Biology Reference
In-Depth Information
Chapter 25
Systems Immunology: From Cells
and Molecules to a Dynamic
Multi-Scale System
Mark M. Davis
1
and Shai S. Shen-Orr
2
1
Department of Microbiology & Immunology, Howard Hughes Medical Institute, Beckman Center, Room B221, Stanford University School of Medicine,
Stanford, CA 94305, USA,
2
Department of Immunology, Faculty of Medicine, Technion, 1 Efron St. Haifa, 31096, Israel
Chapter Outline
Introduction
481
Limitations of a System-Focused Approach
491
Cell-Focused Systems Immunology
484
Multi-Scale-Focused Systems Immunology
491
Reconstructing Cellular Networks
484
System-Wide Meso-Scale Cellular Automata Models of
Immunity
Exploring Cellular Diversity
486
491
Limitations of a Cell-Focused Approach
487
Statecharts as a Rich Framework to Model Immunity
493
System-Focused Systems Immunology
488
Limitations of a Multi-Scale-Focused Approach
494
Human Immune Monitoring
488
Conclusions and Future Challenges
495
Antibody and TCR Repertoire Diversity
489
References
495
INTRODUCTION
Immunity to infectious diseases is orchestrated by a highly
complex and diffuse system of specialized cells and organs
that flourishes on diversity and is in a constant interplay
with its environment. Leukocytes, or white blood cells,
comprise a large number of the specialized cell types that
constitute the immune system. They reside in different
tissues and organs as well as circulate throughout the blood
and lymphatic system. Leukocytes are derived from
a single type of hematopoietic stem cell in the bone marrow
but go through a differentiation process that ultimately
yields several basic cell types, such as lymphocytes,
monocytes and granulocytes (see
Figure 25.1
A for an
overview of the major cell types). Immune responses in
vertebrates are divided into two major types: innate and
adaptive, whereas invertebrates have just the innate types of
responses. The innate system is specific for broad cate-
gories of molecules, such as double-stranded RNAs or
lipopolysaccharides and other molecules that are charac-
teristic of pathogens, and is comprised of cells and mech-
anisms that form the host's first line of defense. In contrast,
the cells of the adaptive immune system are slower to
respond initially yet have molecules such as antibodies or
T-cell receptors that are specific for particular molecules, as
well as a 'memory'-stage cell that can be maintained for
decades if not throughout an organism's lifetime. The cells
of the innate immune system (dendritic cells, macrophages,
among others) serve as a first line of defense, as well as
trainers and prompters to cells of the adaptive immune
system (lymphocytes), making stimulatory cytokines and
also presenting peptides derived from foreign antigens that
are bound specifically to molecules of the major histo-
compatibility complex (MHC) (peptide-MHC) on the cell
surface of antigen-presenting cells for recognition by T-cell
receptors. Whole antigens are also presented to B cells,
which use cell surface immunoglobulins, which upon
binding a specific antigen stimulate those cells to initiate
a response. As research tools have become more sophisti-
cated, new immune cell subtypes (i.e., cells with differing
functionality at a given condition) are continuously being
discovered such that the estimates for the total number of
distinct cells now numbers in the hundreds. These cells are
the 'quanta' of the immune system, each a largely inde-
pendent agent capable of determining its next action based
on environmental input. The importance of the immune
system to human health is difficult
to overstate. The
