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Alternative splicing key to autoimmune diseases

by Ruth SoRelle, MPH

Xiao-Feng Yang, MD, PhD

One oddity of the sequencing of the human genome is the paucity of genes – given the number of proteins required to keep the organism and its cells alive.

Clearly, a gene has to be responsible for the production of more than one protein. Alternative splicing – a natural method by which a single gene makes different forms of proteins – is one way that occurs. Now Xiao-Feng Yang, MD, PhD, assistant professor in the Biology of Inflammation Center and the departments of medicine and immunology at Baylor College of Medicine, says that this phenomenon could also be the key to development of autoimmmune diseases, such as lupus, rheumatoid arthritis, or type 1 diabetes.

Alternative splicing is a method by which the human body's 20,000 to 25,000 genes can make myriad proteins needed for operation of the body's various tissues. As the cell goes through the process of transcribing a gene into messenger RNA that becomes the template for making a protein in the protein making machine -- ribosomes , certain control element can eliminate or include some of the coding regions of the gene, resulting in a different form of the protein.

In a report in a recent issue of the Journal of Allergy and Clinical Immunology, Yang said that if the alternative splicing results in a form of protein that is sufficiently different from that made in early development, the immune system might mistake it for a foreign protein and initiate an attack that results in an immune disease.

"When these isoforms (different protein forms) get above a threshold of difference, immune tolerance to self-proteins breaks down. The immune system starts to attack the proteins and the cells in which they are found," he said.

"There is a potential for a therapeutic effect," he said. "You could find a way to block the troubling form of the protein or to block the immune system's response to it."

To prove his point, he and his colleagues examined 45 self-proteins associated with various autoimmune diseases and compared them with 9554 proteins randomly selected form the human genome. Alternative splicing within specific regions occurred in 100 percent of the proteins called autoantigens. This was significantly higher than the rate of 42 percent found in the 9554 randomly selected proteins.

"In the autoimmune process, why does the immune system pick one cell's proteins to attack and not another?" he said.

He and his colleagues think, from their study of the 45 autoantigen proteins that in the process of editing out some of coding portions of the protein a little new bump or loop called an epitope is formed on the surface of the autoantigen protein. Inflammation can cause the formation of the epitope. This epitope could provide an "irritant" that makes the immune system think the protein is foreign. The immune system, as it is designed, attacks the protein it thinks is foreign.

While his paradigm has been proven in some experimental systems and remains to be proven as a general theory, Yang hopes that others follow suit, trying to prove or disprove his theory. Others who participated in the research include Drs. Bernard Ng, Fan Yang, David P. Huston, Yan Yan, Yu Yang, Zeyu Xiong, Leif E. Peterson and Hong Wang.

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