Key Step in Activating Immune System Discovered

The gene, called NIK, helps remove a molecular "brake" that keeps the immune response in check. Its discovery could lead to the development of drugs to regulate the immune system in a variety of diseases. Drugs that block NIK's effects might be designed to inhibit unwanted immune responses in autoimmune diseases such as juvenile diabetes or rheumatoid arthritis. Conversely, drugs that enhance NIK's effects might be designed to augment immunity in immune deficiency diseases.

"NIK activation is a crucial first step in triggering the immune response," said Prof. David Wallach of the Membrane Research and Biophysics Department, who conducted the study with doctoral students Nikolai Malinin, Mark Boldin and Andrei Kovalenko. Wallach notes that many groups of scientists had been looking for this vital initial step.

"Our finding holds potential for the design of future medications to block or enhance the effects of NIK, depending on the kind of disease, although we still need to clarify the exact reactions that this molecule sets off," he says.

Removing the 'Brake'

Scientists have known for some two decades that a protein called NF-B is a key molecule in the immune response. NF-B belongs to the class of proteins known as transcription factors, which "switch on" certain genes and cause particular reactions to take place.

In particular, NF-B switches on several genes involved in the immune and inflammatory responses to disease and infection. But while NF-B is present in all cells at all times, its effects in healthy cells are usually blocked by a "brake," an inhibitory protein known as IB.

In healthy cells, NF-B and IB are physically attached to one another, but in the case of infection or disease, the "brake" is taken off and destroyed, and NF-B is set free.

Wallach and colleagues set out to find what causes the "brake" to be removed and NF-B to be activated. As described earlier, they found that the key initial step in this process is the activation of the NIK protein.

When they genetically manipulated cells to produce large quantities of NIK, the end result was the activation of NF-B. Wallach is now studying whether NIK removes the IB "brake" directly or through other, intermediary steps. He also aims to develop clinical applications for the newly discovered gene and its protein.

Triggering the Development of AIDS

The discovery of NIK may also throw light on the progress of the HIV virus. Scientists suspect that the virus somehow "recognizes" and responds to NF-B, seeing it as a signal to become more active.

This may explain why HIV carriers often develop full-blown AIDS after suffering from another illness: the other illness results in the activation of NF-B, which sets off the immune response necessary to combat that illness; but at the same time the activation of NF-B also spurs on the HIV virus.

The Weizmann Institute identification of NIK as a necessary step in the activation of NF-B may help in the development of drugs that would control NF-B and through it the progress of HIV.

This research was partly funded by grants from Inter-Lab Ltd. of Nes Ziona, Israel; Ares Trading SA of Switzerland; and Israel's Ministry of Science.