As new classes of inhibitory RNAs continue to be discovered, researchers also are working on assigning functions to already known inhibitory RNAs, and expanding their toolbox for doing so. In the April 27, 2007 issue of Science, back-to-back papers explore the importance of a specific microRNA for optimal functioning of the adaptive immune response. The papers, along with another recent publication in Science and Cell, debut the use of knockout mice lacking microRNAs rather than proteins.

The first report focuses on the importance of miR-155 for normal functioning of the germinal centers - temporary structure in lymph nodes and spleen that form in response to pathogen exposure to make antibodies.

Those antibodies, which are the heart of the adaptive immune response, are "the good part" of the germinal center, senior author Klaus Rajewsky told BioWorld Today. And the bad part? "In the germinal center, there is a high level of cell proliferation, plus there are mechanisms for modifying DNA. So when things go wrong, you get oncogenic mutations - most human lymphomas arise from the germinal centers."

MiR-155 is overexpressed in many B cell lymphomas, and at the recent annual meeting of the American Association for Cancer Research, there also were presentations showing that it is overexpressed in other cancer types. Rajewsky said that the molecular relationship between miR-155 and cancer, like so much of the mechanics of miRNA operation, still is unclear, though apoptosis and cell cycle control are two possible links. But the link of miRNA to cancer appears to be a general one. "It is becoming clear from a lot of studies that deregulated miRNA is often a factor in carcinogenesis," Rajewsky said.

The paper, however, concentrates on the relationship of miR-155 to immune system functioning. The authors, who hail from Tarrytown, NY-based biotech Regeneron Pharmaceuticals, Harvard Medical School, the Italian FIRC Institute for Molecular Oncology, Brigham and Women's hospital and the German Max-Delbrueck-Center for Molecular Medicine, used both knockouts and gain-of-function experiments to determine the role of miR-155, and found that "when you take away this one miRNA, the germinal center reaction is vastly suboptimal," Rajewsky said. Both B cells and T cells were affected. B cells produced fewer cytokines, while T cells appeared to produce different ratios of helper T cells than control mice. In both cell types, cytokine secretions were abnormal.

In the second paper, scientists from the Wellcome Trust Sanger Institute, the Babraham Institute and the University of Cambridge showed a similar suboptimal immune response in miR-155 knockouts. Although immune system cells appeared to grow normally, T cells and B cells, as well as dendritic cells, performed less well. As a consequence, knockout mice were less able to resist infections than their normal counterparts, producing fewer antibodies and mounting a reduced T-cell response. The British team also found that their knockouts developed lung fibrosis similar to the kind that can complicate human systemic autoimmune disorders.

The authors concluded their study "suggests critical roles for miRNAs in vivo, with potentially severe loss-of-function phenotypes directly relevant to human disease."