Balancing the B Cells

Balancing the B Cells

An important cell in our immune response arsenal is the B cell, a white blood cell that fights infection by producing antibodies. However, if the B cell homeostasis is disrupted some of the cells may produce auto-antibodies which attack host tissue.

Dr Tam Quach, an instructor in the Department of Autoimmune Diseases at The Feinstein Institute for Medical Research, NY, is conducting research in order to establish how certain treatments can lead to the disruption of B cell homeostasis. Tumor Necrosis Factor (TNF) inhibitors as well as biologic anti-inflammatory agents are effective treatments for inflammatory arthritis. In some cases, these treatments alter B cell homeostasis and due to the presence of auto-antibodies some patients develop secondary autoimmune conditions such as lupus.

The Centre of Attention

TNF inhibitors alter B and T cell homeostasis by disrupting the formation of the germinal centre (GC). Germinal centres (GCs) are sites within secondary lymphoid organs – lymph nodes and the spleen, where mature B cells proliferate, differentiate, and mutate their antibody genes during a normal immune response to an infection. These develop dynamically after the activation of follicular B cells by T-dependent antigen. The GC is key for high affinity antigen-specific antibody production and negative selection (where binding to the receptor results in cell death) of autoreactive B cells. Dr Quach used a lupus murine model to examine the mechanisms driving the disruption of B cell homeostasis and autobody production when there was a TNF deficiency. TNF deficiency alone was shown to predisposes B cells to dysregulation via the enhanced presence of proinflammatory cytokine T helper cells. It has been known for some time that these T cells enhance antibody production by B cells. The data collected also indicated that additional secondary factors such as an immune response to microbial stimulation, such as an infection, or a genetic predisposition to autoimmune disease helps to drive formation of dysregulated GCs in TNF deficient mice and/or enhanced autoantibody production.

In the continuation of this study Dr Quach will examine whether B cell dysregulation producing pathogenic autoantibodies occurs via defective regulation of autoreactive B cells generated in the GC reaction or by expansion of autoreactive B cells outside the GC.

Treating the Treatment

Having learnt that autoantibody production from dysregulated B cells in TNF deficient mice occurs via multiple pathways, it will be necessary to study the detailed molecular pathways involved and translate results to a more clinical setting by recruiting RA patients who are starting TNF inhibitor treatment for a translational study. “We hope that by having a thorough understanding the mechanism of action of this TNF deficiency/inhibition, we will able to understand how TNF contributes to regulation of autoimmunity, to develop preventive therapies for patients being treated with TNF inhibition, and also to build predictive models to assess risk of using TNF inhibitors of each RA patient.”

Dr Quach witnessed the real-life impact of these diseases as her aunt was diagnosed with RA. She saw the chronic pain and distortion of joints that are associated with RA and how it prevented her aunt for doing simple tasks such as cooking which was something she had previously loved to do. Inspiring Dr Quach to learn more about the condition and focus her research in a meaningful way. She is hopeful that the findings from her research will go a long way in contributing to an improved quality of life for those afflicted with these conditions.

Not Taking it for Granted

Dr Quach believes that the ANRF grant she received has allowed them in the last year to make large I roads towards their objectives. They have been able to successfully identify the pathways through which B cell regulation is impacted by TNF deficiency. The team has also been able to effectively recruit patients necessary in order to take the next steps in their research. The ANRF grant provided the opportunity for Dr Quach to attend a one-week course, systems biology of diseases, in which she learned about different computational analytic tools for large and complex data, and these tools will be applied to the translational study of their patient cohort. Using the grant in this way also embodied the values of the ANRF that stress the importance of collaboration. Dr Quach established relationships with leaders in bioinformatics and mouse models of B cell tolerance who can aid in taking the project further. A manuscript writing up the findings of this study is currently in preparation and a proposal for a K01 award has been submitted, highlighting the quality of the research that has been undertaken with the ANRF grant.

Dr Quach acknowledges the impact of grants such as these on the career path of early researchers. Based on her current work she has been able to apply for additional funding as her research project grows. In the future it is her goal to develop an independent branch of research in systems immunology and lead her own research group. Having seen the success she has achieved thus far with support from ANRF we are confident that these goals are well within her reach and we look forward to following her career with interest.

 


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ANRF
Article Author
Arthritis National Research Foundation
arthritisresearch@curearthritis.org

The Arthritis National Research Foundation's mission is to provide initial research funding to brilliant, investigative scientists with new ideas to cure arthritis and related autoimmune diseases. Writing articles about the patients affected and the science being done to find a cure shows why we need to come together to #CureArthritis!

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