Graphic image of T cells.

Graphic image by UGREEN 3S, Shutterstock.

Stanford Medicine Scope - October 18th, 2016 - by Bruce Goldman

I recently wrote an article for our magazine, Stanford Medicine, about the disturbing tendency of our immune systems, as the years go by, to get stuck in a state of low-grade inflammation — a phenomenon some have nicknamed “inflammaging.” Multiple conditions — from cancer, cardiovascular disease and diabetes to Alzheimer’s, osteoarthritis and autoimmunity — feature inflammatory connections.

So it’s no surprise that trying to explain why inflammaging happens to begin with is one of medical science’s current hot topics. Inflammaging’s causes, like its consequences, are undoubtedly manifold. Now, in a study in Immunity, Stanford rheumatologists Connie Weyand, MD, and Jorg Goronzy, MD, orthopedic surgeon Stuart Goodman, MD, and several Stanford colleagues have identified one of them: a failure in DNA repair that impels important immune cells to become old, crotchety and dangerous.

In their study, the scientists concentrated on roving immune warriors called T cells, which circulate in the blood and patrol our tissues. Critical to detecting and combating infections and cancer, T cells occasionally fail to differentiate friend from foe and, instead, mount an assault on otherwise healthy tissues. Rheumatoid arthritis, for example, is an autoimmune condition in which errant T cells attack joint tissue.

Just like virtually all other types of cells in our bodies, each T cell numbers among its contents 23 pairs of chromosomes: long strings of DNA that contain our genes. At each end of every chromosome is a characteristic structure called a telomere. If chromosomes were shoelaces, telomeres would be the tightly wound rings of cellophane tape at both ends that keep those laces from fraying. Damage to a telomere — say by radiation or some DNA-warping chemical — can make a chromosome begin to unravel, exposing the cell to various random bummers including the possibility that it will start replicating without restraint: the definition of a cancer cell.

To ward off that prospect, cells have evolved numerous ways of sensing and responding to telomere damage. They can, for example, send in crews of DNA-repair enzymes to the site. If that fails, they can step on internal molecular brakes that prevent the cell from ever dividing again. The good news is that a replication-arrested cell can’t morph into a tumor. The bad news: Such a cell is thrust into a senescent state wherein it still functions a bit, but  poorly — and tends to emit inflammatory signals that, over time, tend to wreck its neighborhood.

In rheumatoid arthritis, it’s known, T cells age prematurely. In the study the investigators showed that RA patients’ T cells are deficient in a DNA-repair enzyme called MRE11A. This deficiency results in telomere damage in T cells, triggering changes that make these cells inflammatory and prone to attacking normal joint tissue. But, the researchers also found, MRE11A deficiency doesn’t stop affected T cells from dividing. They proliferate and become hyper-aggressive.

Happily, restoring adequate MRE11A activity reversed this progression and rejuvenated joint tissue, making the enzyme an excellent therapeutic target for rheumatoid arthritis. “Restoring MRE11A is a powerful anti-inflammatory intervention,” Weyand told me. Insofar as MRE11A deficiency results naturally during normal aging, too, arresting that decline may also foil inflammaging.

Originally published at Stanford Medicine Scope Blog