Immunology courses sometimes gloss over innate immunity to focus
on acquired immunity, the system of T cells, B cells and antibodies
that respond to specific antigens. The innate immune system, roaming
scavenger cells that comprise the body's first line of defense,
causes the inflammation that makes a mosquito bite itch and a sore
throat ache, but it can also go into overdrive in the face of severe
burns, trauma or infection, leading to organ failure or even death.
A new study published in Nature takes a major step forward in understanding
innate immunity and the systemic inflammation it can bring.
The study started with a genome-wide expression analysis of four
people infused with endotoxin, a bacterial toxin that activates
the innate immune system, causing inflammation that runs its course
within 24 hours. Four people were used as a control, and the researchers
took blood samples at several points to look at gene expression
in their leukocytes (white blood cells) over time. Of tens of thousands
of genes examined, the researchers identified 3,714 unique genes
whose expression changed in response to the endotoxin.
Experimental data like this can be overwhelming and hard to interpret.
This team of scientists, which was brought together by an NIGMS "glue
grant" and included experts in surgery, critical care medicine,
genomics, bioinformatics, immunology and computational biology,
wanted to identify functional networks involved in the systemic
activation of inflammation. They therefore turned to a new bioinformatics
method to tie their data into all the comprehensive knowledge of
mammalian biology that other researchers have already accumulated.
The group used a knowledge base compiled by Ingenuity Systems,
Inc., of Mountain View, Calif. To build that knowledge base, content
and modeling experts systematically encoded findings in peer-reviewed
publications, incorporating over 200,000 published reports on more
than 9,800 human, 7,900 mouse and 5,000 rat genes. An "interactome," a
molecular network of direct physical, transcriptional and enzymatic
interactions, was computed from this knowledge base to detail molecular
relationships involving over 8,000 genes. This tool enabled the
group to examine their experimental data in the context of known
The group constructed a "prototypic inflammatory cell" containing
292 representative genes involved in inflammation and innate immunity,
and charted its course over time. Then, using the knowledge base
to computationally decipher the networks involved, they identified
well over a thousand genes involved in inflammation. Their analysis
revealed unexpected pathways that will increase our understanding
of inflammation, including the widespread suppression of mitochondrial
energy production and protein synthesis.
According to NIGMS, the team next plans to study both gene and
protein activity in a large group of trauma and burn patients over
longer periods of time. It will be important to confirm whether
these patients in a real-life situation show responses similar
to those of the healthy, endotoxin-challenged subjects in this