Controlling Our Immune System — 4

Three of four individuals with autoimmune diseases are women, but the explanation for that has been elusive, even though we’ve known it must have something to do with having two X chromosomes (men have only one). A molecule called Xist randomly inactivates one of the X chromosomes in women, silencing its gene expression. Xist clings like Velcro to its X chromosome, but sometimes it essentially breaks loose, fails to deactivate gene expression, and causes a pernicious immune response. Moreover, Xist has associated proteins that can induce autoantibodies, some of which have been identified in women with lupus, scleroderma, and dermatomyositis. That’s only a partial explanation of where autoimmune diseases come from—after all, most people with type 1 diabetes are male, and about 20 percent of autoimmune conditions are found in XY individuals. Sex hormones may play a role too, as has been seen with plasma estradiol concentration correlating with antibodies developed after flu shots.

Although there’s heightened risk for autoimmunity in women, they have an advantage over men for a favorable profile of “immune resilience,” meaning they have a very good, rapid immune response while also having the ability to control it from overreacting and the following inflammation. From an extensive assessment of adaptive immunity in over forty-eight thousand participants, this trait of immunocompetence-inflammation balance is associated with longevity, improved survival from COVID-19 or sepsis, and more resistance to severe influenza or HIV infections. It’s like a Goldilocks story of just the right capability of fighting off infections while at the same time not having an exuberant inflammatory response that can be deleterious.

With aging, immunosenescence sets in, with a decline in responsiveness in multiple ways: the time it takes, the ability to recognize self, decline in young, naive T cells and the diversity of T cells, decrease in circulating B cells, and weaker antibody production. There is also “inflammaging,” a low-grade, chronic inflammation process that may relate to older cells being more likely to secrete cytokines. The extent of these changes varies considerably between individuals with the same chronological age. From a group of 135 healthy adults at different ages, including seventy-two participants aged sixty to ninety-six years, with serial, comprehensive assessment over a nine-year period, an individual’s immune age score predicted all-cause mortality. This finding, reinforced by several other reports, reflects how closely our immune system is tied with health span and lifespan. Beyond age per se, using single-sequencing, there has even been the discovery of frailty-specific immune cells from frail, older adults. We also know that our T cell aging, via epigenetic clocks, can be far out of step from our chronological age. After age sixty, about 2 percent of people develop persistent self-directed antibodies against type-1 interferon, which increases their vulnerability to viral infections.