Immunology

shyam.unniraman@duke.edu

• PhD, Indian Institute of Science (india), 2001
• MS, Indian Institute of Science (india), 1997
• BS, All India Institute of Medical Science, 1974

Mice and men – along with many other organisms – encounter an array of pathogens during their life, and have evolved a complex immune system to protect against infections. A cornerstone of this protection is the process of V(D)J recombination that randomly combines V, D and J segments to generate a large pool of receptors (T cell receptors and antibodies) that can detect any pathogen that invades the host. However, out of necessity, these receptors are generated prior to the actual infection. As a result, in a developing B cell, once an antibody reaches the cell surface, it is primarily selected for its inability to bind components of the host itself. But later in life when antibodies encounter a pathogen, the body now can use this pathogen as a template to generate much better antibodies. This is achieved by somatic hypermutation (SHM) – a process wherein high levels of mutations are introduced into the antibody genes eventually leading to higher affinity antibodies. SHM not only for prevents recurrent infections by a single pathogen, but also forms the basis of protection conferred by many vaccines.

There are several curious features of SHM –
1. It starts with conversion of cytosines to uracils by a protein called activation induced deaminase (AID).
2. It is specific to activated B cells and, within these, to antibody genes.
3. Uracils are one of the most common lesions naturally encountered by normal cells and, therefore, not surprisingly, cells have very robust repair pathways to correct these.
4. But SHM utilizes many of the factors involved in normal repair and perverts them to generate a lot of mutations in the variable region of the antibody genes.
5. AID also produces uracils in the switch regions a few kilobases downstream of the variable region and, again, recruits many of the same repair factors. But here it leads to double strand breaks and class switch recombination (CSR). This allows the cell to generate antibodies of different isotypes and therefore switch effector functions.
6. Most interestingly, despite sharing AID and many repair factors, SHM and CSR can and do occur independent of each other.

Using cell line and transgenic mouse models, we are interested in understanding how SHM and CSR unfold differentially at the molecular level. And why they lead to high levels of mutations and breaks in the immunoglobulin genes while sparing the rest of the genome. This is especially important since mistargeting of these processes can lead to B cell lymphomas and possibly other types of cancers.

• Upton, DC; Gregory, BL; Arya, R; Unniraman, S. AID: a riddle wrapped in a mystery inside an enigma. Immunologic Research: a selective reference to current research and practice. 2011;49:14-24.  Abstract
• Chatterji, M; Unniraman, S; McBride, KM; Schatz, DG. Role of activation-induced deaminase protein kinase A phosphorylation sites in Ig gene conversion and somatic hypermutation. Journal of Immunology. 2007;179:5274-5280.  Abstract
• Unniraman, S; Schatz, DG. Strand-biased spreading of mutations during somatic hypermutation. Science. 2007;317:1227-1230.  Abstract
• Unniraman, S; Schatz, DG. AID and Igh switch region-Myc chromosomal translocations. DNA Repair. 2006;5:1259-1264.  Abstract
• Rush, JS; Liu, M; Odegard, VH; Unniraman, S; Schatz, DG. Expression of activation-induced cytidine deaminase is regulated by cell division, providing a mechanistic basis for division-linked class switch recombination. Proceedings of the National Academy of Sciences of USA. 2005;102:13242-13247.  Abstract
• Unniraman, S; Fugmann, SD; Schatz, DG. Immunology. UNGstoppable switching. Science. 2004;305:1113-1114.  Abstract
• Unniraman, S; Zhou, S; Schatz, DG. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc. Nature Immunology. 2004;5:1117-1123.  Abstract
• Unniraman, S; Nagaraja, V. Catechol dioxygenase is an insensitive reporter for transcription in Mycobacterium smegmatis. BioTechniques: the journal of laboratory technology for bioresearch. 2003;35:256-262.  Abstract
• Unniraman, S; Chatterji, M; Nagaraja, V. A hairpin near the 5' end stabilises the DNA gyrase mRNA in Mycobacterium smegmatis. Nucleic Acids Research. 2002;30:5376-5381.  Abstract
• Unniraman, S; Chatterji, M; Nagaraja, V. DNA gyrase genes in Mycobacterium tuberculosis: a single operon driven by multiple promoters. Journal of Bacteriology. 2002;184:5449-5456.  Abstract
• Unniraman, S; Prakash, R; Nagaraja, V. Conserved economics of transcription termination in eubacteria. Nucleic Acids Research. 2002;30:675-684.  Abstract
• Chatterji, M; Unniraman, S; Mahadevan, S; Nagaraja, V. Effect of different classes of inhibitors on DNA gyrase from Mycobacterium smegmatis. Journal of Antimicrobial Chemotherapy. 2001;48:479-485.  Abstract
• Sikder, D; Unniraman, S; Bhaduri, T; Nagaraja, V. Functional cooperation between topoisomerase I and single strand DNA-binding protein. Journal of Molecular Biology. 2001;306:669-679.  Abstract
• Unniraman, S; Nagaraja, V. Axial distortion as a sensor of supercoil changes: a molecular model for the homeostatic regulation of DNA gyrase. Journal of Genetics. 2001;80:119-124.  Abstract
• Unniraman, S; Prakash, R; Nagaraja, V. Alternate paradigm for intrinsic transcription termination in eubacteria. Journal of Biological Chemistry. 2001;276:41850-41855.  Abstract
• Chatterji, M; Unniraman, S; Maxwell, A; Nagaraja, V. The additional 165 amino acids in the B protein of Escherichia coli DNA gyrase have an important role in DNA binding. Journal of Biological Chemistry. 2000;275:22888-22894.  Abstract
• Parbhane, RV; Unniraman, S; Tambe, SS; Nagaraja, V; Kulkarni, BD. Optimum DNA curvature using a hybrid approach involving an artificial neural network and genetic algorithm. Journal of Biomolecular Structure and Dynamics. 2000;17:665-672.  Abstract
• Unniraman, S; Nagaraja, V. Regulation of DNA gyrase operon in Mycobacterium smegmatis: a distinct mechanism of relaxation stimulated transcription. Genes to Cells. 1999;4:697-706.  Abstract