Scientific Retreats 2009

Monday, April 6, 2009 (historical)

B Cells in Autoimmune Diseases

This session will explore disease pathogenesis in autoimmune diseases. Specifically, animal models and the success of B cell-targeted therapies in improving disease manifestations in rheumatoid arthritis (RA) and other conditions demonstrate an important role for B cells. However, how B cells contribute to autoimmune diseases in humans is poorly understood in most instances. The purpose of this session is to identify research opportunities for NIAMS to address that will define mechanisms of action of B cells in autoimmune diseases in humans so that more targeted and more effective therapies can be developed.

Background/Relevance to NIAMS Mission

Recently, targeted biologic therapies have shown remarkable success in the treatment of autoimmune diseases, such as RA. The beneficial effect of rituximab in RA has brought B cells back into the spotlight as perpetuators of autoimmune diseases. Rituximab is a human/murine chimeric cytolytic monoclonal antibody that specifically targets the transmembrane protein CD20, which is only expressed on B cells. Rituximab causes a prolonged depletion of circulating B cells in the blood. Rituximab is FDA-approved for the treatment of RA with methotrexate in adult patients with moderately to severely active disease who have inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Newer studies have demonstrated that rituximab is effective in treatment-nave patients and improves X-ray findings in patients who have failed TNF inhibitors. Furthermore, rituximab has recently been used in clinical trials in several other autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis, and type 1 diabetes.

B cells are thought to contribute to autoimmunity through several mechanisms: production of auto-antibodies; antigen presentation and co-stimulation during initiation of immune responses; regulation of secondary lymphoid tissue organization and neogenesis; and release of inflammatory and immunomodulatory cytokines. B cells may also play a role in negative modulation of the immune response through the production of interleukin (IL) 10 by certain B cell subsets. B cell depletion after treatment with rituximab may help reestablish immune homeostasis and tolerance. Clearly, B cells have a multifaceted role in autoimmunity, and may play different roles in different autoimmune diseases or even subtypes of heterogeneous diseases such as SLE. Generally, mechanistic studies of B cell involvement in autoimmune diseases have been developed with mouse models. However, clinical studies using B cell depletion therapy in autoimmune diseases provide the opportunity to develop new insights into disease mechanisms in humans. Additionally, human genetics research informs our understanding of disease mechanisms. Results from genome-wide association studies (GWAS) have been useful for identification of pathogenic pathways and therapeutic targets in complex rheumatic disorders such as RA and SLE.

The NIAMS portfolio of research grants and contracts includes a number of studies relevant to B cells in autoimmune diseases. These studies are varied and include B cell studies in animal models of autoimmune disease, B cell function in human autoimmune diseases, a study of the mechanism of blocking a B cell activation factor (BAFF) in patients enrolled in a clinical trial of the agent for lupus, and a multi-center clinical trial of rituximab in adult and juvenile myositis.

Expected Session Outcomes

The intention of this session is to:

  • inform the audience of the current thinking on the role of B cells in autoimmune diseases;
  • identify opportunities for novel approaches to use information collected from studies of human B cell depletion therapies, clinical trials of other immunomodulators, other clinical studies (e.g., genetics) and animal models to understand the role of B cells in these diseases;
  • clarify research needs and opportunities

Key Questions

Now that we know that B cells contribute to manifestations in diseases such as RA, what are the experimental approaches to define mechanisms?

What have we learned from rituximab?

What are useful biological correlates of effective targeting of B cells? Can experiences from other diseases help us to understand and evaluate potential latency in the appearance of therapeutic response biomarkers in autoimmune diseases?

What are possible reasons that B cell depletion in the clinic has been more successful in RA versus SLE?

What is the role of animal models in further understanding the role of B cells in autoimmune diseases?

What scientific approach(es) would be best to use this information, towards developing effective therapies for a broad range of autoimmune diseases?

How should the NIAMS be involved?