Mike Magee MD
In Session I of our three session review of the past, present and future of the field of Immunology, we focused on establishing the context for this still emerging field of Medicine. Originally the founders of this new field of study positioned it as a battle between microbe invaders and the human organism. Even before our first understandings in the mid-19th century of germ theory, cell theory, and public health practice, scientists understood this was a deadly battle.
As we discussed, human civilizations from the begin were acutely aware of the threat of “contagion” and the spread of plagues along trade routes, and memorialized them in early printed maps. The cause, and intermediary facilitators would come much later, but from the beginning certain tactics like quarantine, isolation, masking and contact avoidance were practiced without understanding exactly what was being avoided.
But as we will discuss in this session, as scientific knowledge of microbes grew throughout the 20th century, a more nuanced appreciation of our relationship with other life forms steadily revealed the secrets of Immunology. And as this occurred, it became clear the this system of defining and responding to “self vs. non-self” wasn’t so much an armed continuous conflict, but a modulated coexistence designed to protect against pathogens, but also to be certain that the cure (constance surveillance and reaction to predatory microbes) was not ultimately worse than the threat itself.
As Augustus De Morgan, scientist and poet, describes the competition for resources, “Great fleas have little fleas upon their backs to bite ‘em, And little fleas have lesser fleas, and so ad infinitum.” As ecologists gradually gained ground in describing life’s various cycles of mutual interdependence, the pillars for ecology became firm ground for growing scientific understanding. These included defining “a complex web of relationships”, “identifying and neutralizing threats”, “creating an effective memory and response system”, and “long term evolutionary success.”
Understanding that all living things were constructed of cells as basic units of life was a critical step forward. But as experts gradually realized, “it’s more complicated than that…, the pathogen must get close enough to interact with individual cells . . . and seem to make peace with the human organism.” There is, at work, the art of mimicry, and adaption as a constant at the heart of the battle between “self” and “non-self.”
As the 19th century was drawing to a close, and cell theory emerged side by side with germ theory, not-surprisingly scientists (aided by ever improving microscopes) concentrated on human blood cells.
Eighty percent of all human cells are blood cells. The vast majority of these are red blood cells (RBCs) which lack a nucleus. Fewer than 1% of our blood cells are nucleated white blood cells (WBCs).
Over the following century, understanding would grow, much of it focused on the role of WBCs. In all, 26 Nobel Prizes in Medicine would be awarded to Immunologists in the century ahead. Tracking them provides at least some appreciation for the path of discovery that has built Immunology as a discipline – and also some informed guesses about what may come about over the next decade.
Immunologists these days have their own association – The American Association of Immunologists (AAM). They are understandably proud of their list of Nobel Prize winners and include their biographies on their website. #2 on their list is an Austrian physiologist, Karl Landsteiner. In examining RBSs microscopically in 1900, he realized that their surfaces were not silky smooth as they had first appeared. Rather they were speckled with what turned out to be bits of protein and carbohydrates.
Dr. Landsteiner’s analysis revealed that RBCs surface proteins (termed antigens) in four different varieties. Each human’s store of RBCs came in one of these varieties, and a simple agglutinin test defined which of the four blood types an individual was – A, B, AB, and O. This was not simply an esoteric finding. Landsteiner had been exploring why the fledgling practice of human to human blood transfusion, popularized in part by life-saving efforts in battlefield trauma during the Civil War and other conflicts, often resulted in deadly reactions. His conclusion was that mismatching blood types somehow caused the recipient to experience a rejection.
In 1930, Landsteiner was awarded the Nobel Prize for this discovery. By then he and his family had resettled in New York City where he had joined the Rockefeller Institute, the premier medical research center of its day. It was here that Landsteiner also identified another blood sub-type in 1937 which he labelled Rh+ (when present) and Rh- (when absent). Thirty three years later, this knowledge and treatments to avoid the loss of “blue babies” (Rh+ babies born to Rh- mothers) would solve this mysterious condition that had long claimed otherwise healthy infants worldwide.
Blood cells continued to draw scientists curiosity through much of the first half of the 20th century, accelerated by the emergence in 1937 at Chicago’s Cook County Hospital of the first “Blood Bank” and the pressing need for blood transfusions during WW II. It was a French scientist, Jean Dausset, who began to focus his study in 1952 on a group of patients who had experienced blood transfusion reactions even though they had been matched correctly with donor blood from blood banks. Six years later, in 1958, he was able to explain why.
Dr. Dausset demonstrated that WBC’s also contained surface antigens which he labelled “Human Leukocyte (a term for WBCs) Antigens” or HLAs. In fact, as we will see, these HLAs are endless in variety, identifying every human – one fro another- even identical twins. Over time HLAs earned the nickname “HLA fingerprint.” Dausset was the 16th scientist to make it to the AAI Nobel Prize list, earning the award in 1980.
By then additional secrets of the HLA system were beginning to be revealed, ultimately reinforced by electron microscopic imaging and DNA genomics. Specifically, scientists were able to confirm that the genetic instructions for creation of each human’s Human Leukocyte Antigen (HLA) came from a tiny section on the short arm of their 6th chromosome. Termed “The most genetically variable region in the human genome,” this highly polymorphic instruction manual was capable of mixing and matching a startling 28,000 different varieties, which when combined, were more that enough to ensure each human possessed his or her own identifier.
As important, the functionality of the HLA molecule eventually revealed itself as well. Aside from being a genetic fingerprint on each and every nucleated cell in your body (effectively labelling “you” as “you”), HLA do double time in exposing fraudulent molecules that don’t belong in or on your cells. Before migrating to your cell surface, HLAs are busy cleaving intracellular (foreign and domestic) proteins into small 8 to 10 amino acid bites, and then transporting them to display on the cell surface where they might reveal whether this cell is friend or foe. More on that in a moment.
The scientific awareness of this system of flagging “self” vs. “non-self” was pivotal. It was soon clear that small bits of displayed foreign protein were enough to define and expose an invader with great specificity. As scientists revealed “A measles virus is made of different proteins from those of a rabies virus. An E. coli bacterium has a different structure from that of a spirochete.” How the body surveils itself, and how it responds, we’ll come to in a moment.
But one of the perplexing right turns in the story of Immunology (and there are many) was that, at certain times, the body decides not to respond to “non-self”, but rather to “tolerate” and even “cooperate” with a non-human molecule. A first glaring example of tolerance was described by veterinarian scientist, Ray D, Owen in 1945. As was reported, “Twin cattle sharing a common placenta had a stable mixture of each other’s red blood cells. His study showed the body could be tolerant of these foreign tissues.” Similarly, human identical twins with different HLA fingerprints tolerated each other’s blood cells without mounting an attack on the partner babies unique “foreign” cells.
Further studiers in pregnant women revealed that the developing child’s fetal cells begin to cross over the placenta and enter the mother’s circulation at 4 weeks development. Mother’s immune cells and proteins are detectable in the fetus by week 13. In both cases, the incursion of “non-self” cells and proteins are tolerated. The term for harboring cells of differing origins has a label – “chimerism.”
This mysterious coexistence carries over into birth. During pregnancy, the baby is developing in a sterile environment and doesn’t need immune protection. But at birth, this under-utilized protective cascade must awaken – and this takes approximately 2 months. During this period the fetal immune system is antigenicly inexperienced. Luckily, mother’s breast milk is rich in immune cells . In fact her first milk (colostrum) contains 3 million immune cells in a single milliliter of milk. For all infants, breast fed or not, pediatricians remain extremely cautious when it comes to exposures during the first 8 weeks of life. This is because, during this immune catch up period, babies are vulnerable, especially bacteria like strep, staph, meningococcus, H. influenza, and pneumococcus.
Although more vulnerable in the first few weeks of life, babies are not completely defenseless. They are born with two types of immunity – Innate Immunity and Adaptive Immunity.
Innate Immunity is a natural quick response system against any and all invaders. It has evolved over a billion years and includes physical, chemical and cellular barriers. The physical barriers are designed to deny access. These include our protective skin covering with strategic placement of hair for example within nasal passages and human eyelids. These protections are augmented with various chemical washes for example nasal mucus, human tears, saliva and gastric acids. And finally there are WBCs derived from the granulocytic bone marrow stem cell line.
The granulocytic stem cells deliver approximately 85% of all of our WBCs. The four major types are neutrophils, monocytes, eosinophils, and basophils. They rapidly and indiscriminately amass when invasive microbes or foreign bodies cross and penetrate our standing barriers. Neutrophils and monocytes are usually first to the scene and are reliable and effective killers. They possess the ability to excrete digestive enzymes that literally “bleach” invaders to death. They then engulf and digest the remains through a process called phagocytosis. Their response is immediate, non-specific, and aggressive – but does not always contain the invaders infective spread. When they fail, our Adaptive Immune system takes over.
How does the Adaptive System know it is needed? The answer lies with the other 15% of WBCs – the lymphocytes which develop from their own unique bone marrow stem cell line. As it turns out, they are not only responsible for constant surveillance but also for an effective “second punch” in defense of the human organism.
They come in two varieties – B-cells and T-cells. Both originate in the Bone Marrow (thus the “B”) but T-cells migrate almost immediately in utero to the thymus gland (thus the “T”). According to the Cleveland Clinic, “Your thymus is a small gland in the lymphatic system that makes and trains special white blood cells called T-cells. The T-cells help your immune system fight disease and infection. Your thymus gland produces most of your T-cells before birth. The rest are made in childhood and you’ll have all the T-cells you need for life by the time you hit puberty.”
When it comes to surveillance, one sub-type of T-lymphocyte is in charge. It is called a Helper T-cell (also CD4 cell), and its primary purpose is to provide oversight of the HLA protein clips displayed on your nucleated cells to ensure “normalcy.” If the HLA protein displayed is your’s, all well and good. But if Helper T-cells detect “abnormal’ protein chips, they trigger an immune cascading response.
Helper T-cells are able to detect “non-self” protein with great specificity. A surface chip from a measles virus looks different than a rabies virus chip. An e-coli bacterium is different than than a spirochete. But in general, everything not viewed as “self” is a threat, and is marked for destruction.
Pathogenic microbes are not defenseless in these battles. They have advantages. As one expert put it, “Infections reproduce much more rapidly than their hosts and can change their appearance to allow them to evade recognition.” By now, most of us know many of the major bacteria and viruses by name. Viruses distinguish themselves by their need to penetrate our nuclei and commandeer our DNA, redirecting its instruction manual to produce its own viral progeny which break out of the host cell, free now to circulate and spread throughout the body.
The Helper T-cell (also labelled the CD4 cell) orchestrate, with short delays, an adaptive response which is specific, includes both cellular and molecular components, and preserves a memory of the vanquished attackers so that, if they reappear, the next response is both immediate and overwhelming. Vaccines take advantage of this phenomenon. They purposely expose you to a weakened and relatively powerless microbe, and instigate an immune reaction. Should you be later exposed to the real version of the pathogen, your educated and waiting immune response eliminates the threat before it can gain a foothold.
When Helper T-cells send out an alarm it signals the appearance of another T-cell sub-type, the Killer T-cell (also known as a CD8 cell). It aggressively and specifically attacks the infected cell releasing chemicals to kill it, and then digesting the remains. At the same time, the Helper T-cell attracts B-cells, marked to destroy the specific microbe offender, by generating a broad cellular and humoral attack that is systemic, reaching every niche and corner of the body. The cellular army is created by B-lymphocytes cloning themselves. The humoral elements are created by these targeted clone cellular soldiers.
You likely already are at least casually familiar with these B-cell generated proteins. They are called antibodies or immunoglobulins. They are often represented in cartoon fashion by a “Y”. This is a simple representation of their actual structure as seen under an electron microscope. An antibody is constructed of two light protein chains and two heavy protein chains. They are created to mirror their specific invaders. The crux of the “Y” is a specific binding receptor mirroring the virus, bacteria, or cancerous offending body that needs to be eliminated. These proteinaceous circulating and detecting binders are released in massive quantities, capable of basically clearing the circulatory system of the threat before it multiples and gathers enough strength to overwhelm its human host.
Should the situation become dire, the human immune system can also release a cascade of generalized inflammatory chemicals, called the Complement System, to double and redouble the attack. Such a failsafe is useful but also requires an “off” switch because left unmanaged, these chemical responses can damage normal cells as well. That “off” switch comes in the form of another sub-type of T-cell, the Regulatory T-cell (Treg), a braking system capable of suppressing the immune response. Treg’s represent approximately 5% of all your T-cell supply.
Viewed in its entirety, the Adaptive Immune System then includes three components: a cellular response, a humoral response, and a breaking system delivering what some call “immunotolerance.” Tregs were only recently discovered. One of their discoverers was immunologist, Mary E. Brunkow, the #26 member on the AAI “Noble Prize” winner list. Professor Brunkow received the prize in 2025, and was one of 232 prize winners in Medicine since the award’s creation and the 14th woman scientist in the group.
The discovery of Treg and its functionality represented a missing link in our understanding of Adaptive Immunity, as well as expanding our understanding of human physiology and pathophysiology. For nearly a century the human neurologic and endocrine systems, with their wired and unwired messenger systems and feedback loops, have been viewed as the primary reason we are able to maintain or reassert balanced functioning, harmony, and homeostasis of the enormously complex collection of human cells that together create an autonomous human life. The insertion of Treg effectively provides the third regulatory system, the Immune System, with a feedback loop of its own. And more than that, it raises the questions whether, and how, these three different regulatory systems might communicate with each other.
The philosophy being embraced is an ancient one – Holism. It was first entertained by Aristotle in the 4th century BC. As one expert suggested “Systems should be studied in their entirety, with a focus on the interconnections between their various components rather than on the individual parts. Such systems have emergent properties that result from the behavior of a system that is “larger than the sum of its parts”. Historians note, “A major shift away from holism occurred during the Age of Enlightenment when the dominant thought of ‘dissection science‘ was to focus on the smallest component of a system to understand it.”
The insights have come fast and furious. The latest term embraced by the scientific community is “Holobiont.” “A holobiont is a collection of closely associated species that have complex interactions, such as a plant species and the members of its microbiom.” Expanded to include our recent insights, “Modulators of the immune system, maintain homeostasis, tolerance to microbiome, and maternal-fetal crossover.” Specifically, human system experts, from maternal-fetal medicine, gastroenterology, auto-immune disease management, and the science of aging have seized on this new knowledge of immune-tolerance, and began to hypothesize what might be the modulating effect of Treg.
Could twin babies sharing a placenta and each other’s cells do so because Treg told them to? Could mother’s tolerance of her baby’s cells crossing over into circulation be allowed as part of an ancient evolutionary ruling that allowed this to occur in the interest of survival of the species? Could the trillions of cooperative microbes that inhabit the human gastro-intestinal system with beneficial effect have been given a “pass’ when it came to the “self” and “non-self” rules? And what about rheumatoid arthritis, and Lupus, Multiple Sclerosis or Alzheimers Disease? Are these cases of Treg being shut down, or infectious molecules mirroring in design human chemical structures, and because of the “mimicry” inadvertently triggering an attack on “self.” And finally, in reverse, what if cancer cells were able to harness Tregs? Could they sheild themselves from immune attack long enough to multiply and metastasize?
To say that ecologists were intrigued by these new possibilities would be an understatement. Not long ago, their paradigm was simply “unsocial organisms cause disease.” As the microbiome rose in prominence, enlightened investigators declared that “interaction of self and non-self species creates stable networks.” But this new knowledge was suggesting that “Interconnection of all lifeforms through microbiota” was the norm, not the exception. One expert defined it as “a community of commensal, symbiotic, and pathogenic microorganisms sharing common space.” Another stated, “New sequencing technologies and accumulated sequence data have highlighted both the ubiquity of microbial communities in association within higher organisms and the critical roles of microbes in human, animal, and plant health.”
From this platform, it was a short leap to envisioning a holistic approach to human physiology and pathophysiology that imagined immunologic connectivity with coordinated message sharing (whether by neural wiring, hormonal secretion, or Helper T-cell directed cellular and humoral selection of winners and losers in the battle for survival and the maintenance of normalcy.
So the table has been set (energized by AI engineering) for expansive discoveries in the field of Immunology in the next few years. In Session III, we’ll explore some of the near future possibilities including mRNA vaccines, why we have not cured (but have controlled) HIV/AIDS, organ transplantation rejection, the connection between Epstein Barr virus and MS, immunotherapy for metastatic melanoma, immunosenescene and its role in lifespan expansion, and more.
