Paying the Price of Protection

Is the wanton killing of cells in autoimmune disease a case of mistaken identity, or does it arise from an important physiological service? The first is the commonly accepted view – that autoimmune attack is a sort of mistake. But the latter view may be closer to the truth, according to a new model proposed by researchers at the Weizmann Institute of Science. Among other things, the model suggests a solution to the long-standing riddle of why some organs are susceptible to autoimmune diseases while others are not. The findings were published in the journal Immunity.

Yael Korem Kohanim, a doctoral student in the lab of Prof. Uri Alon in the Institute’s Department of Molecular Cell Biology, who led the study, explains that autoimmune diseases can be divided into two types – systemic ones like lupus that attack many organs in the body, and those like type 1 diabetes that affect just one organ. One of the riddles about this second, organ-specific type of autoimmune disease is why some organs get autoimmune diseases while others do not. The pancreas is an extreme example: the insulin-producing beta cells that make up 2-4% of the pancreas are highly prone, while the rest of the pancreas almost never gets an autoimmune disease.

Likewise, Hashimoto’s thyroiditis affects the thyroids of some 7% of the population, whereas the parathyroid glands right next to them are rarely affected by autoimmune syndromes. These organ-specific autoimmune diseases tend to follow a similar pattern, arising in children or young adults (unlike genetic diseases that appear at birth, or those of aging), and they involve the destruction of cells that secrete essential hormones. Immune cells called T cells somehow identify these endocrine cells as dangerous and eradicate them on contact.

Korem Kohanim, Prof. Alon, and the research group, including Dr. Avichai Tendler, Dr. Avi Mayo, and Prof. Nir Friedman in the Department of Immunology, asked: What if the T cells are meant to kill these cells all along?

Keeping supply matched to demand

The researchers hypothesized that T cells might be “kept on the payroll” as an extra layer of protection to ensure that hormone levels stay within narrow limits. Hormones – insulin, thyroid, cortisol – tend to function in feedback loops; too little is as harmful as too much. When demand for the hormone rises – for example, a demand for insulin when glucose is repeatedly sensed – the cells not only step up production, they ramp up cell division to help meet that demand. But cell division carries risks, as a certain percentage of the new cells are likely to carry mutations. Most such mutations are harmless, but if one disrupts the cell’s delicate sensing machinery, the cell will misread the demand as high when it is actually low. The result is deadly: the cell will continue not only to pump out extra hormones, it will divide again and again to produce new cells with the same mutation, which will then divide again and produce even more of the hormone, soon causing severe disease.

T cells, which select their targets by recognizing small pieces of proteins that identify the cells they are meant to kill, could conceivably target the over-secreting cells in healthy organs. They act, in this case, as secret agents, removing cells that threaten to take over the organ and secrete too much hormone. In autoimmune diseases, the T cells might be primed to accomplish the same task but get overzealous, killing off non-mutant cells.

Was this hypothesis reasonable? Korem Kohanim, Prof. Alon, and the team delved into the literature and bioinformatics data on several single-organ autoimmune diseases, then creating a mathematical model for the functioning of healthy organs in which small numbers of T cells kept a low profile. In this model, the organs stay fit and productive as long as the T cells have a means of being highly selective, so that most of their targets would be the mutated cells.

This result agrees with the findings from research on the diseases showing that, in each one, the T cells identify proteins specifically connected to the production or secretion of the target cells’ hormones. In healthy organs, those T cells could use the same identification codes to target any cells that are overproducing the hormones. In other words, autoimmune diseases could be the result of a tradeoff: a layer of regulation preventing diseases linked to overproduction, while risking the opposite effect – reduced production – in some people.

The glands that refuse to pay the price

If other glands are not susceptible to autoimmune disease, does this mean they also forgo T-cell protection? The team went back to the literature and found that the parathyroid, for example, is highly prone to noncancerous growths called adenomas that are common in post-menopausal women, affecting as many as one in 50. These adenomas secrete huge amounts of hormone, causing a disease called hyperparathyroidism. Other examples, though less dramatic than parathyroid adenomas, supported the idea that a lack of T-cell intervention, as the model would suggest, could result in unchecked hormone secretion and cell growth.

“The model explains a number of puzzling findings,” says Korem Kohanim. “For example, we looked at genetic sequences of T cells found in healthy people, and noted that some of them indeed have the exact same protein-identifying receptors as the T cells found in those with autoimmune diseases. The explanation has always been that the apparently healthy people have a mild form of the disease, or one in its initial stages. But the findings are more logical if you assume these auto-reactive T cells are meant to be there; that they are meant to keep us from getting diseases of cell division and hormone overproduction.”

So far, says Korem Kohanim, the model provides a solution to a riddle that has long plagued researchers, though experimentation is needed to see if its claims are borne out. However, it has already garnered interest in the field and is generating discussion among top immunologists. The Alon lab will continue to collaborate on the project with the Friedman lab as they develop means of experimentally testing the model’s results.

“We think that autoimmune diseases do not come out of nowhere. They are a malfunction, but one of a physiological system that is already in place,” Korem Kohanim says.

“We follow in the footsteps of pioneers at Weizmann – Irun Cohen and Michal Schwartz and their students – who emphasized the immune system as tending our bodies as well as fighting pathogens,” Prof. Alon says, adding: “I can’t wait to see if this theory is fruitful in the sense of generating new experiments that will teach us about the mysteries of autoimmune diseases.”

Prof. Uri Alon’s research is supported by the Sagol Institute for Longevity Research; the Jeanne and Joseph Nissim Center for Life Sciences Research; the Braginsky Center for the Interface between Science and the Humanities; the Kahn Family Research Center for Systems Biology of the Human Cell; the Zuckerman STEM Leadership Program; the Rising Tide Foundation; the estate of Olga Klein – Astrachan; and the European Research Council. Prof. Alon is the incumbent of the the Abisch-Frenkel Professorial Chair.

Prof. Nir Friedman’s research is supported by the David and Fela Shapell Family Institute for Preclinical Studies; the Dr. Dvora and Haim Teitelbaum Endowment Fund; the Pearl Welinsky Merlo Foundation for Scientific Progress Research Fund; the Florence Blau, Morris Blau, and Rose Peterson Fund; the Rising Tide Foundation; the Park Avenue Charitable Fund; Gertrude Comninos; the estate of Robert Einzig; and the estate of Emile Mimran. Prof Friedman is the incumbent of the Eugene and Marcia Applebaum Professorial Chair.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. The Institute’s 3,800-strong scientific community engages in research addressing crucial problems in medicine and health, energy, technology, agriculture, and the environment. Outstanding young scientists from around the world pursue advanced degrees at the Weizmann Institute’s Feinberg Graduate School. The discoveries and theories of Weizmann Institute scientists have had a major impact on the wider scientific community, as well as on the quality of life of millions of people worldwide.

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