News about Activation-induced cytidine deaminase : Review article in “Cancer Immunology, Immunotherapy”.
Diana Mechtcheriakova, Martin Svoboda, Anastasia Meshcheryakova & Erika Jensen-Jarolim
zum Vergrößern des Bildes bitte hier klicken.
The research work of Diana Mechtcheriakova and her team aims at the identificationand characterization of novel pathways and targets, contributing to pathophysiological conditions such as inflammation, aberrant immunity, and cancer. One research project focuses on a molecule named activation-induced cytidine deaminase (AID) and addresses the pathogenic potential of AID to link inflammation and cancer.
The discovery of AID strongly influenced our understanding of basic mechanisms for antibody diversity and the field of immunology. AID is considered as the only B cell-specific factor which is absolutely necessary to initiate mutations and DNA-breaks within immunoglobulin genes. Although mutations and gene rearrangements may be regarded as harmful, they can also be beneficial, as evidenced by the fact that B lymphocytes increase the diversity and efficacy of immune responses using the AID-driven, cellular mutation-making machinery.
Thus, a single enzyme modifies DNA to control two very different diversifying phenomena: hypermutation of the variable region and class switch recombination.
Consistent with this, the production of various immunoglobulin isotypes (IgA, IgG1-4) with high affinity for antigen is achieved. To keep in mind, AID activity as well accounts for the IgE subclass of immunoglobulins exhibiting outstanding affinities for their epitopes on allergens and mediating allergic reactions.
AID needs to be tightly regulated and a number of mechanisms restricting AID expression/activity to distinct cell types, time frames and target genes have been identified. However, chronic inflammation in combination with additional, not-yet-identified factors may trigger aberrant AID expression in B cells as well as in other cell types. Under these circumstances, AID may target non-immunoglobulin genes, e.g. those associated with cancer development or progression. Consequently, AID promotes severe multifactorial diseases such as autoimmune disorders, B cell leukemia, lymphoma, and myeloma, or solid tumor development. However, the complete understanding of fundamental aspects is still lacking e.g. (i) what are the crucial factors triggering aberrant AID expression/activity during inflammation and (ii) to what extent may aberrant AID in human B- and non-B cells lead to abnormal cell state associated with an increased rate of genomic alterations as point mutations, small insertions or deletions, and/or recurrent chromosomal translocations during tumor development and progression?
The research group of Diana Mechtcheriakova has developed novel approaches to address these questions. The review presents this methodology and gives an integrated overview on biological processes based on the multigene signature approach followed by creation of AID-associated functional gene network.
Link to Pubmed
http://www.ncbi.nlm.nih.gov/pubmed/22527246
Link to Molecular Systems Biology and Pathophysiology Group at IPA
Schnellinfo
Featured
