The Blurry Line Between Tolerance and Rejection

Posted on | February 23, 2026 | No Comments

Mike Magee

Are you for us, or against us? Will you tolerate border incursions, or deter, destroy, and extract? Will you bend (and how far) to accommodate your former enemies and betray your friends?

These questions may sound provocative and political, but they have nothing to do with our current leadership disarray in the U.S. Rather they refer to an active scientific debate raging in the field of Immunology. As one scientist noted recently, “Immunologists generally view the notion of self and non-self as part of a broader, more contextual understanding of immune function, rather than a rigid dogma.”

For nearly a century, experts in the field leaned heavily on the belief that “self” was static and concrete rather than a “context-dependent state.” In the 19th century, the debate was as likely to engage philosophers and theologians, as it did biologists and mathematicians. The consensus back then was that the human organism was committed to identifying and preserving its cells and vital chemicals, which required means to identify and destroy any entities (dead or alive) that penetrated human space.

But what does it mean to be “oneself?” Until recently most experts leaned on concrete boundaries and substrates. Yet recent forays into the biologic underpinnings of memory and consciousness suggested that human life is dynamic, interactive, and evolutionary.

At the dawn of the 20th century scientists theorized that serum proteins had the capacity to identify specific biologic molecules. In time, they were revealed as highly organized and responsive systems including the complement cascade and a range of immunoglobulins or antibodies.

In response to war injuries in WW II, attempted transplantation led to tissue rejection, and in response the discovery of individual specific Human Leukocyte Antigens (HLA) and Major Histocompatibility Complexes (MHC) – “self-markers” if you will that added a piece to the puzzle and triggered a “convergence of ideas.” Frank Macfarlane Burnet is credited with first uncovering that lymphocytes play a critical role as immune mediators. They posses special receptors on their cell surface capable of recognizing and binding foreign proteins. Each replicating clone of lymphocytes is specific to one invader. Once bound, “the forbidden clone” is marked for destruction and digestion. One’s own proteins are not bound, and therefore not destroyed.

In the late 1980’s, Charles Janeway, suggested that our immune system wasn’t so much focused on random invading protein antigens, but rather reliant on receptors that existed on the surface of innate white blood cells that had memory and had evolved and been inherited and handed down through generations. This tipped the scale away from the classical two-phase definition of our cellular and humoral defense department that included an initial general innate response followed by a second target specific adaptive strike when necessary.

The newer still evolving theory envisions an innate system with swagger that is based on “ancient pattern recognition” embedded with evolutionary knowledge of what is dangerous, and what is not. This newer vision includes a higher level of tolerance and understanding extended to certain “foreign elements” that mean no harm. This subtle shift redefines the role of the immune soldier, once a border cop, but now a transit manager.

Why the new emphasis on plasticity? Because reality was not cooperating with classically held beliefs. For some time researchers were aware for example that fetal cells that escaped into a mother’s circulation could continue to thrive, unattacked as foreign for a lifetime. The mothers “foreign cells” suggested a “fetal-maternal tolerance” termed microchimerism. That same type of free pass was also extended to consensual microbiome bacteria that appeared integrated into endocrine and neurologic control systems. And finally, in the field of transplant immunology, it became possible to use modified pharmacologic intervention to prod the recipient’s defense system to grudgingly accept foreign tissue that had been partially, but not completely matched to a recipient’s tissue type.

The field of Immunology is just catching up with the reality that we humans are willing hosts of trillions of microbes. How exactly they get a “stay out of jail” card remains a mystery for the moment. But one thing is certain, they are critical to our normal physiologic functioning. And the reverse is true as well, that the immune response can be “pathologically misdirected” with cataclysmic over response as in “anaphylaxis,” or chronic self-destructive inflammatory cascades as in the case of autoimmune diseases such as hemolytic anemia or rheumatoid arthritis.

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The Blurry Line Between Tolerance and Rejection

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