Type 1 Diabetes Mutations: Understanding Autoimmune Diseases
I recently discussed Monogenic (Permanent Neonatal Diabetes) and just reviewed a fascinating basic science paper in the May 2010 issue of The Journal of Clinical Investigation. In the study "The diabetogenic mouse MHC Class II molecule I-Ag7 is endowed with a switch that modulates affinity," Yoshida, Corper, Herro, Jabri, Wilson and Teyton discuss the possible molecular basis that may predispose someone to autoimmune or type 1 diabetes. I have always found genetics to be a fascinating subject having majored in the biological sciences with a concentration in genetics during the 1970s at Cornell University. Indeed, much has changed during the next 30 to 40 years and what was once considered to be "dogma" in genetics has been reversed!
During my undergraduate studies, one of the most exiting discoveries that perked my eventual interest in medicine was the revelation that a simple amino acid substitution (or base pair) may alter the shape of a protein and predispose a susceptible individual to a genetic disease. An example of this is Sickle Cell Anemia in which a mutation may change the shape of a hemoglobin molecule (hemoglobin S as compared to hemoglobin A) which causes "sickling" of the red blood cells, thereby decreasing oxygen binding and increasing the red blood cell destruction that clogs up blood vessels with the resulting symptoms of the disease. The inheritance pattern is autosomal recessive. Why this discussion of Sickle Cell disease? After reading a synopsis of the paper mentioned above in Diabetes in Control (online diabetes updates) and upon review of the original paper, it occurred to me that Sickle Cell disease is now often very controlled with medications based on molecular biology, etc. Why not apply the same knowledge for type 1 diabetes?
This present study was conducted in diabetogenic mice wherein genetic susceptibility to autoimmune diseases is often associated with specific alleles in the Histocompatibility Locus. All alleles linked with type 1 diabetes share a common non-aspartic acid residue at position 57 of their Beta chain.
"Diabetogenic MHC Class II molecules such as human HLA- DQ8 (on chromosome 6 in humans) and mouse 1-Ag7 have a small uncharged amino acid residue at position 57 of their Beta chain which results in the absence of a salt bridge between B57 and Arg alpha76 which is adjacent to the P9 pocket of the peptide -binding groove." In summary then, according to in this 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 1 diabetes, MHC molecules usually have a negatively charged residue at position 57. In contrast, disease-causing MHC molecules have a neutral residue at position 57 and as a consequence, 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 (based on Diabetes in Control interview with the authors). It was demonstrated in this investigation that T cell behavior was modified due to the reshaped patch and resultant "neutral charge" predisposing to a more positive charge on these complexes. These "killer T cells" may respond by not recognizing their own peptides and subsequently attack them as "not self" and perceive them as a threat. Apparently the region around position 57 is visible to the T cell receptor. Thus, the MHC region in the Histocompatibility Locus is not only "essential for peptide binding, but also critical for the selection of T cells." In essence, these molecular changes are purported to account for the basis of autoimmune disease such as type 1 diabetes and celiac disease (these authors have published interesting findings in regard to the molecular etiology of celiac disease, as well).
Why is this complicated basic science information so important? If there is an understanding of the molecular basis for the predisposition to autoimmune disease, research may (and will) be directed toward preventing the T cells from attacking the structurally and electronically altered peptides that they perceive as not self. Based on the Diabetes in Control interview, the authors are investigating molecular therapies (or antibodies) that could target and correct the mutated region in MHC.
(Please remember that these studies are still at the mice level. I have no doubt, however, that human studies will be soon forthcoming!)