F. van Maldegem
- Immunoglobulin gene alterations in normal and neoplastic B cells
C.J.M. van Noesel
- Award date
- 19 November 2009
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
The production of high affinity antibodies is crucial in the combat of pathogenic invaders. Somatic hypermutation and class switch recombination are two DNA modifying processes that take place in the lymph node germinal centres, in order to increase antibody affinity and determine its effector function. However, recurrent subjection of B cells to these immunoglobulin gene alteration processes, due to chronic and recurrent infections or autoimmunity, may lead to accumulation of collateral DNA damage, this way increasing the risk of malignant derailment. This thesis deals with the molecular side of antibody diversification and its role in lymphomagenesis. A putative role for alternative splicing in the regulation of the enzyme responsible for the DNA modifications, i.e. activation-induced cytidine deaminase (AID), is investigated. Structure-function analysis of artificial AID mutants further substantiate this research. The significance of the B cell receptor and its antigen-specificity for lymphoma development, is explored by studying the immunoglobulin sequences of normal germinal centre and malignant lymphoma B cells. Biased immunoglobulin repertoires, in perspective to the genetic and environmental background of these tumours, provide insight in the origin and development of B cell malignancy.
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