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Scientists reveal how genetic mutations may cause type 1 diabetes
4/22/2010

Scientists from the Scripps Research Institute have provided an answer to the 40-year-old mystery of how three genetic variations located in the region of the genome called HLA, human leukocyte antigen, are known to dramatically increase risk of coming down with type 1 diabetes.

These three genes encode molecules that present peptides to the body’s T cells. T cells then determine whether the peptide being presented is dangerous and needs to be eliminated from the body or whether the peptide is “self,” part of the host and something the immune system needs to leave alone. However, in the context of type 1 diabetes, T cells aggressively attack the body’s own cells. In particular, the researchers said they wanted to know why a single residue at certain position seemed to be linked to the disease.

In the study the researchers found that diabetes-causing mutations changed the charge at one end of the MHC peptide-binding groove. In individuals not predisposed to type 1diabetes, MHC molecules usually have a negatively charged residue at the position. In contrast, disease-causing MHC molecules have a neutral residue at the position 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.

The study was published in an advanced, online issue of the Journal of Clinical Investigation on April 19, 2010, and will appear in the May print edition of the journal.

“People have been looking for the mechanism linking HLA and autoimmunity for 40 years,” said Scripps Research Professor Luc Teyton, who led the study with Scripps Research Professor Ian Wilson. “This study provides a big leap forward in understanding and suggests a critical new target to intervene in type 1 diabetes.”

The study was supported by the National Institutes of Health.

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