In autoimmunity, the immune system becomes dysregulated and mistakenly attacks portions of the patient's own biochemistry. The broad variety of autoimmune conditions are differentiated from one another on the basis of exactly which structures and cells come under attack. Some autoimmune conditions are highly disabling or lethal, while others are comparative mild, but even lesser autoimmune conditions such as rheumatoid arthritis still shorten life expectancy. To the degree to which autoimmunity results in increased inflammation, a shorter life is the expected outcome, even when the tissues targeted by the immune system are less vital. Chronic inflammation is a major downstream mechanism of aging, and speeds the development and progression of all of the common fatal age-related conditions.
Most autoimmune disorders are comparatively poorly understood. The immune system is enormously complex, and far from completely mapped. Many of the autoimmune conditions in which etiology remains obscure may turn out to be collections of distinct conditions with varied causes and a similar outcome. Further, numerous forms of autoimmunity tend to arise with age as the immune system becomes worn and dysfunctional, and are presently lumped in with the other serious consequences of a failing immune system. These age-related autoimmunities are even less well understood than their more widely recognized counterparts, and it is very likely that many more remain to be discovered in the first place, let alone comprehensively investigated. Consider that the prevalent late life condition of type 4 diabetes was only cataloged a few years ago, for example.
Why does autoimmunity shorten life spans? Cardiovascular disease is the obvious candidate, and inflammation is the obvious link to investigate wherever there is a raised risk of cardiovascular mortality. Researchers here narrow down the connection to the inflammatory cytokine interleukin-17, and show that it is possible prevent the increased cardiovascular disease risk by blocking interleukin-17, at least in mice. This in turn suggests that existing drugs targeting this cytokine, used to treat some autoimmune conditions, might reduce cardiovascular disease risk in older people without autoimmunity. This is one of many examples to suggest that sophisticated control over inflammation could slow the progression of aging to some degree.
People with psoriasis and lupus are two to eight times more likely to suffer a heart attack than people without these diseases. For young and middle-aged adults with rheumatoid arthritis, cardiovascular disease is the top cause of death. Psoriasis is characterized by patches of red, thickened, scaly skin. The thickening is partly due to an excess of collagen, the main protein in connective tissues such as skin and blood vessel. Researchers suspected that the walls of blood vessels also might be webbed with too much collagen. They created a light-sensitive form of high-density lipoprotein (HDL) - the molecular carrying case for cholesterol - that fluoresces when hit with a laser beam, and inserted it into mice. The researchers then induced a psoriasis-like disease in the mice.
By following the fluorescent cholesterol carrier, the researchers could see that HDL cholesterol was delayed in getting out of the bloodstream in the mice that received the compound. This was true not only in the skin, but in internal arteries near the heart. In addition, the skin and blood vessels were more densely interlaced with collagen and more resistant to stretching. Further, when the researchers fed mice a high-cholesterol diet for three weeks, the mice in the experimental psoriasis group developed significantly larger cholesterol deposits in their blood vessels.
An immune cell type called Th17 cells multiplies robustly in autoimmune diseases such as psoriasis, lupus, and rheumatoid arthritis, releasing copious amounts of the immune molecule IL-17. When the researchers neutralized IL-17 in mice with psoriasis-like disease, using an antibody, collagen density went down and cholesterol deposits shrank. "It'll take a few years before we know for sure, but we predict that the anti-IL-17 antibodies that already are being used to treat autoimmune diseases will be effective at reducing risk of cardiovascular disease."
Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4+ T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen.