London - Researchers have provided new insight into the mechanisms behind autoimmune diseases, thereby suggesting a potential therapy.
Autoimmune diseases, such as Type I diabetes and rheumatoid arthritis, are caused by an immune system gone haywire, where the bodyâ€™s defense system assaults and destroys healthy tissues.
A mutant form of a protein called LYP has been implicated in multiple autoimmune diseases, but the precise molecular pathway involved has been unknown.
Now, researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) show how the errant form of LYP can disrupt the immune system.
In doing so, they also found a potential new therapy for autoimmune diseasesâ€”a chemical compound that appears to inhibit this mutant protein.
In Caucasian populations, a mutated form of LYP (short for lymphoid tyrosine phosphatase) is the third most common single-gene cause of Type 1 diabetes. It ranks second for rheumatoid arthritis.
Researchers have known that LYP and another protein called CSK (C-terminal Src kinase) work cooperatively to keep the immune systemâ€™s destructive T cells from being activated.
Because the uncontrolled activation of T cells is a hallmark of many autoimmune diseases, the proper functioning of LYP with CSK is thought to keep T cells in check.
While the normal form of LYP can bind CSK, the disease-associated mutant LYP cannot.
In the new study, Sanford-Burnham researcher Lutz Tautz, Ph.D. led an international group of scientists in showing that normal LYP can disassociate itself from CSK, which paradoxically makes LYP better at dampening the signals that activate T cells.
These findings explain why the mutant form of LYP is better at limiting T cell activation than normal LYP.
One possible explanation, Tautz said, is that the mutant LYP weakens the action of regulatory T cells, which control the other type of T cells, the kind that causes autoimmunity.
In their study, the researchers also screened 50,000 drug-like chemical compounds and found 33 that have a specific effect on LYP activity.
One compound, called LTV-1, blocked the action of the mutant LYP protein in human T cells. In fact, under physiological conditions, LTV-1 is the most potent LYP inhibitor reported to date.
Tautz said he plans to next develop the LTV-1 compound further, in part by modifying it chemically to make it more effective as a drug. Tests in mice, however, could be problematic because a separate study recently showed that mice with a corresponding LYP mutation donâ€™t get sick at all.
The study has been published in Nature Chemical Biology.