CLIP: Computational Laboratory for Immunology & Pathology

Our group combines techniques from dynamic modeling, systems biology and bioinformatics to better understand the immune response. We are particularly interested in the generation and selection of high affinity B lymphocytes in germinal centers during immune and autoimmune responses. Areas of research include the development and application of: (1) model-based techniques for analysis of time-series labeling data from flow cytometry to estimate proliferation, apoptosis and differentiation rates, (2) stochastic models of germinal center population dynamics to link B cell lineage trees with the underlying biology, (3) statistical methods to elucidate B cell somatic hypermutation targeting and to detect selection in Ig V region sequences. We are also interested in developing new computational methods for detecting synergistically regulated genes from large-scale expression experiments (e.g., microarray) combined with computational detection of transcription factor binding sites. As part of PRIME (Program for Research on Immune Modeling and Experimentation), we are developing mathematical models to elucidate the viral mechanisms of induction and subversion of type 1 interferon responses and maturation of dendritic cells by Category A-C viral pathogens.

Software that we have developed can be found here

Selected Research Collaborations

Ann Haberman: In vivo two-photon microscopy of germinal centers

Yoram Louzoun: B cell lineage trees

Michael Robek: Inhibition of HCV replication by interferon

Mark Shlomchik: Affinity maturation and adaptive immunity

David Schatz: Somatic hypermutation and AID targeting

PRIME (Program for Research on Immune Modeling and Experimentation)

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People

Steven H. Kleinstein (PI)

Graduate Students

Christopher R. Bolen
Jamie L. Duke
Mohamed Uduman

Postdocs and Research Associates

Uri Hershberg
Gur Yaari

Bioinformatics Programming

Susanna Marquez

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Recent Publications

Activated germinal center B cells undergo directed migration. Mark J. O'Connor, Anja E. Hauser, Ann M. Haberman and Steven H. Kleinstein. Proceedings of the IEEE International Conference on Bioinformatics & Biomedicine (In Press, 2009).

Salmonella Typhimurium type III secretion effectors stimulate innate immune responses in intestinal epithelial cells. Vincent M. Bruno, Sebastian Hannemann, Maria Lara-Tejero, Richard A. Flavell, Steven H. Kleinstein, and Jorge E. Galan. PLoS Pathogens (2009) 5(8):e1000538.

Getting Started in Computational Immunology. Steven H. Kleinstein. PLoS Computational Biology (2008) 4(8): e1000128.

Interleukin-29 functions cooperatively with interferon to induce antiviral gene expression and inhibit HCV replication. Nicole E. Pagliaccetti, Roger Eduardo, Steven H. Kleinstein, Xinmeng Jasmine Mu, Prasanthi Bandi, and Michael D. Robek. The Journal of Biological Chemistry (2008) Oct 31;283(44):30079-89.

Improved methods for detecting selection by mutation analysis of Ig V region sequences. Uri Hershberg, Mohamed Uduman, Mark J. Shlomchik and Steven H. Kleinstein. International Immunology (2008) May;20(5):683-94.

Two levels of protection for the B cell genome during somatic hypermutation. Man Liu, Jamie L. Duke, Daniel J. Richter, Carola G. Vinuesa, Christopher C. Goodnow, Steven H. Kleinstein and David G. Schatz. Nature (2008) Feb 14;451(7180):841-5.

Definition of Germinal-Center B Cell Migration In Vivo Reveals Predominant Intrazonal Circulation Patterns Anja E. Hauser, Tobias Junt*, Thorsten R. Mempel*, Michael W. Sneddon*, Steven H. Kleinstein*, Sarah E. Henrickson, Ulrich H. von Andrian, Mark J. Shlomchik, and Ann M. Haberman. Immunity (2007) Vol. 26, 655-667.

Mutation parameters from sequence data using graph theoretic measures on lineage trees. Reuma Magori Cohen, Yoram Louzoun and Steven H. Kleinstein. Bioinformatics (2006) Vol. 22 No. 14, e332-e340.

Nonuniform sampling for global optimization of kinetic rate constants in biological pathways. Steven H. Kleinstein, Dean Bottino, Anna Georgieva, Ramesh Sarangapan and G. Scott Lett. Proceedings of the 2006 Winter Simulation Conference (2006).

Estimating hypermutation rates from clonal tree data. Steven H. Kleinstein, Yoram Louzoun and Mark J. Shlomchik. The Journal of Immunology (2003) Vol. 171 No. 9, 4639-4649.

Why are there so few key mutant clones? The influence of stochastic selection and blocking on affinity maturation in the germinal center Steven H. Kleinstein and Jaswinder Pal Singh. International Immunology (2003) Vol. 15 No. 7, 871-884.

Toward quantitative simulation of germinal center dynamics: Biological and modeling insights from experimental validation Steven H. Kleinstein and Jaswinder Pal Singh. The Journal of Theoretical Biology (2001) Vol. 211 No. 3, 253-275.

Simulating the Immune System Steven H. Kleinstein and Philip E. Seiden. Computing in Science and Engineering 69-77. July/August 2000.

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