Science Editor

You don't have to go looking for weapons of mass destruction in Iraq or other suspect rogue nations. Diabetes mellitus fills that WMD bill.

Estimated victims of the disease worldwide number 135 million men, women and children. Diabetes is the seventh leading killer in the U.S., the No. 1 cause of limb amputations and kidney failure and a leading perpetrator of heart disease, stroke and blindness. Moreover, this multiple mayhem is largely self-inflicted in Type I by autoimmune T cells, which seek and destroy antigens generated by the body's own immune system.

Diabetes has been termed the epidemic of the 21st century. Over the past 50 years in Western societies it has doubled in incidence every 15 years. It exacts a huge socioeconomic toll because of its devastating physical complications and the need for patients to comply with lifetime daily therapeutic regimens. The childhood-onset form of diabetes, Type I, accounts for 10 percent of all cases. It's the product of a T-lymphocyte (T-cell) autoimmune activity, which specifically destroys the insulin-secreting beta cells studding the islets of Langerhans in the pancreas.

Diabetes comes in two flavors - Type I and Type II. "Type I's prevalence in the U.S.," observed immunologist Teresa DiLorenzo, at the Albert Einstein College of Medicine in New York, is about 0.4 percent, and there are 1 million to 2 million people who have Type I - insulin-dependent diabetes mellitus [IDDM]. So it must not be confused with Type II diabetes, which, of course, is much more common.

"The onset of IDM can range from very, very young kids to roughly 30 years of age. Symptomology in both versions is marked by excessive urination and excessive thirst. Those are its two distinguishing signs - polyuria and polydipsia. The onset can be sudden," DiLorenzo continued. "The immunological destruction takes a while, and about 80 percent of the young patient's beta cells are destroyed. At that point he or she can't make enough insulin to regulate glucose metabolism. But as the beta cells are being wiped out, they still have enough there that still make insulin, so you really don't know that you've got this metabolic war going on inside you. It's only until a critical mass of beta cells has been obliterated do you have symptoms showing that you fail to regulate glucose metabolism."

IGRP's Highly Strategic Huge Acronym

DiLorenzo is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS) released online June 16-20. Its title: "Identification of the b-cell antigen IGRP targeted by a prevalent population of pathogenic CD8⁺ T cells in autoimmune diabetes." (IGRP stands for a humongous but highly strategic acronym, namely: "Islet glucose 6 phosphatase catalytic subunit related protein.")

"The first overall finding of our paper," she told BioWorld Today, "is that we found a novel beta-cell antigen that's targeted in diabetes. The second important finding is that we know this antigen is targeted by T cells. A number of antigens have been identified, targeted by antibodies," she went on, "but it's really the T cells that do the damage in diabetes. So what's important is that we found an antigen that we know is targeted by a prevalent population of T cells. Not just one or two but a large proportion of the T cells that you find in the islets. And in fact the paper shows that you can even find these T cells in peripheral blood of the non-obese mice that go on to develop the diabetes of which they are prone.

"The practical significance of our IGRP discovery is that what we need to do now is find out if this is an antigen in Type I diabetes patients. No human studies have been done yet. That's what we need to do next. Then, if we do in fact find that IGRP is an antigen in humans, one could imagine all sorts of things that might be managed - a new diagnostic test, perhaps new therapies, new methods to monitor treatments, new ways to assess risk. But we need to look in the human system first.

"IGRP," DiLorenzo explained, "is a protein similar to a very important liver enzyme - glucose 6 phosphatase. Although they're homologous in terms of their sequence, no activity has been demonstrated for IGRP. So as of now its function is unknown. T cells, unlike antibodies," DiLorenzo pointed out, "recognize antigenic peptide fragments complexed with MHC [major histocompatibility complex] molecules presented on the surface of the cell, to expose its antigens to the immune system. What we did was purify the MHC molecules from billions of beta cells, and then those peptides were fractionated repeatedly by high-pressure liquid chromatography.

"And at every fractionation those fractions were tested for T-cell recognition. One of the peptides we sequenced turned out to be the right one. It stimulated the T cell, and still had thousands of peptides there. So we had to refractionate, repeat the procedure over and over. Finally we were able to sequence peptides out of the positive fraction and found the one - the IGRP - that turned on the T cells. There's a single gene in the mouse and as far as we know there's a single gene for it in humans."

Some Flawed IGRP Variants Offloaded Onto MHC

"IGRP is interesting because in humans at least there's a lot of spliced variants of it, which means that some of those RNAs encode proteins that would neither fold nor localize properly. So one hypothesis is that those defective IGRPs are misdirected, misfolded, which is why they end up being degraded and loaded onto MHC molecules. In both mice and humans what you see as the disease develops is the islets become infiltrated with leucocytes, T cells, B cells, macrophages, dendritic cells. It's just the inflammation that occurs in the islets prior to the destruction of the beta cells."

"So far," John Harb, the college's director of biotechnology and dean for scientific operations, told BioWorld Today, "we have filed one patent application, on May 20, for Teresa's key invention. It's titled Antigens targeted by prevalent pathogenic T cells in Type I diabetes, and uses thereof.' We have not yet attempted to market the technology," Harb concluded.