That’s not even accounting for the exposome. Even among twins, no two people occupy the exact same psychosocial niche.2 Perhaps one had a slightly higher workload or a more stressful year, or lived in a house with more radon exposure—a frighteningly common phenomenon in the Midwest. Perhaps they differed in insurance coverage, proximity to care or the structure of their daily responsibilities. When social and economic stressors intersect with genetic predisposition, the balance can tip toward immune dysfunction and disease—particularly in rheumatology, in which multimorbidity is the norm, not the exception.
This is what makes our field both maddening and magnificent. The variables that shape our disease are countless, and the traditional dichotomy of nature vs. nurture does a disservice to the interconnectedness of it all. Sometimes, we simply have to marvel at how complex and intricate human variation is.
Situated Choice Among Immune Cells
Not too long ago, I fell down an internet rabbit hole and found a term in the sociology literature that appealed to me: situated choice. Sociologists use this term to describe how a decision or action is understood within the context of a specific environment, situation or location.3
As an immunologist, my first thought was about lymphocytes. After all, the way an immune cell makes decisions is never in a vacuum, but in the context of its surroundings. A T cell in a lymph node facing one set of cytokines will behave quite differently than that same T cell encountering an even slightly different milieu in the synovium or gut.
These decisions are contingent, local and adaptive. They’re not unlike the choices we make in our own lives, shaped by environment, history and proximity to others.
This application of situated choice to health has profound implications for how we can conceptualize disease pathogenesis. Why does one individual, like Bob, with a genetic predisposition develop an autoimmune disease while another doesn’t? Perhaps it comes down to where and when an immune cell encountered its antigen, what signals it received from surrounding cells, how cosmic rays displaced subatomic particles leading to a mutation, or what genetic and epigenetic states coincided at that time.
What’s more, these cellular choices, if we can give some liberties to immune cells for decision making, aren’t made solely once—they are part of a continuous chain that extends throughout all phases of the cell’s life. Multiplying this by thousands and millions of cells, it becomes clear that the immune system is in a perpetual state of negotiation, arbitrating between tolerance and attack, between regulation and activation. Our immune systems have evolved to become exquisitely sensitive to context, and because that context is always in flux, immune behavior—and therefore disease—becomes highly unpredictable.
