Mike Magee
In Alfred Nobel’s 1895 will, he created and designated his Nobel Prizes be awarded annually “to those who, during the preceding year, have conferred the greatest benefit to humankind.” The original prizes were to be awarded in five categories – Physics, Medicine and Physiology, Chemistry, Literature, and Peace.
Since then, 218 men and 14 women have been awarded the Medicine and Physiology Nobel, and 28 of these have been members of the American Association of Immunologists.
The first awardee was male, physiologist Emil von Behring, who received the prize in 1901 for developing a life-saving vaccine for diphtheria, the leading killer of infants at the turn of the century.
The first woman awarded the Nobel Prize in this field was Gerty Cori for her 1947 elucidation of the specifics of glucose metabolism. The most recent woman to be honored was immunologist Mary E. Brunkow for her discoveries of the workings of regulatory T cells (Treg) and their role in modulating the immune response, and fine tuning human’s management of cancer and auto-immune diseases.
The 2025 Nobel Prize Committee award said it well: “The immune system is a marvel of intricate checks and balances, enabling robust defences against infections while, in most cases, avoiding destructive responses against the body’s own tissues. How is this balance maintained? This question has puzzled immunologists for more than a century.”
The Committee’s next paragraph reads like a high school science class: “A robust immune system is critical for our survival and health. Without it, we would be highly vulnerable, as we are constantly exposed to microbes in our environment. The immediate response following an infection is provided by the innate immune system, while the adaptive immune system requires a few days to be mobilised. A hallmark of the adaptive immune system is its ability to ‘remember’ pathogens we have been exposed to previously, so we can respond quicker and more efficiently the next time we encounter the same agent.”
About 80% of our bodily cells by count are blood cells. Most of these are red blood cells (RBCs). Approximately 1% of total blood volume are nucleated white blood cells (WBCs), and only 15% of these are lymphocytes which take the lead in providing humans with critical Adaptive Immunity. This form of immunity is fueled by constant surveillance for abnormality internally and threats externally. It is highly specific, slow in reacting but with long-term memory, and capable of deadly force by coordinating a cellular and humoral response. In short, lymphocytes “hold a grudge”, laying in wait at the site of a prior insult, and responding with speed and force to a second assault.
The 1958 prize winner, Jean Dausset, (#16 on the list of the 28 AAI winners), is credited with having uncovered the fact that all of an individual’s nucleated cells possess identification tags – Human Leukocyte Antigen (HLA) molecules that are derived from individual specific genetic instructions from a small locus on the short arm of chromosome 6. These molecules define you as “one of a kind” and “tolerable” or excluded from preemptive self-attack.
As time went on, it became clear that HLA’s were the key to a surveillance system allowing the human organism to differentiate between “self” and “non-self” – the lifeblood of Immunology. No part of our body is cut off from its surveillance. For this reason, in aggregate, immunity consumes enormous resources, producing the large number of cells that it depends on for successful surveillance functioning.
As the new century approached, it became clear to scientists that turning off the immune system might be as important as turning it on. This insight first was associated with failed attempts at tissue and organ transplant which early on were met with rejection. As HLA matching became routine, the problem with rejection lessened but never fully disappeared. Even with relatives as donors, no two HLA fingerprints were identical. But the addition of drugs that could suppress immune reactivity extended the life of donated organs.
A second challenge was the growing understanding of a group of chronic diseases lumped together as auto-immune diseases. These included Multiple Sclerosis, Rheumatoid Arthritis, Lupus, and others. Long term treatments of these diseases, where the immune system misinterprets “self” as “non-self” and attacks, remains challenging. Finally, as the 21st century dawned, scientists began to challenge a century of dogma on “self and non-self”, and the clear distinction between innate and adaptive immunity.
Fundamental questions had arisen. How and why did the body tolerate the flourishing and cooperative microbiome organisms? Why do mothers not reject fetal cells that leak into maternal circulation during pregnancy? And how was it that exposure to a relatively benign virus, Epstein Barr Virus, seemed to predispose individuals to later development of Multiple Sclerosis. Was “molecular mimicry” at fault?
Scientists knew that lymphocytes held the key to solving these mysteries. There are two main types of lymphocytes. The first is the “B-lymphocyte.” The B stands for bone marrow, the site where these cells originate. The second is the “T-lymphocyte.” It too develops initially in the bone marrow but rapidly migrates to the Thymus gland where it nests, matures, and awaits further instructions. The two cells work in unison but have different functions.
The capacity of lymphocytes to remember and respond relies on a system of “constant surveillance.” Each human possess an entirely unique set of Human Lymphocyte Antigens (or HLA’s) that attach to the surface of every one of our nucleated cells. One of the major functions of B-lymphocytes is to produce and secrete HLA-sensing receptors into the general circulation.
These are called antibodies or immunoglobulins. They are “Y-shaped” proteins constructed of 2 light chain proteins and 2 heavy chain proteins. Each functions as a circulating antenna, surveilling, checking and double checking that every cell belongs to you. If the answer is yes, all well and good. No action is required. But if the answer is no, an immediate response occurs.
The detection system of the circulating Y-antibody uses the “V” top of the “Y” to detect and bind to circulating foreign proteins. Each invader is also distinct chemically. An antibody or immunoglobulin not only can detect a microbe cell that is not your’s, but also what that organism is. A protein of a measles virus, is different than a rabies virus. An e-coli bacteria is not to be confused with a spirochete. With a huge volume of constantly circulating antibodies providing this very active form of monitoring and a stringent exacting verification process, everything not human is identified as a threat.
Once the invader is marked as a threat, the standing column end of the “Y” attracts helper T- lymphocytes. A signal from the T-cell labels the invader for destruction and calls in B-cells that “recognize” the specific invader. With “specificity” established, the B-lymphocyte makes millions of clones of itself to join the attack and also neutralizes any harmful toxins released into the circulation by the invader.
How exactly does the body remember? First. the millions of B-lymphocytes produce Y-shaped antibodies (or immunoglobulins – Ig) traveling in the blood. They are able to go anywhere blood goes, and are distributed evenly throughout the body. Invaders are identified with specificity and helper T-lymphocytes (stimulating highly specific B-lymphocyte clones) are called to the site. When the job is done, Killer-T cells will continue to reside in the tissue around the former site of action, alert but not activated, ready to attack if reinfected. This offers future protection, and in effect, survival.
As is now clearly evident, the immune response system is enormously complex and purposefully redundant since so much is at stake. Beyond the constantly evolving tools of the innate system (including liquid, chemical and cellular barriers), a granulocytic and lymphocytic cell line, HLA antigens attached to every nucleated cell in the body, and HLA receptor sensors on millions of immunoglobulin antibodies, there is also a fail safe emergency response inflammatory cascade, the complement system, that can be triggered in an emergency.
Which brings us back to immunologist Mary E. Brunkow (#28 0n the list of AAP Nobel Prize winners.) She and her colleagues were able to identify a sub-type of T-cells that turn off the inflammatory immune response. These auto-regulatory T-cells are labeled Tregs for short. And their therapeutic value may be inestimable. On the one hand, “turning off” the system could be life-saving in autoimmune diseases, and in cancers that have been shown to recruit the cells to offer a shield from immune destruction of these deadly cells.
As the 2025 Nobel Prize announcement summarized: “As our understanding of Treg cells deepens, so does the potential to harness their power for therapeutic benefit—protecting us from the twin perils of autoimmunity and immunopathology, while ensuring immune system homeostasis.”
