Investigating the role of BCAP in human immunodeficiency and B-cell malignancy

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A functioning immune system is essential for responding to infection and preventing the body attacking itself in autoimmunity or inflammation. Primary Immunodeficiencies (PID) are rare diseases caused by poor functioning of the immune system and are characterised by infections, often with autoimmunity and/or cancer. For some of these PID, an underlying genetic cause has been identified, which allows diagnosis, supports our understanding of how the disease occurs, and can enable the development of new targeted treatments. However, for the majority of PID, the cause is not known.We recently identified an individual with PID and loss of a gene called PIK3AP1, which normally produces a protein named 'B-cell adaptor for phosphoinositide 3-kinase' (BCAP). This protein has been studied in animal models, which have shown BCAP to be important in many parts of the immune system, including: the maturation of B-cells, which produce antibodies to fight bacterial infections; the specialisation and survival of T-cells, which act as helpers to B-cells and are also important in the response to viruses and cancer; and other immune cells, mediating the response to inflammation. Problems with BCAP causing PID in humans have never been described before. However, BCAP has been shown to play a role in certain B-cell blood cancers, where its function can be abnormally increased, contributing to resistance to certain cancer treatments. This project aims to understand how BCAP deficiency causes PID in humans. As a complete lack of B-cells and inability to produce antibodies was the main issue seen in the individual described above, we will first examine how BCAP deficiency causes problems in B-cell numbers and antibody production in humans. We will also investigate whether BCAP deficiency impacts other immune cells, such as T-cells and macrophages, in humans. Finally, as BCAP has been shown to play a role in certain B-cell blood cancers, we will test whether BCAP could be targeted for treatment of these, or other, diseases. To do this, we will use human cell line models of BCAP deficiency and patient cells, to study the role of BCAP in cell signalling pathways. Methods include stimulating BCAP-deficient and healthy cells with substances that are expected to activate a BCAP-associated signalling pathway and measuring whether proteins in the pathway are activated, using a range of laboratory techniques. We will also look at how BCAP protein interacts with other proteins in immune cells, using specialist mass spectrometry that can identify proteins bound to BCAP. We will explore the role of BCAP in B-cell development by investigating at what stage BCAP-deficient stem cells fail to develop into B-cells, and to see if we can rescue this by restoring BCAP expression. Finally, for certain B-cell blood cancers where BCAP-related pathways are known to be affected, we will examine BCAP function, its role in resistance to cancer treatment, and the impact BCAP deficiency may have on halting tumour growth using blood samples from patients. This could lead to the development of new blood cancer treatments.This project represents the most detailed study of human BCAP to date. It will expand our understanding of the role BCAP plays in human immune cells and the genetic causes of PID, as well as assisting diagnosis for other patients. It has implications beyond PID to other disorders, such as B-cell cancers, where targeting B-cell function is a desirable treatment.