As I type this story, each press of the shift key or the letter “a” sends a tiny jolt of pain through the little finger of my left hand. It’s not bad enough to keep me from typing or send me in search of ibuprofen, but it’s an irritant and always at the back of my mind as I try to concentrate on the more important job of writing. The source of the pain is osteoarthritis, visible as a small bump and a slight crook in the top joint of my little finger—and one of many diseases in which chronic inflammation is a contributing factor.
It’s entirely possible that you, too, are plagued by one of those diseases. They include acne, allergies (to food, pollen and other substances), asthma, arthritis (osteo, rheumatoid and psoriatic), atherosclerosis and other cardiovascular diseases, COPD, diabetes (types 1 and 2), eczema, inflammatory bowel diseases like Crohn’s and ulcerative colitis, lupus, multiple sclerosis, Parkinson’s disease, periodontal disease, psoriasis, rosacea, some cancers, obesity, Sjögren’s syndrome, and possibly even depression and Alzheimer’s disease. Given the length and variety of that list, it’s not altogether surprising that the Harvard Health Letter recently referred to inflammation as a “unifying theory of disease.”
Of course, inflammation—essentially, the body’s response to an invader or tissue damage—isn’t all bad. In fact, acute inflammation—that fights the invader, vanquishes it and then subsides—is a very good thing. When a pathogen—a virus, bacterium, fungus or parasite—enters the body, cells in the immune system recognize it as foreign and initiate a response to destroy it, releasing substances known as inflammatory mediators. These substances dilate the blood vessels at the site of the invasion, which increases blood flow so that an army of white blood cells can get to the field of battle more quickly. The dilation also renders the vessels more permeable so they can leak healing fluid. Some of the mediator hormones affect surrounding nerves, increasing pain sensitivity to alert the brain that something’s afoot. Taken together, these reactions create the classic signs of inflammation: heat, redness, swelling, pain and loss of function.
The same process occurs in chronic inflammation, except that it doesn’t subside as quickly. Chronic inflammation can last for months, years, or a lifetime. And rather than heal the body, it can cause pain, debility and lasting damage, and lead to ongoing disease. We’ve known about this kind of harmful inflammation for decades, but only in the past few years has it become apparent that the process is a component, and even a driving force, in such a wide array of illnesses.
This fresh knowledge has spurred a research revolution, with scientists working feverishly to understand more about chronic inflammation in order to develop better ways of stopping it in its tracks. In New Jersey, that research is being spearheaded by Rutgers University’s Center for Immunity and Inflammation (CII), part of the school’s Biomedical Health Sciences Institute for Infectious & Inflammatory Diseases (i3D), where some of the country’s top scientists are examining the crossroads between inflammation and chronic disease in the hopes of creating breakthrough treatments for many of humankind’s most persistent maladies.
Illustration by Nicole Xu
IN SEARCH OF TRIGGERS
What causes the immune system to wield the intricate and sometimes lifesaving process of inflammation against the body’s own cells and tissues? The definitive answers—and there are probably more than one—are what scientists like CII director William Gause are trying to puzzle out. In some infectious diseases—tuberculosis, for instance—chronic inflammation is an ongoing response to a pathogen that persists in the body in spite of the immune system’s strenuous efforts to eradicate it. More frequently, though, the specific cause of chronic inflammation is a mystery. Researchers believe that it’s often triggered by an infectious agent of some kind, but regardless of whether the infection is cleared, inflammation keeps chugging along, damaging the body in the process.
That can be the case with lupus, an inflammatory autoimmune disease in which the immune system attacks the body’s own tissues and organs, including the joints, kidneys, skin, blood, lungs and brain. Jason Weinstein, whose CII lab focuses on lupus research, believes that, while sufferers may be genetically predisposed to the disease, the inflammation that characterizes it is likely set off by something in the environment. “Some of it could simply be how you respond to a viral infection,” he says. “So you just may get a cold and, because you have certain genes, it may trigger this kind of inflammation.” He notes that other inflammatory diseases might be generated in a similar way.
What we do know is that, in a process called sterile inflammation, the trigger can be something as seemingly benign as a particle of metal or plastic. Gause notes, for instance, that knee, hip and other prosthetic joints can cause inflammation when the immune system attacks so-called wear debris—microparticles produced when pieces of the prosthetic rub against one another. “The response then leads to chronic inflammation in the joint around the implant,” he says, “which can eventually lead to bone damage, loosening of the implant, and a requirement for its replacement—and all this may occur in the complete absence of infectious agents.” The same response has recently been noted in women with textured breast implants and can also be activated, Gause says, by particulate pollutants.
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THE CASE OF THE DISAPPEARING WORMS
The question remains: Why would a trigger as modest as a cold virus (or, in the case of allergies, a grain of pollen or a few molecules of peanut) move the body to attack itself? Researchers like Mark Siracusa, an assistant professor in the department of medicine who studies inflammation at CII, believes insight may come from studying a group of parasitic worms known as helminths.
For thousands upon thousands of years, helminths have infected human beings; in fact, the two evolved together. Then, about 50 years ago, helminths virtually disappeared from their human hosts in the developed world, thanks largely to improved hygiene. It’s no coincidence, Siracusa believes, that inflammatory ailments, including Crohn’s disease, allergies and asthma, are considerably more common and on the rise in the developed world than in areas where water supplies are often contaminated with helminth worms, where children are more likely to go barefoot (the worms can enter the body through the skin of the feet), and where people come into frequent contact with soil via agriculture.
In those less developed regions, infection with helminth worms is commonplace. Siracusa believes—and he’s far from alone in this view—that the worms may play an important role in calibrating the human immune system. “The worms produce a massive inflammatory response,” he says, “and I think the immune system calibrates itself to that—it learns what truly dangerous is.” In the absence of the worms, he postulates, it never learns that lesson, and so a few flakes of cat dander “can cause the immune system to fire off like it’s World War III.”
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Of course, no one is suggesting we reinfect ourselves with helminths, which can cause abdominal pain, dysentery and blindness. But it’s clear that current treatments for chronic inflammation, and the diseases that give rise to it, are less than optimal. The most common treatment, steroids, reduce inflammation and are used, in one form or another, to treat a host of inflammatory conditions, including allergies, asthma, arthritis, skin conditions like eczema and psoriasis, and autoimmune diseases like lupus and multiple sclerosis.
But steroids can cause unpleasant side effects like mood changes, weight gain and insomnia. And they work by halting the inflammatory process, which means that they can also keep the immune system from doing its job, making the body more susceptible to infection. More recent autoimmune-disease treatments (for instance, DMARDs, or disease-modifying antirheumatic drugs, like methotrexate for rheumatoid arthritis), which work, like steroids, by interrupting the immune response, have risky side effects.
“One of the problems with many of our treatments for inflammatory diseases today is that they’re generalized,” says Gause. “They’re like sledgehammers—they downregulate the whole immune response.”
Researchers at CII are among the growing number of scientists studying the inflammatory response in order to treat chronic inflammation without hammering the immune system. Weinstein’s lab, for instance, is searching for genes that are either turned off or on when inflammation progresses from acute to chronic in lupus patients. If one or more of these genes is identified, researchers hope they can specifically target it to create a drug that attacks only a component of the inflammatory response, rather than the entire immune system. “If this is a way to shut off inflammation in lupus,” Weinstein says, “you could potentially use it in other inflammatory conditions.”
In diseases where a pathogen is still active in the body, you wouldn’t want to shut off inflammation entirely, but it could be beneficial to limit it, notes Padmini Salgame, a professor of medicine and researcher at Rutgers New Jersey Medical School Center for Emerging Pathogens, who studies tuberculosis. That’s particularly critical with TB, for which treatment can typically take six months or longer, during which time the inflammation that’s fighting the disease can also do significant, long-lasting damage to the lungs. This can make patients more susceptible to chronic lung conditions like COPD. According to Salgame, researchers are looking for ways to “induce a balance that will minimize inflammation” by, say, targeting cells that secrete inflammatory mediators. In fact, she adds, there are several so-called host-directed therapies—treatments that effect changes in the human body, as opposed to the pathogen attacking it—already on trial, notably statins (usually used to control cholesterol) and metformin (which treats type 2 diabetes). These drugs, she says, may work by attacking the bacterium that causes TB, but they might also help to control inflammation.
At the other end of the spectrum are conditions—notably allergies and asthma—in which shutting down the inflammatory response would be a good thing. Siracusa and his team have been looking at how helminth worms turn on inflammation in the body and have uncovered a number of targets—including enzymes that regulate the inflammatory response—for potential new treatments. Some of these treatments have shut off allergic inflammation in animal models and could be developed for human patients within a decade, Siracusa says.
And those helminths? You might just find them—or parts of them—in the skin-care aisle in the near future. Because the worms have the ability to modulate the human immune system, a group of researchers at i3D is hoping to “mine them,” in Gause’s words, for molecules that could shut off harmful inflammation in acne and other skin diseases.
“It’s a very exciting time for research into inflammatory treatments,” Gause says. He notes that researchers are looking into ways to harness the part of the human immune system that keeps inflammation in check.
“This next generation of treatments,” Gause says, “is going to be much more targeted and, I think, more effective in controlling harmful inflammation.”
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Until that generation is unveiled, is there anything we can do to protect ourselves against chronic inflammation?
Clearly, we can’t change our genetic history, and we can’t dodge every germ and particle that might spark a chronic inflammatory response. Diet could make a difference, though to what degree, researchers haven’t yet determined. A 2019 study out of Rutgers’s Robert Wood Johnson Medical School found some evidence that insufficient levels of omega-3 polyunsaturated fatty acids, available in large amounts in mackerel and salmon, contributed to inflammation that could lead to acne. A number of other studies indicate that omega-3s can lower inflammation in autoimmune diseases like multiple sclerosis. The much publicized Nurses’ Health Study, ongoing since 1976, found a link between inflammation and trans fats, found largely in partially hydrogenated oils and many prepackaged baked goods.
There are also indications that fresh fruits and vegetables can help reduce inflammation and that sugar and refined starches can raise it, though to date, no one has proven that diet can actually prevent any of the chronic inflammatory ailments. On the other hand, it couldn’t hurt to switch to a diet high in fresh fruits, vegetables and fish (especially fatty fish like salmon) and low in sugar, refined starches and trans fats. Even if the diet doesn’t cure your inflammation, it’s likely to promote good health in lots of other ways. While researchers continue to look for novel treatments to turn off or modulate chronic inflammation, I’m willing to give diet a try—for the sake of my little finger and, with luck, the rest of my body as well.