Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks1

  title={Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks1},
  author={Jennifer H. Anolik and Rajan Ravikumar and Jennifer Barnard and Teresa Owen and Anthony Almudevar and Eric C. B. Milner and Chase H. Miller and Paul O. Dutcher and James A. Hadley and I{\~n}aki Sanz},
  journal={The Journal of Immunology},
  pages={688 - 692}
Rheumatoid arthritis (RA) is mediated by a proinflammatory cytokine network with TNF at its apex. Accordingly, drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a… 
High levels of memory B cells are associated with response to a first tumor necrosis factor inhibitor in patients with rheumatoid arthritis in a longitudinal prospective study
In patients with RA, high levels of baseline memory B cells were associated with response to TNFi, which may be related to TNFα-dependent activation of the T helper type 1 cell pathway.
Activated Peripheral Blood B Cells in Rheumatoid Arthritis and Their Relationship to Anti–Tumor Necrosis Factor Treatment and Response: A Randomized Clinical Trial of the Effects of Anti–Tumor Necrosis Factor on B Cells
This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti‐TNF therapy in RA to describe the role of B cells in rheumatoid arthritis synovium.
Modulation of T-cell responses by anti-tumor necrosis factor treatments in rheumatoid arthritis: a review
This could be useful to better understand the therapeutic efficiency and the side effects that are encountered in RA patients, and better targeting of T cells in RA could help set more specific anti-TNF strategies and develop prediction tools for response.
Contrasting contributions of TNF from distinct cellular sources in arthritis
Distinct TNF-producing cell types may modulate disease development through different mechanisms, suggesting that in arthritis TNF ablation from restricted cellular sources, such as myeloid cells, while preserving protective TNF functions from other cell type may be superior to pan-anti-TNF therapy.
Anti-tumour necrosis factor therapy and B cells in rheumatoid arthritis
  • M. Leandro
  • Medicine, Biology
    Arthritis research & therapy
  • 2009
The efficacy of B-cell depletion therapy in rheumatoid arthritis (RA) has led to a renewed interest in B cells and their products and the role they play in the pathogenesis of the disease. Agents
Anti-TNF treatment blocks the induction of T cell-dependent humoral responses
Analysis of longitudinally the effect of TNF blockade on B cell activation and the maturation of humoral responses against TD and T cell-independent vaccines in patients with arthritis indicates that T NF blockade severely impedes the induction of primary TD humoral responds, probably by interfering with the germinal centre reaction.
B cell therapies for rheumatoid arthritis: beyond B cell depletion.
Cell-type–restricted anti-cytokine therapy: TNF inhibition from one pathogenic source
Cell-targeted inhibition of TNF is more effective than systemic TNF ablation in protecting mice from TNF-mediated hepatotoxicity and provides a rationale for the development of novel anti-TNF agents.


Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells.
TNF-alpha is a necessary autocrine growth factor for human B cells stimulated via two independent CsA-sensitive pathways and plays a role similar to that of interleukin 2 in T-cell proliferation.
In Vivo Neutralization of TNF-α Promotes Humoral Autoimmunity by Preventing the Induction of CTL1
A therapeutic TNF-α blockade may promote humoral autoimmunity by selectively inhibiting the induction of a CTL response that would normally suppress autoreactive B cells.
Effects of tumor necrosis factor and lymphotoxin on peripheral lymphoid tissue development.
This work reports that mice which express a tumor necrosis factor receptor p60-Fc fusion protein develop unique lymphoid abnormalities, demonstrating that TNF and LT are crucial for normal peripheral, but not central lymphoid organ development.
Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response
A physiological role for TNF alpha in regulating the development and organization of splenic follicular architecture and in the maturation of the humoral immune response is established.
Distinct Profiles of Human B Cell Effector Cytokines: A Role in Immune Regulation?1
A novel paradigm of reciprocal regulation of B cell effector cytokines is described, and active roles for human B cells are ascribed in either promoting or suppressing local immune responses through context-dependent cytokine production.
Network communications: lymphotoxins, LIGHT, and TNF.
  • C. Ware
  • Biology, Medicine
    Annual review of immunology
  • 2005
Pharmacological disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens, a finding that challenges the molecular paradigms of autoimmunity and perhaps will reveal novel roles for this network in pathogenesis.
Inflammation Controls B Lymphopoiesis by Regulating Chemokine CXCL12 Expression
It is proposed that TNFα and IL-1β transiently specialize the BM to support acute granulocytic responses and consequently promote extramedullary lymphopoiesis.
Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus.
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.
Complementary Effects of TNF and Lymphotoxin on the Formation of Germinal Center and Follicular Dendritic Cells1
It is demonstrated that either T or B cell-derived TNF is sufficient to restore FDC/GC in the presence of LT-expressing B cells, however, TNF itself is not required for GC reactions if the FDC network is already intact.
Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.
In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotRexate, provided significant improvement in disease symptoms at both weeks 24 and 48.