Diabetes 101: thymic selection part 2

July 14, 11:37 PMDiabetes ExaminerRobert Scheinman

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T cell recognizing antigen

To recap from yesterday’s column: when a thymocyte finds a piece of self presented as an antigen, and if it responds…reluctantly, then it will survive and eventually leave the thymus as a T cell; soldier and defender of that self it so reluctantly recognized. This is called positive selection. It is nothing short of bizarre that desultory recognition of self ensures robust recognition of other.

Each of the T cell soldiers has the capacity to recognize self. Indeed, researchers have shown through clever genetic manipulations in mice that T cells MUST continue to react to self - to touch self to survive. So it appears that even the tough T cell has fears of abandonment. But in addition, the same T cell receptor recognizes some undefined other shape which presumably can fit much better into that key hole. This shape, this other, is the pathogen…..unless it is not.

There is something “funny” about certain shapes derived from proteins enriched in the pancreas. Insulin, for example. We know that children who are in the process of developing type I diabetes have activated T cells that recognize insulin because they have convinced B cells to make anti-insulin antibodies. Indeed the presence of these antibodies is an important predictor of disease onset. Why has the T cell made this mistake? Why the pancreas and not some other organ – like the kidney? One possibility involves the secretory nature of the pancreas. Insulin because it travels extensively is highly “visible” and is more likely to attract T cell attention then the non-secretory kidney.

Another reason for T cells to attack self involves a failure of something we call “tolerance”. We know that the deletion of potentially autoreactive T cells is only part of the myriad ways in which the immune system holds T cells in check. We will discuss these mechanisms elsewhere. For the moment, let us just say that tolerance to pancreatic secretions is a bit more tenuous than for other parts of the body.

Finally, certain pathogens actually have bits that look a lot like insulin. Viral infections including enteroviruses, rubella, mumps, rotavirus, parvovirus and cytomegalovirus have all been linked to the rise in type 1 diabetes and the evidence is compelling. Here, the T cell activates in response to one antigen but then goes after another (bystander activation).

An important piece of evidence that points to recognition of antigen as the culprit in the process leading to type 1 diabetes comes from research into the genetics of risk. It turns out that 50% of the risk comes from one set of genes. These are the genes who’s job it is to present antigen to the T cell. These genes are collectively called MHC (major histocompatibility complex, read more about it here) and are better known for making it virtually impossible for a patient to accept an organ transplant unless the donor is an identical twin.

To sum up: T cells start out in life with a passing interest in self and through this are somehow capable of robustly responding to some foreign antigen. Tolerance mechanisms keep these T cells in check. Certain pancreatic gene products like insulin appear to engender less tolerance than other genes. When tolerance is broken through an unfortunate combination of MHC presentation and T cell receptor combination or the unfortunate collateral casualty of viral defense, it is the pancreas that takes the brunt of it.

“Every man has a mob self and an individual self, in varying proportions.”  ~D.H. Lawrence