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The Birth of Immunology

Posted on | April 29, 2025 | Comments Off on The Birth of Immunology

Mike Magee

The field of Immunology is little more than a half-century old and still shrouded in a remarkable degree of mystery. Even describing what we do know is a complex challenge. One way to proceed is to climb the scaffolding provided by the wide array of Nobel Prizes in Physiology or Medicine over the last half of the 20th century.

What has been clear for centuries  is that humans are vulnerable to contagious plagues and epidemics. For most of our history, these were attributed to toxic vapors or “miasmas.” The threat literally arose out of thin air it was believed. That was what Benjamin Rush thought as he and others struggled with the epic outbreak of Yellow Fever in Philadelphia in 1793.

But European medical detectives including Vienna General Hospitals head of maternity services, Ignaz Philip Semmelweis, in 1847, and John Snow in London nine years later, proved indisputably that human behavior, whether from lack of hand washing in a hospital, or accessing dirty water from a public pump, could place humans in harm’s way.

The “Germ Theory,” fleshed out by Louis Pasteur, Robert Koch, Joseph Lister (The Famous Trio) and others made it clear the microorganisms of all shapes and sizes were the culprits, and that public health adjustments could lessen the risk, while scientific discoveries might retroactively target specific offenders.

Not surprisingly, we humans see the “battle against disease” as a complex, uphill, centuries-long engagement. It’s a bitter and highly personal battle as Mary Putnam Jacobi and Abraham Jacobi, two physicians instrumental in overcoming raw milk laden diphtheria in turn of the century New York City learned when they lost their only child, 7-year old Ernst Jacobi, to the disease.

Our modern day view of immunology builds on and incorporates centuries old learnings including acquired immunity and vaccination. Inoculation for protection from disease was aggressively promoted back in 1716, when the wife of the  British Ambassador to Constantinople, Lady Mary Wortley Montagu, after observing the practice among Turkish religious sects, had her only daughter, Mary Alice, innoculated against smallpox.

Later in that century, British physician Edward Jenner crossed species when he noticed that a young dairymaid, Sarah Nelms, had typical cowpoke pustules on her hands (spread from infected cow udders) but no generalized spread to her face or elsewhere. This led him to two insights: 1)The lesions were very similar to human smallpox, 2) the cowpox infection was less severe than small pox. He surmised then that exposure to mild cowpox lesions might protect those inoculated from future smallpox contagion. His ethically compromised experiment on an 8-year old son of his gardener, James Phipps, inoculating him first with cowpox, and later with smallpox, happily resulted in a mild infection and the child survived. Jenner labeled what he had created a “vaccine” after the Latin word for cow – vacca.

Immunity too has Latin roots from the word immunitas which in Roman times was offered to denote exemption from the burden of taxation to worthy citizens by their Emperor.  Protection from disease is a bit more complicated than that and offers our White Blood Cells (WBCs) a starring role in “recognizing, disabling, and disposing” of the bad guys. These cells are produced in the bone marrow, then bivouacked in the thymus and spleen until called into action.

They are organized in specialized divisions. WBC macrophages are the first line of defense, literally gobbling and digesting bacteria and damaged cells through a process called “phagocytosis.” B-cells produce specific proteins called antibodies, designed to learn and remember specific  invaders chemical make-up or “antigen.” They can ID offenders quickly and neutralize target bacteria, toxins, and viruses. And T-cells are specially designed to go after viruses hidden within the human cells themselves.

The first ever Nobel Prize in Physiology or Medicine went to German scientist, Emil von Behring, eleven years after he demonstrated “passive immunity.” He was able to isolate poisons or toxins derived from tetanus and diphtheria microorganisms, inject them into lab animals, and subsequently prove that the animals were now “protected” from tetanus and diphtheria infection. These antitoxins, liberally employed in New York City, where diphtheria was the major killer of infants, quickly ended that sad epidemic.

Where Jenner, and later Pasteur’s (anthrax) weak exposures prevented subsequent disease, von Behring’s antitoxin cured those already infected. More than that, it unleashed the passion and excitement of investigators (which continues to this day) to understand how the human body, and specifically its cellular and chemical apparatus, pull off this feat?

The body’s inner defense system began to reveal its mysteries in the early 1900s. Brussel scientist Jules Bordet, while studying the bacteria Anthrax, was able to not only identified protein antibodies in response to anthrax infection, but also a series of companion proteins.  This cascade of proteins  linked to the antibodies enhanced their  bacterial killing power. In 1919 Bordet received his Nobel Prize for the discovery of a series of “complement” proteins, which when activated help antibodies “drill holes” through bacterial cell walls and destroy them.

Scientists now focused as well on the invaders themselves, termed as a group, “antigens,” and including microorganisms and other foreign bodies. How did the body know the threat and respond? Occasionally a brilliant breakthrough dreamer and the thinker would appear with a wild theory that turned out to be proven right. 

That was the case with UK scientist Nils Jerne in 1955. Three decades later his theories were proven out and he received the 1984 Nobel Prize. As his award outlined, “He asserted that all kinds of antibodies already have developed during the fetus stage and that the immune system functions through selection. In 1971, he proved that lymphocytes teach themselves to recognize the body’s own substances in the thymus gland… An immunological reaction arises when an antigen disturbs the system’s equilibrium.”

By then, those Jerne’s WBCs had been termed “B lymphocytes” by an Australian scientist named Macfarlane Burnet, a 1960 Nobel laureate, who also saw antibodies already established in the fetus. Arguably, dreamers were well established at the turn of the century. For example, Robert Koch’s main assistant was Paul Ehrlich, who imagined the inner workings of the cell this way, “In his eyes, cells were surrounded by tiny spike-like molecular structures, or ‘side-chains’, as he called them, and that these were responsible for trapping nutrients and other chemicals, and for drawing them inside the cell.” 

The “side chains” were in fact antibodies, large protein molecules made up of two long and two short chains. Roughly 80% of the four chains are identical in all antibodies. The remaining 20% varies, forming unique antigen bonding sites for each and every antigen. Already scientists began to wonder whether they could reconfigure these large proteins to create “monoclonal antibodies” to fight cancers like melanoma.

Imagination has occasionally carried the day. But more often direct problem solving uncovers answers. That was the case when French scientist, Jean Dausset, investigated a blood transfusion reaction in a patient who received blood type and Rh type compatible blood, a process defined by the Australian biologist Karl Landsteiner in 1930. What 1980 Nobel Laureate Dausset determined is that the incompatiblity lay not with RBCs, but with WBCs. The donor WBCs had incompatible attached antigens which were later termed human leucocyte antigens (HLAs). These are  so individualized that they are often referred to as an “HLA fingerprint.”

One question always leads to another. In this case, “Why do HLAs exist?” What was eventually uncovered was that certain microorganisms (viruses) take up residence inside human cells gaining protected status.  To deal with the problem, humans possess a specialized WBC – termed “T-cell.” We are familiar with them since they have been much publicized in our epic battle with the HIV virus. But for the T-cell to destroy an intracellular virus, it must “recognize and respond” to two messaging signals. First, the virus’s antigen. Second, a permissive signal that informs that the virus is housed in a host cell that deserves protection. The fingerprint HLA is that signal.

The downside of course is that the body’s own cells under certain circumstances can trigger an over reactive  immune response. Most of us have experienced a bee sting or peanut allergy gone bad. This alarming cascade of symptoms called “anaphylaxis” derives from the Greek ( ana– against, philaxis-protection), and clearly involves HLAs. The same is true of auto-immune diseases which may involve genetic variants of HLAs. Finally, successful organ transplantation relies on compatibility of donor and recipient HLAs.

So to sum it all up, Immunology is a mysterious, complex, and evolving field of study.  Host and predators (including everything from a microorganism invader to a roque cancer cell, to a wooden splinter left unaddressed could be fatal. But to respond the host must first identify the threat, and activate a specific and effective response, without inadvertently injuring the host itself. As our understanding has grown, harnessing the immune system to chase down metastatic cancer cells, or suppress a deadly response to a transplanted organ, or self-modify to avoid auto-immune diseases are clearly within our grasp in the not to distant future.

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