Unravelling the antibody deficiency in Ataxia Telangiectasia

M van der Burg

Research Project information

Principal researcher: Associate Professor Mirjam Van der Burg
Institute: Leiden University Medical Centre (LUMC), The Netherlands
Cost: £100,000 over 24 months
Start Date: January 2018

What are the researchers proposing to do?
Ataxia Telangiectasia (A-T) is a rare inherited condition characterised by progressive cerebellar ataxia, chromosomal instability, immunodeficiency, and cancer susceptibility. Patients’ lives are shortened, usually from cancer or chronic lung failure, which is partly due to recurrent infections. They have an increased risk on developing severe infections because of a defect in immunoglobulin/antibody production by white blood cells (i.e. by B-cells). The defect in immunoglobulin production is not seen in every A-T patient to the same extent. Variation is even seen within families carrying the same ATM mutation. A severe antibody deficiency is associated with early-onset A-T and an increased risk for malignancies. Additionally, patients need to be treated with prophylactic antibiotics and intravenous immunoglobulins to prevent severe infections. The aim of this proposal is to unravel the cause of the immunoglobulin production defect in patients with A-T. With a combination of different cellular and molecular techniques, the team will investigate the effect of ATM mutations on the formation of B-cells in bone marrow and on the production of immunoglobulins by B-cells. This will contribute to a better understanding of the condition, and potentially identify new targets for therapy, which is important for improvement of clinical management of the antibody deficiency in A-T.

Why?
Understanding why the immunoglobulin production is hampered in patients with A-T will contribute to better understanding of the condition and could lead to identification of potential targets for therapy, which will contribute to improved clinical management. Earlier and more targeted treatment for A-T patients with severe antibody deficiency could prevent or reduce the number of severe infections and potential organ damage.

How will the research be done?
To investigate the role of ATM in B-cell development in humans and to unravel what causes the diverse antibody deficiency by:

  1. Determining the role of ATM on the formation of B-cells in bone marrow and to investigate why or to what extent the production of B-cells in bone marrow is affected in A-T patients. For this they will be using cell lines, culture systems and bone marrow samples from A-T patients.
  2. Investigating the role of ATM in B-cell differentiation in blood and to investigate the potential of B-cells of A-T patients to produce antibodies in culture, and the focusing on the role of mutant ATM on precursor B-cell development.

By combining these results, the team aim to gain further insight into the mechanism causing the antibody deficiency in patients with A-T.

How could it make a difference to the lives of those affected by A-T?
Understanding why the immunoglobulin production is hampered in patients with A-T will contribute to a better understanding of the condition, and could lead to the identification of potential targets for therapy. In turn this will contribute to improved clinical management, as clinicians could be able to administer treatment earlier and in a more targeted way for A-T patients with severe antibody deficiency. The ultimate aim is to prevent or reduce the number of severe infections and potential organ damage in these patients.