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Vol. LVII, No. 19
September 23, 2005
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Insights into Inflammation

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 genome-wide interactions.

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 study.