More MS news articles for January 2001

Mutation in CD45 Leads to Autoimmune Disease in Mice

http://www.medscape.com/reuters/prof/2001/01/01.03/20010102scie005.html

WESTPORT, CT (Reuters Health) Jan 02 - A point mutation in the CD45 phosphatase found on immune cells leads to a lupus-like disease in mice, according to investigators from the University of California, San Francisco, who report their findings in the December 22nd issue of Cell.

"While researchers have studied [lupus] intensively, the cause - or causes - have proven difficult to pin down," senior investigator Dr. Arthur Weiss commented in a university statement. "It may well be that at least part of the answer to the puzzle lies with a very small change in a signaling protein that underlies many different cell functions."

The key to the findings rested with earlier work showing that dimerization of CD45 turned off its phosphatase activity. The structure of a related receptor protein tyrosine phosphatase suggested that the inhibition of activity after dimerization was due to a "wedge" region on its intracellular domain, which blocks the catalytic site. Confirming this, mutation of a glutamine in the conserved wedge region led to inappropriate inactivation of CD45.

In the present work, Dr. Weiss and colleagues mutated a critical conserved amino acid in the CD45 wedge region, glutamate 613, to arginine in mice. The mice appeared normal for the first few months. However, they eventually developed a lymphoproliferative, lupus-like syndrome, with polyclonal T and B cell activation, severe autoimmune nephritis, and production of autoantibodies. All mice eventually died of disease.

Unlike other predispositions to autoimmune disease, which are usually recessive, both homozygotes and heterozygotes developed disease, indicating that the mutation was dominant. They note that the types of cells regulated by CD45 dimerization are unknown.

Although lupus is widely thought to result from a complex interplay of many genes, "it is possible that this disease is a collection of rare simple Mendelian disorders as well as polygenic disorders," Dr. Weiss and colleagues suggest. They further suggest that "some cases of human systemic lupus erythematosus could result from alleles that disrupt the dimer-induced inhibition of CD45 function." Studies are in progress to address this, they note.

"If we confirm that CD45 plays a regulatory role to control proliferation of T-cells or B-cells, then developing a drug to dimerize CD45 proteins might well provide a treatment for a range of pernicious auto-immune diseases," lead author Ravindra Majeti concludes in the university statement.

Cell 2000;103:1059-1070.