In medicine, as in the rest of life, it's all very simple in principle: Support the good guys and vanquish the bad ones.

But in medicine, also as in life, the details get complicated fast. In the plethora of pathways and factors that are up- and down-regulated in any disease, telling friend from foe from civilians, and who started what, can be a daunting task.

Multiple sclerosis is a prime example of such confusion. Once MS is in full swing, it's clearly an autoimmune disease, with T cells attacking the myelin sheath that enables the speedy transmission of signals across long axons. But beyond that, things get murky fast. Manolis Pasparakis, professor at the University of Cologne in Germany, told BioWorld Today, "I doubt if T cells are what starts it, and I doubt they are the most crucial component."

So far, Pasparakis acknowledged, there are more possibilities than data about what does start multiple sclerosis. But he and his colleagues published an animal model in an upcoming issue of Nature Immunology, now available via early online publication, that help sort out helpful from harmful factors in multiple sclerosis once it is under way - specifically, by investigating the role of the signaling molecule nuclear factor kappa B or NFkB. Besides the University of Cologne, the researchers hail from the University of Goettingen, also in Germany; the University of Vienna in Austria; the European Molecular Biology Laboratory Mouse Biology Unit in Monterotondo, Italy; and Harvard Medical School in Boston.

NFkB, which actually is a family of five factors, activates gene expression in response to inflammatory cytokines and chemokines, which is what makes it of interest in the study of multiple sclerosis, where its levels are elevated.

But NFkB's role is not limited to inflammation. "It is expressed in most, if not all, cells of the mammalian organism," Pasparakis said. Add to that that it's not a picky molecule: "Almost anything that causes stress can activate the pathway - and then it activates many different genes."

That omnipresence is what made it hard to genetically dissect NFkB's role, since a total knockout does not make it past the fetal stage. Pasparakis and his team created brain-specific knockouts of three upstream activators of NFkB: the proteins NEMO, IKK1 and IKK2.

They found that while the inactivation of IKK1 did not have much of an effect, knocking out NEMO completely blocked the effects of NFkB, and knocking out IKK2 led to what Pasparakis characterized as "severe inhibition" of the pathway. In a surprise finding, both NEMO and IKK2 knockouts had a milder phenotype of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis.

"I was expecting they would show a worse phenotype," Pasparakis said. "But they do not."

Focusing on the NEMO knockouts, which showed the most striking effects with regard to multiple sclerosis phenotype, they found that, as one would expect, T-cell function was unaffected in mice lacking NEMO in the central nervous system. The most likely mechanism for the protective effect of knocking out NEMO was that several proinflammatory cytokines and chemokines were reduced in NEMO knockouts with induced multiple sclerosis.

"What we believe is that NFkB functions as an amplifier of inflammation within the CNS," Pasparakis summarized. "It doesn't start it, but it makes it worse."

Targeting NFkB in the clinic, of course, may prove a task akin to finding a needle in a haystack. A straightforward pharmacological inhibitor of NFkB probably would be just as bad as a global knockout for the health of the organism. Pasparakis acknowledged that translating findings about NFkB's effects into therapies is a difficult problem. But he also pointed out that drugs always have a balance of wanted and unwanted effects.

"I wouldn't lose my hope," he said. "If we manage to gain enough knowledge to understand how the system functions in different cells, we may manage to fine-tune a therapeutic regimen."

In the meantime, the ability to do cell-specific NFkB knockouts should prove to be a boon for a basic understanding of its effects, which may depend very much on the cell type. "Now that we have the capacity to do knockouts of NFkB in different cell types," Pasparakis said, "I think we have some surprises coming up."