Heads of Laboratories
Associate Professor
Laboratory of Lymphocyte Biology
Nina.Papavasiliou@rockefeller.edu
One of the unique features of the immune system is that it has evolved to raise antibodies against an unlimited number of antigens, a number too large to be encoded in the genome. At the same time, many pathogens have evolved similar mechanisms to alter their surface antigens, thereby evading the immune response. Dr. Papavasiliou’s research focuses on the different processes that immune cells and certain pathogens, such as parasites, employ to generate surface receptor diversity.
Using a combination of biochemistry, cell and molecular biology, Dr. Papavasiliou is studying the molecular basis of somatic hypermutation, the mutagenic process that, in B lymphocytes, is essential for their ability to recognize diverse antigens. When B cells, specialized cells that produce antibodies against foreign molecules, encounter an antigen, mutations are introduced in the genes of their B cell receptors that recognize that antigen. This process helps some of those B cells to acquire a higher affinity for the antigen, and those cells then become selected for survival; i.e., the immune system selects the B cells that are the best candidates for long-term memory against the antigen. Without somatic hypermutation, an individual may become immunocompromised in the ability to deal with antigens.
Hypermutation in B cells is dependent on a protein called AID (activation-induced cytidine deaminase). When AID is expressed in these cells, it changes cytidine residues in the DNA to uracil, which is then recognized as DNA damage. Normally, the cell repairs uracil lesions by properly converting them back to cytidine; somehow, in B cells the damaged antibody genes are mis-repaired, such that the uracil lesion is converted to thymidine. How AID targets antibody genes for deamination and why uracil lesions in antibody genes are mis-repaired, even though they are properly repaired in all other contexts, are questions under investigation in the Papavasiliou lab.
AID was thought to be exclusively expressed in B cells during antibody maturation. Work in the Papavasiliou lab has shown that AID is also expressed in early progenitor B cells after viral transformation, suggesting that it may constitute an ancient host response to transformation. Since that initial finding, others have shown that AID can be expressed in cancers of various tissues and in some cases (e.g., B cell lymphomas, prostatic carcinomas) it has been demonstrated that AID plays a direct and functional role in driving the cells toward aggressive malignancy. Intriguingly, very recent evidence suggests that AID can also deaminate methylated cytidine to thymidine, which is then repaired to cytidine, effectively demethylating DNA. This new role of AID as a demethylase appears to be important in reprogramming cells toward pluripotency, and is an active interest of the lab especially with regard to the involvement of AID in driving cancer progression and relapse.
Finally, in vertebrate immune systems, AID catalyzed deamination can also result in gene conversion, depending on the DNA repair pathway used to repair the uridine lesion. Recent evidence suggests that gene conversion may be the real driving force behind the generation of adaptive immunity in jawless vertebrates. Gene conversion is also used by some pathogens to specifically evade antibody recognition by diversifying their surface receptors. For instance, surface antigen variation in parasites like the African trypanosome (Trypanosoma brucei, the causative agent of sleeping sickness) is generated by gene conversion between silent cassettes and one active expression site. Understanding the mechanism that initiates targeted gene conversion in these parasites is the third area of interest in the lab (and is an active collaboration with George A.M. Cross’s lab).
CAREER
Originally from Greece, Dr. Papavasiliou received her undergraduate degree in biology, with a minor in German literature, from Oberlin College in 1992. She completed her Ph.D. in molecular immunology in 1998 at The Rockefeller University. After postdoctoral studies at Yale University, Dr. Papavasiliou returned to Rockefeller as assistant professor in 2001, becoming associate professor in 2007.
In 2005 Dr. Papavasiliou received the Alexandrine and Alexander L. Sinsheimer Fund Scholar Award. She is a 2003 Searle Scholar and a 2002 Keck Fellow.
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