Every time a vaccine or infection triggers an immune response, a DNA-cutting enzyme called AID starts scribbling mutations into antibody genes inside B cells, a process called somatic hypermutation that fine-tunes antibodies to grab hold of pathogens more tightly. This matters because AID does not always stick to its target. It sometimes mutates cancer-causing genes, driving B cell lymphomas, or creates self-reactive antibodies that attack healthy tissue in autoimmune diseases. Researchers know that AID prefers certain DNA sequence motifs, but they do not understand why some motifs mutate far more often than others. Recent evidence suggests a hidden “sequence grammar” in the surrounding DNA controls how efficiently AID works at each motif—but the molecular mechanism remains unknown. This project will use artificial intelligence to predict which genomic features influence mutation rates, then test those predictions experimentally. The team will also compare whether the same rules govern AID’s activity at antibody genes versus its dangerous off-target sites in lymphoma cells. This is fundamental science. It will not produce a vaccine or drug tomorrow. But understanding the grammar of antibody evolution could eventually reveal why some people develop autoimmune diseases or B cell cancers, and point toward ways to steer AID away from dangerous targets—much as past work on DNA repair enzymes unexpectedly led to cancer therapies.
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Background and importance: Antibodies are essential for all long-term serum immunity against pathogens and vaccines. When challenged by infection or vaccination the immune system must produce highly specific and potent antibodies capable of neutralizing any foreign pathogen from a limited number of antibody-encoding genes. At the heart of antibody diversification lies the process of somatic hypermutation (SHM) whereby mutations are introduced into the antibody-encoding genes in B lymphocytes or B cells by the enzyme activation-induced deaminase (AID). Mutations create subtle changes in the "shape" of the antibody which alters its binding strength (also called affinity) for the target antigen on the pathogen or vaccine. However. this mutagenic process is not without risk. For instance, AID has undesirable "off-target" activity at cancer-causing oncogenes, which can lead to various B cell lymphomas. Moreover, SHM can generate self-reactive antibodies targeting healthy tissues that have severe pathological consequences in autoimmune diseases. Therefore, elucidating the mechanism of SHM is essential not only for our fundamental understanding of the immune response but also for our understanding of the origin of autoimmunity and major B cell malignancies. Aims and objectives: During SHM, AID preferentially mutates certain signature DNA sequences (also called sequence motifs). However, some motifs mutate much more frequently than others. Recent research has suggested that the DNA sequences surrounding the mutated motifs play a crucial role in determining mutability, hinting at the existence of a sequence grammar that dictates how efficiently AID acts at a given motif. However, the underlying molecular mechanism is unknown and constitutes a major gap in our knowledge of SHM. Understanding the sequence grammar regulating SHM and, therefore, how antibodies evolve during the immune response, is one of the core areas of research in the field of antibody diversification and the focus of this research proposal. We will approach this question by using the power of artificial intelligence to make predictions about genomic features linked with mutation followed by testing these predictions experimentally. Similarly, we will ask whether the rules governing SHM at antibody genes are the same or different at AID off-target sites in B cell lymphomas. Potential benefits and relevance: By gaining a deeper understanding of SHM biology, our research will paint a clearer picture of how our immune system achieves its impressive adaptability in combating pathogens. In doing so, this research will advance our basic knowledge of the "rules of life", a core priority of the BBSRC's long-term vision.
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