Two years ago around this time my cousin Polly reluctantly taught me a new pair of words: hemophagocytic lymphohistiocytosis. It’s a hard phrase to remember unless you make a jingle out of it:
Hemo-
phago- cytic
Lympho-
histio- cytooo sis
This polysyllabic hematology jargon was a new one on me. Her hematologist had taught her these words as she lay in her bed on the 8th floor of San Francisco General Hospital, facing the news that she had a rare auto-immune disorder that translates into “too many blood-eating white cells.” Her own immune system was eating up her blood, making her anemic and prone to infection. Why? she wanted to know. Why now, why me, why this way? Nobody knew. Two months later she died at home, defenseless against multiple fungal infections. Her immune system, after guarding her faithfully for 68 years, suddenly had turned on her.
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Last year around this time my sister-in-law Mary spent several months in Johns Hopkins University Hospital learning new words for what turned out to be “Anti-Neutrophilic Cytoplasmic Autoantibody,” or ANCA Vasculitis, a series of attacks by her immune system not on her blood but on the walls of the small arteries of first her sinuses, then her ears, later her lungs, kidneys, and heart. None of her specialists could answer her “why” questions, but they did manage to save her. She now leads a life ruled by the cautions imposed by an immune system prone to stoking wildfires in targeted organs.
For most of my thirty years in psychiatric practice I’ve worked with the occasional patient with multiple sclerosis (MS), but during the past five years the number with MS has steadily increased, and currently I regularly see at least six, most of them women. These events are my brush with what seems to be a mysterious recent rise in the rates of auto-immune disorders. I used to think of auto-immune disorders as rare, the sort of thing only immunologists took care of. But look at this list: Type 1 Diabetes, Celiac Disease, Lupus, Multiple Sclerosis, Crohn’s Disease, Psoriasis, Rheumatoid Arthritis, Ulcerative Colitis, Ankylosing Spondylitis, Sjogren’s Syndrome, Hashimoto’s Thyroiditis. There are household words on this list. You probably know people with some of these conditions.
What these disorders share is immune systems that have lost their ability to a) regulate their inflammatory processes, and b) distinguish between host and foreign cells. These immune systems attack selected populations of their own cells, such as the islet cells of the pancreas in Type 1 Diabetes, with an unregulated fury that is normally reserved for foreign cells. It’s a form of mutiny or civil war, the self attacking its own. Imagine the US Capitol Police attacking the members of Congress they’re hired to protect, and trashing the building in the process.
Roughly 4% of the global population has at least one auto-immune disorder. That makes it about as common as major depression or coronary disease. In the UK the rate is closer to 6%, and in the US it’s about 8%. And rising, some say, though it’s hard to know, since there is no registry for auto-immune disorders. Why should our rates be so much higher here? Last year a good large population study in the US found that a risk marker for auto-immune disorders, anti-nuclear antibody (ANA), had jumped sharply from 11.5% in 1999-2004 to 15.9% in 2011-12, corresponding to an increase from 27 million to 41 million people, with especially alarming rates of increase in ages 12-19. This is data about a risk marker, not a disease, but it’s suggestive of something mysterious going on during the past twenty years.
For some auto-immune disorders, such as MS and rheumatoid arthritis, rates for women are two or even three times the rates for men. Why should that be so? The leading guesses focus on hormones and the X chromosome, which carries many of the genes that regulate immune function. People with two X chromosomes (most females) usually have one set of immune genes deactivated, but as many as 23% of X-linked genes escape deactivation. This raises the possibility that in women with auto-immune disorders, overactivation of some immune functions could account for the higher rates in women.
Our COVID pandemic has treated us all to a steady diet of epidemiologic mysteries. We’re stuffed with questions and starved for answers. One lesson this pandemic has hammered home is that modern medicine does not understand well enough how our immune systems function and how they fail. Why do some of us respond to SARS-CoV-2 with mild reactions and some of us respond with violent, sometimes lethal overreactions? The cytokine storms of COVID bear some similarities to auto-immune disorders in their ravaging the very systems they’re designed to protect.
We don’t have good measures for identifying immune systems that are vulnerable to either overreaction, as in vaccine allergies or cytokine storms, or underreaction, as in sepsis or multisystem organ failure. The best measures we collect are the occasional samples of antibody or cytokine levels, but we know nothing about what’s going on in the intervals between these occasional samples. You can’t make a movie out of snapshots, and a system as complex and dynamic as the immune system requires a movie to capture it. The same is true for each of the other organs in our stress response system—heart, lungs, gut, nerves, muscles, hormones, skin. In the not-too-distant future, when we have learned how to monitor these systems in action during daily life, we will look back with wonder on these days of guessing about complex systems based on occasional data samples. Fifty years ago we were even deeper in the dark.
So when you find yourself feeling impatient with this pandemic, remember how little we still know about our lines of defense against viral invaders and the civil wars within us.