In the past few weeks two separate papers, both in Nature, have probed the link between proteins of the coagulation cascade and immune function in three diseases: multiple sclerosis, septic shock and hemorrhagic fevers.

The findings showed that connections between the immune system and coagulation pathways "range from sepsis to autoimmunity, and that is a very impressive swathe of immunology," Lawrence Steinman, who is the senior author of one of those papers, told BioWorld Today.

Clotting proteins play a role in systemic inflammation. Indeed, the only treatment for sepsis, activated protein kinase C, works by inhibiting several clotting factors. In a paper published online Feb. 28, researchers showed that coagulation and inflammation proteins intersect in the immune system's dendritic cells, leading to a positive feedback loop that is responsible for the runaway inflammation that characterizes sepsis.

"It is really the clotting that drives the inflammation," senior author Wolfram Ruf, professor at The Scripps Research Institute, told BioWorld Today. His team's paper noted that the same connection appears to hold in hemorrhagic fevers.

The protease activated receptor, or PAR, is a well-known component of the coagulation cascade. In their paper, Ruf and his colleagues demonstrated that in several sepsis models, if PAR signaling on dendritic cells - a cell type that is important in inflammation but not in blood clotting - was blocked either pharmacologically or through genetic techniques, inflammation and coagulation responses initially developed but then resolved on their own instead of spinning out of control.

Ruf and his colleagues found that in sepsis, dendritic cells are activated by PAR signaling, and in turn activate coagulation proteins, among them sphingosine-1 phosphate or S1P. Dendritic cells also have S1P receptors, and their stimulation leads the cells to migrate out of the lymph nodes and throughout the lymph system.

And when they do, the cytokines they produce end up in the lungs and other organs. In their paper, Ruf and his colleagues call the runaway dendritic cells "a surprisingly simple mechanism for the intimate coupling of exacerbated inflammation and coagulation in deregulated innate immune responses."

By blocking either PAR or S1P receptor signaling on the dendritic cells, the authors were able to prevent dendritic cells from leaving the lymphatic system. Endothelial cell signaling was not necessary for systemic inflammation to occur, showing, Ruf said, that "it is not in the vascular system, but in the lymphatic system, and on the same cell" that coagulation and inflammation intersect.

Ruf said his team's work may show a new strategy for fighting systemic inflammation. In the 1990s, he said, multiple companies tried to target cytokines to treat sepsis. "All those drugs failed, and the reason they failed is that we need these inflammatory cytokines to fight infections" - especially in sepsis, which often is brought on by infection in the first place.

But by targeting PAR1, Ruf said, "it is actually possible to rebalance a systemic inflammatory response and relocalize it back to the lymph nodes, which is the primary place where infections are fought."

Another paper, published online Feb. 17, 2008, reported that a link between coagulation cascade proteins and inflammation also appears to exist in multiple sclerosis, which is due to an autoimmune attack on the myelin sheath that insulates neurons and makes long-distance neural transmission possible.

By a combination of proteomic profiling and bioinformatics, researchers were able to catalog both the proteins that are common to three different types of multiple sclerosis lesions - acute, chronic active and chronic plaque, respectively.

The authors found more than 2,300 proteins that were related to MS lesions, and more than half of those were proteins of unknown function. But five proteins were parts of the coagulation cascade.

Senior author Steinman, professor of neurology and director of the program in immunology at Stanford University and co-founder of a number of biotech companies, said that his team chose those five proteins for further study "in a more or less opportunistic way," because of an educated guess that "coagulation proteins, situated where they are at the blood-brain interface, might have a big role" in MS.

Further experiments bore out that hunch. Steinman and his team were able to use the thrombin inhibitor hirudin on experimental autoimmune encephalitis, the animal model of MS. Xigris, or activated protein kinase C, also lessened the severity of experimental autoimmune encephalitis.

Two modified versions of the protein that had no effect on clotting and on the PAR1 receptor, respectively, were less effective, suggesting, the authors wrote, that "both activities of [activated protein C] may be required for maintaining an extended effect in this model."

Xigris is an approved treatment for sepsis made by Eli Lilly and Co., of Indianapolis, and several researchers from Lilly Research Laboratories are co-authors on the paper.

Asked about the findings' ultimate clinical prospects, Steinman said that the paper showed that Xigris could be modified to be specific for multiple sclerosis without affecting blood clotting, calling it a "remarkable platform" that could give Lilly a potential blockbuster for the treatment of inflammation.