Washington: In a key breakthrough which may pave the way for more effective treatment for blood sugar, scientists have finally cracked the 40-year-old mystery of how certain genetic mutations lead to type 1 diabetes.
"People have been looking for the mechanism linking human leukocyte antigen (HLA) and autoimmunity for 40 years.
This study provides a big leap forward in understanding and suggests a new target to intervene in type 1 diabetes," Prof Luc Teyton who led a team at Scripps Research Institute, said.
The new study focuses on Type 1, or insulin-dependent diabetes, a rapidly progressive disease of the young which leads to high blood sugar, coma, and death if not treated with
replacement insulin,the `Biology and Nature` journal reported.
In their study, the scientists wanted to know on a molecular level how mutations in immune surveillance machinery could lead to type 1 diabetes.
"We were interested in trying to understand why certain MHC molecules (which are molecules in mice analogous to HLA molecules in humans) are linked to autoimmune disease, particularly type 1 diabetes," said co-scientist Adam Corper.
"In particular, we wanted to know why a single residue at position 57 on the ? chain of HLA molecules seems to be linked to the disease," he added.
So, the team used a series of structural and biophysical studies to answer that question.
The scientists found that diabetes-causing mutations changed the charge at one end of MHC peptidebinding groove. In individuals not predisposed to type 1 diabetes, MHC molecules usually have a negatively charged residue at position 57. In contrast disease-causing MHC molecules have neutral residue at position 57 and consequently the surrounding region is more positively charged.
The result of this molecular change was that the mutated MHC molecules selected a unique subset of T cells that bound to it strongly, with "higher affinity". These T cells may overreact and potentially misidentify "self" peptides as dangerous rather than harmless.
"We found that the MHC region around position 57 can be seen by the T cell receptor. That`s the big novelty of the paper for the first time, we show that it is not only essential for peptide binding, but also critical for the selection of T cells. Finally, we have an idea of why those MHC molecules are associated with disease," said Teyton.
Added Corper, "What we have here is potentially a way of breaking `tolerance` -- the mechanism where the immune system doesn`t respond to self. Obviously, if that breaks down you get autoimmune disease."
PTI
