Immunology's Other Lesson

Immunology studies how we maintain our body’s integrity. When one thinks of immunology, it is the mechanisms of our defense that first come to mind. White blood cells converging on bacteria, antibodies identifying a biological threat. But hidden within these mechanisms is “immunity’s central motif,” our definition of self and other. I think every parent has a moment when speaking with their child, that they begin channeling their parents. Why am I hearing my father’s words and tone as I counsel or console my son? How did my father come to reside within my ‘self?’ What boundary conditions separate us from other? Why, does it feel at times so clear-cut and others so amorphous? Differentiating self from other has many scales, not just immunology or my internalized parent’s voices. Self and other has been used to separate tribes, ethnicities, nations.

Immunity is found in all animals with varying sophistication and complexity, subject to evolutionary influences for well over 200 million years. The long existence of the immune system makes me believe it is incredibly well-tuned for our environment. Immunity is the cellular means of identifying self from others providing boundary conditions to separate our self from other – bacteria, viruses, other people. Immunity is our biologic version of Immigration and Customs Enforcement (ICE).

The initial concepts of immunity built upon the work of French scientist Claude Bernard – the milieu intérieur, homeostasis. Bernard’s formative work took place in a nineteenth-century Europe that saw the Napoleonic Wars and by mid-century class struggle fueled civil uprisings and national aspirations to expand (Britain and France) as well as to consolidate (Italy and Germany). So, it is not surprising that Bernard’s choice of metaphors to describe the boundary conditions defining self-are well-demarcated, absolute, not porous at all

“The living body, though it has need of the surrounding environment, is nevertheless relatively independent of it. This independence …derives from the fact that in the living being, the tissues are in fact withdrawn from direct external influences and are protected by a veritable internal environment.”

For Bernard, a boundary insulates the well-functioning interior from the exterior. Internal instability results in reactive internal changes restoring the steady-state balance. In protecting the internal environment (self), we withdraw and are independent of external influences (the other) -  metaphorically reflecting Europe’s cultural concerns.

The next sentinel figure in immunology is New Zealander Macfarlane Burnet, raised on the large island, socially isolated from his peers. His formative years both as a teen and young scientist span the early 20th century when New Zealand, despite its distance from Europe, contributed 10% of its population to fighting World War I. New Zealand troops took part in the disastrous Gallipoli campaign as well as the stalemate on the Western front marked by futile attacks and counterattacks suffering an overall casualty rate of 58%.

Burnet developed his Nobel prize winning view of immunology in the late 1930’s the early days of World War II. Burnet’s model involved exposure of immunity’s foot soldiers, lymphocytes, to self during fetal development. Once they could identify self, everything else was other and was other forever more. The subsequent exposure of these lymphocytes to foreign antigens mobilizes and amplifies the immune response to other.

“For Burnet, the hostile meeting between self and non-self – with its attendant imagery of combat, invasion, aggression, or counter-attack – is the archetypical description of immunity…”

Burnet’s boundary conditions are more porous than Bernard's wall, and immunity functions as an opposing army, countering the unavoidable porosity of boundary – much like one might envision the Western Front.

In both these early models of immunity, self is central either assumed by Bernard or learned as described by Burnet. Like the earth before Copernicus, self was central. And like earth after Copernicus, ‘self’ lost its central position as scientific investigation refined our understanding of immunity. By the mid to late 20th century, there had been a preemptive attack on Pearl Harbor, a second World War, the detonation of atomic weapons and a cold-war equipoise based upon mutually assured destruction, the Star War Defense, our increasing use of National Technical Means of Verification (e.g. spy satellites). This was the time of “trust but verify.”

The immune system is responsible for many cellular functions, repairing tissue damage, removing senescent cells, and eliminating malignancy. Why would immunity respond only to foreign attack? Why wait for the Pearl Harbor moment? Shouldn’t the immune system have a system of surveillance?

Immune surveillance not only protected self but helped define it. Self was not Bernard’s and Burnet’s single, static and immutable entity. Self was a property shaped by responses of the immune system; continuing to shape shift as long as surveillance continue. Exposures define self - looking at our immune system we could see contacts with chickenpox, or measles, or strep. Boundary conditions are more than porous, self is a response to the others breaching the border of the homeland. Self has a diffuse identity emerging through interaction with ‘other,’ a biologic equivalent of ‘trust but verify.’

In 1854, John Snow literally mapped London’s epidemic cholera deaths visualizing its source, the Broad Street pump. His cognitive heirs advanced a new meme in the late 20th century – networks. Networks of people and ideas, patterns of weather or economies, life’s constant clamor and dialogue of life forms webs of networks. What if immunity was a system of interlocking activity that responds when disturbed?

Immunity could now be understood solely using homeostasis, defense, and surveillance. Self was no longer central, it was perhaps no longer necessary. Self was embodied in pattern recognition which, in turn, was subservient to context. If the pattern of incoming antigens (other) increasingly disturbs homeostasis, the immune system is increasingly activated. Our response to other is no longer just a reaction to the presence of foreign antigens, but arises from how many, where and when, “temporal and ‘spatial’ patterns of antigens.” In this model, the immune response is not due merely to the presence of other; it requires additional signals of perturbation of our steady-state, injury.

We know that signals indicating injury or threat are necessary, the mere presence of other is insufficient, because of the protection of chimerism – the presence of two different genetic cell lines, two separate genetic selves, in one individual. Pregnancy is a natural form of chimerism Consider the multitude of differing genetic cells lines within all of us. Mitochondria and the microflora of the gut biome are both ‘other’ and our constant companions, our symbionts. We could not survive without mitochondria, those others that provide our energy, or without the microflora of the now popularized gut biome that make nutritional building blocks we cannot make or ingest. We are incomplete without these others. The immune self is many different and necessary genetic threads. We are holobionts, communities of various genetic selves.

“the immune system also develops, in part, in dialogue with symbionts, and thereby functions as a mechanism for integrating microbes into the animal-cell community… So while the defensive role of immunity is clearly prominent in the medical and agricultural contexts, that point of view must be balanced with how the internal milieu of the individual organism integrates ‘foreign’ elements.”  

Boundary conditions are wholly porous there is no longer a clearly defined inner and outer, self and other. The network of self interacts with the networks of ‘other selves.’ Self and other lose the polarity and separation implicit in their definitions, existing as an ecologic whole.

These four models of immunity and self, Bernard’s, Burnet’s, surveillance and ecologic network are increasingly better approximations of reality. Each model provides insight and builds upon one another. Each model employs the metaphors of their time, walls giving way to armies, then surveillance and now communities. Our history and cultural values are reflected in the descriptions of immunity, self, and boundary.

Bernard’s vision of boundary is reminiscent of the United States through the mid 19th century, isolated and looking inward. The Barbary Coast Wars, the War of 1812, asserting our sovereignty. The Civil War the ultimate homeostatic process. Burnet’s model of the boundary, it’s inevitable porosity and needs for defense echo the late 19th century through the cold war era. Beginning with the ‘Yellow’ Peril and influx of unwashed from Eastern and Southern Europe with their different clothes, food, and ideas; the turning back of the MS St. Louis, the quota system. There were also chimeric moments - Emma Lazarus, the Melting Pot and the 13th Amendment. And moments that were like autoimmune responses, when immunity turns upon itself, the war on Native Americans, the internment of the Japanese, Jim Crow.

Understanding immunity’s solution to self and borders, crafted through 200 million-years of evolution – offers a different view of our American self. Is the real source of American exceptionalism, our society’s holobiont nature?

The United States cannot be described by its geographic borders, or by cultural criteria imagined as family values or the Protestant work ethic. The diversity of other is already within our borders, serving our country and its development. Like humans, like holobionts “the United States also develops, in part, in dialogue with others, and thereby functions as a mechanism for integrating others into the community… Indeed, the extraordinary diversity and richness of others’ functions have led to a growing understanding of how our internal ecology confers an ever-evolving identity.”

Perhaps we need to heed the lesson evolution, and our immune system provides.

Note: I have drawn on an overview of immunity to both update my medical school knowledge and consider the evolution of our understanding of immunity.