Ronald Germain, M.D., Ph.D., Chief
The major research activities of Laboratory of Immune System Biology (LISB) are focused on the basic genetics, molecular biology, and cell biology of the immune system, as well as on human disease informed by these more basic studies. How dysregulation of the immune system results in immunodeficiencies, autoimmunity, inflammation, allergy, chronic infections, and lymphoproliferative diseases and what strategies might be valuable for therapeutic or vaccine development related to these conditions as well as cancer are important topics of interest, as is the behavior of the meta-organism (the combination of the host and the commensal microbiota).
A key aspect of LISB research is the development and application of systems and quantitative approaches to dissect how the molecules, cells, and commensals studied by LISB investigators together shape emergent immune system behavior. Modern technology now allows the analysis of immune responses and host-pathogen interactions at a global level, across scales ranging from molecular interactions to intracellular signaling and gene regulatory networks to individual cell behavior to the functioning of a tissue, an organ, and the whole organism. The challenge is to organize and integrate this information to extract biological insights that can help enhance our understanding of how the immune system operates in health or disease or how pathogens affect their hosts. To move towards these goals, LISB scientists seek to collect detailed quantitative as well as qualitative data on the state, organization, and operation of the immune system to develop computational models (mechanistic, statistical, and machine-learning) that can be used to predict the behavior of a complex biological system, uncover the components involved, and help explain the mechanistic basis for physiological and pathological responses to infection or vaccination or to design new therapies or vaccines.
Achieving this goal requires an interdisciplinary effort, and LISB is designed to address this challenge. Although it is composed of independent laboratories, the LISB is intended to operate in many of its research efforts as an integrated group of scientists and support staff. Although it has been established within NIAID, it is expected to play a major role in fostering the growth of immunology and systems biology efforts across the National Institutes of Health (NIH) through its development of software tools for complex systems modeling, new experimental paradigms, advanced imaging modalities, high-throughput screening efforts, and novel approaches to microbiome analysis. LISB members are involved in an extensive web of formal and informal interactions with other intramural NIH scientists and with extramural groups in the United States and abroad that have a common interest in a systems approach to biology in general and immunology in particular.
Major Areas of Research
- Quantitative systems-level studies of humans and of animal models
- Development, differentiation, and plasticity of immune cells, including T cells, B cells, and innate lymphoid cells
- Transcriptional and post-transcriptional regulation of lymphocyte differentiation and function
- Regulation of primary and secondary immune responses
- Mechanisms of pattern recognition and antigen receptor signaling and transcriptional control
- Gene expression profiling, high-content imaging of immune signaling pathways, RNAi and CRISPR/Cas9 for the discovery of pathway components, high-throughput proteomic and genomic analysis
- Translational immunogenomics: integrative analysis of the human immune system’s response to vaccines, medications, and disease states, in vitro and in vivo
- Detection and analysis of gene defects and pathogenetic mechanisms in human inborn errors of immunity
- Single-cell biology: quantitative and functional analysis of cellular heterogeneity and stochastic gene expression
- Advanced dynamic and static multiplex imaging of mouse and human tissues
- RNA-binding protein and miRNA-mediated regulation of immune cells
- Host-pathogen interactions
- Immune-microbiota interactions
- Role of nutrition on the immune system
- Tissue-specific immunity
- Fetal hematopoietic stem cells
- Programmed cell death and autophagy
- Biology of regulatory T cells and their role in autoimmunity and chronic infection
- Induction of T-cell tolerance and treatment of autoimmunity
- Structural and functional studies of macromolecules involved in antigen processing and presentation, adaptive and innate immune recognition, and viral immunoevasion
- Detection and analysis of gene defects pathogenetic mechanisms in human inborn errors of immunity
The Laboratory of Immune System Biology includes the following principal investigators, staff scientists, and/or staff clinicians:
- Iain Fraser, Ph.D.
- Ronald Germain, M.D., Ph.D.
- Sinu P. John, Ph.D.
- Joshua R. Lacsina, M.D., Ph.D.
- Michael Lenardo, M.D.
- Rose Mage, Ph.D.
- Kalpana Manthiram, M.D.
- David H. Margulies, M.D., Ph.D.
- Martin Meier-Schellersheim, Ph.D.
- Stefan Muljo, Ph.D.
- Aleksandra Nita-Lazar, Ph.D.
- Pamela L. Schwartzberg, M.D., Ph.D.
- Ethan M. Shevach, M.D.
- Rachel Sparks, M.D.
- John Tsang, Ph.D.
- Jinfang (Jeff) Zhu, Ph.D.
Simmune is a suite of software tools that guides the user through the multiple hierarchical scales of cellular behavior, facilitating the generation of comprehensive models. It was originally created to simulate immunological phenomena—hence its name, Simmune—but it is applicable to a very broad class of cell biological models.