peripheral blood B cells and in vivo on tonsillar B cells with an activated phenotype. In vitro CD137 expression is enhanced by CD40 stimulation and IFN-γ and is inhibited by IL-4, -10, and -21. The expression of CD137 on activated human B cells is functionally relevant because engagement with its ligand at the time of activation stimulates B cell proliferation, enhances B cell survival, and induces secretion of TNF-α and -β. Our study suggests that CD137 costimulation may play a role in defining the fate of Ag-stimulated human B cells.

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Section: Discussionmentioning

confidence: 99%

CD137 Promotes Proliferation and Survival of Human B Cells

Zhang

Voskens²,

Sallin³

et al. 2009

The Journal of Immunology

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“…One recent study has shown that TNFa blockade reduces the ability of lymphoid tissue to form germinal centers and decreases the number of follicular dendritic cells, raising the possibility that a perturbed germinal center environment induced by TNFa blockade may promote the emergence of a neoplastic B-cell clone. 26 Specific mechanisms by which blockade of CD25, CD11a, or IL-1 receptor signaling may promote lymphoma are unknown. In our series, anti-CD11a therapy was associated with lymphomas (two cases) and non-lymphomatous lymphoid proliferations (one case), with all cases positive for EBV.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulator agent-related lymphoproliferative disorders

Hasserjian

Chen²,

Perkins

et al. 2009

Modern Pathology

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The recent development of inhibitors of key immune response proteins has revolutionized the therapy of autoimmune diseases; these immunomodulator agents include monoclonal antibodies and receptor antagonists. However, as with all therapies, these new agents are not without side effects and complications. In particular, anti-tumor necrosis factor alpha (TNFa) agents have been reported to be associated with an increased incidence of lymphoproliferative disorders, infections, and vasculitis. We evaluated the clinicopathological features of 18 cases of immunomodulator agent-related lymphoproliferative disorders (IAR-LPD) from several institutions. These included 6 cases of B-cell lymphoma, 2 cases of T-cell lymphoma, 3 cases of classical Hodgkin lymphoma, and 7 atypical lymphoid proliferations that did not fulfill diagnostic criteria for lymphoma; two of the latter regressed after discontinuation of the immunomodulator agent therapy. All eight lymphoma patients with available information had also received prior chemotherapy (methotrexate or 6-mercaptopurine). EBV was strongly associated with the B-cell and classical Hodgkin lymphomas. This case series illustrates that a broad range of lymphoid proliferations can occur after immunomodulator agent therapy and that these immunomodulator agent-related lymphoproliferative disorders have considerable overlap with other well-defined lymphoproliferative diseases associated with iatrogenic immunosuppression. Further study is warranted to evaluate how these therapies interact with other immunosuppressive agents and the underlying abnormal immune system to enhance the development of lymphomas and atypical lymphoid proliferations.

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“…In this study, our findings suggest that APCs for B cells of hematopoietic origin, which are significantly depleted after stem cell transplantation, would be largely dispensable for proper reactivation of virusspecific MBCs. Finally, our studies presented herein warrant investigations of the reactivation of virus-specific MBCs under conditions of long-term TNF/LT blockade, which is frequently used for the treatment of rheumatoid arthritis and psoriasis, as it has been recently suggested from the analysis of FDCs and MBC populations in these patients (48).…”

mentioning

confidence: 99%