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Somatic Hypermutation of the Genome

Description of the research

Recognition and elimination of pathogenic invaders while avoiding damage to host tissues is the foundation of our protective immune system. This requires great precision, which is largely attributable to B cells and antibodies they produce. The antibodies neutralize and activate the elimination of pathogens and recognize malignant host cells. Failures of this system can result in autoimmune diseases, immune deficiencies and cancer.

We study how B lymphocyte antigen receptor (antibody) genes are diversified to optimize recognition of molecular targets. This process is initiated by mutator enzyme AID. While cells generally keep somatic mutations at minimum to avoid genome instability and potential tumorigenesis, the germinal center B lymphocytes undergo somatic hypermutation (SHM) to generate mutations at antigen receptor genes. This physiological process helps to produce an effective and long-term antibody-mediated immune response and underlies successful vaccination. Failure to correctly target SHM can have severe consequences for genome integrity and has been implicated in several forms of cancer, particularly lymphoma and leukemia. Our focus is to understand how SHM machinery is targeted genome wide. We use e.g. reporter assays, genome manipulation and whole genome analysis techniques.

Members of the research group

Paulina Budzyńska, PhD, Post-doctoral researcher
Minna Kyläniemi, PhD, Post-doctoral researcher
Anni Soikkeli, MSc, Doctoral candidate

Selected Publications

Budzyńska PM, Kyläniemi MK, Lassila O, Nera KP, Alinikula J. BLIMP-1 is insufficient to induce antibody secretion in the absence of IRF4 in DT40 cells. Scand J Immunol. Mar;87(3), 2018

Budzyńska PM, Kyläniemi MK, Kallonen T, Soikkeli AI, Nera KP, Lassila O, Alinikula J. Bach2 regulates AID-mediated immunoglobulin gene conversion and somatic hypermutation in DT40 B cells. Eur J Immunol. Jun;47(6):993-1001, 2017

Williams A, Maman Y, Alinikula J and Schatz DG. Bcl6 Is Required for Somatic Hypermutation and Gene Conversion in Chicken DT40 Cells. PLoS One. 11(2):e0149146, 2016

Alinikula J and Schatz DG. Super-Enhancer transcription converges on AID. Cell. 159:1490-1492, 2014

Buerstedde J-M, Alinikula J, Arakawa H, McDonald JJ and Schatz DG. Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. PLoS Biology 12(4): e1001831, 2014

McDonald JJ, Alinikula J, Buerstedde J-M and Schatz DG. A critical context-dependent role for E boxes in the targeting of somatic hypermutation. J Immunol 191(4): 1556-1566, 2013

Alinikula J, Nera K-P and Lassila O. Alternate pathways for Bcl6-mediated regulation of B cell to plasma cell differentiation. Eur J Immunol 41:2404-2413, 2011

 
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 PhD Jukka Alinikula

 
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