The pre-B cell receptor and its role in disease

Group leader: This email address is being protected from spambots. You need JavaScript enabled to view it. (Professor, PhD)

B-lymphocytes (cells) are central to the immune system in their role as antibody producing cells. Antibodies, assembled from immunoglobulin (Ig) heavy and light chains, are found on the surface of B cells and in blood. They are protective in that they bind to unique structures on pathogens, which lead to formation of immune complexes that the body can dispose off by different mechanisms. Each B cell synthesises a unique antibody due to a process in which antibody (Ig) gene segments are randomly recombined. This, however, also leads to synthesis of autoantibodies, i.e. antibodies that recognise auto (self) antigens. Autoantibodies are one of the hallmarks of autoimmune disease, eg rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and are involved in organ destruction. Other diseases involving B cells are immunodeficiency, which is characterised by a lack of antibodies (agammaglobulinemia) and is associated with persistent infections. In addition, several cancers are B-lineage derived, eg myeloma, lymphoma and leukaemia. These diseases are complex, including genetic components. Moreover, B cells are an important part in vaccine development and in the use of monoclonal antibodies as therapy for disease.

The research pursued in my lab is focused on the pre-B cell receptor (pre-BCR), a receptor expressed on precursor (pre-) B cells. This receptor is assembled from antibody (Ig) heavy chains and, instead of bona fide Ig light chains, the invariant surrogate light chain. Work from several groups including mine has shown that mutations that affect the expression of the pre-BCR may underpin the development of B cell immunodeficiency, systemic autoimmunity and leukaemia. The aim of my group's current research is to understand the underlying mechanisms that may result in such disparate diseases. We expect our results to increase our understanding of diseases, e.g. immunodeficiency, autoimmunity and cancer.

Important publications:
Mårtensson, I-L., Keenan, RA., and Licence, S 'The pre-B cell receptor' Current Opinion in Immunol. 19: 137-42 (2007)

Keenan RA, De Riva A, Corleis B, Hepburn L, Licence S, Winkler TH and Mårtensson I-L 'Censoring of Autoareactive B Cell Development by the Pre-B Cell Receptor' Science, 321:696-9 (2008)

Daly J, Licence S, Nanou K, Morgan, G. and Mårtensson, I-L 'Transcription of both the productive and non-productive VDJH-recombined allele after Ig heavy chain allelic exclusion' EMBO J 26: 4273-4282 (2007)

Parker, M.J., Licence, S., Erlandsson, L., Galler, G.R., Chakalova, L., Osborne, C.S., Morgan, G., Fraser, P., Jumaa, H., Winkler, T.H., Skok, J. and Mårtensson, I-L 'The pre-B-cell receptor induces silencing of VpreB and l5 transcription' EMBO J. 24:3895-3905 (2005)

Galler, R.G., Mundt, C., Parker, M, Mårtensson, I-L. and Winkler, T 'Surface m heavy chain signals downregulation of the V(D)J-recombinase machinery in the absence of surrogate light chain components' J. Exp. Med. 199:1523-1532 (2004)

Mundt, C., Licence, S., Shimizu, T., Melchers, F. and Mårtensson, I-L 'Loss of precursor B-cell expansion but not allelic exclusion in VpreB1/VpreB2-double deficient mice' J. Exp. Med. 193:435-446 (2001)