Introduction
When Ilya Metchnikoff first pinned small thorns into the transparent larvae of a starfish in the late 1800s, he saw mobile cells within the larvae quickly surround the thorn and attack it. In essence, he saw what we now know as the immune response in action.
Since then, our understanding of the immune system, especially that of humans, has exploded – a far cry from the few cells Metchnikoff saw under his microscope. We now understand, for example, that the human immune system has two components: the innate immune system, which elicits a rapid, non-specific immune response (similar to that of the starfish larvae), and the adaptive immune system, which recognizes specific characteristics of a pathogen, termed antigens, and triggers a pathogen-specific response.
Yet, when thinking about that initial experiment, one has to appreciate how simple the immune system of a starfish larva is in comparison to that of a person, given the distance of our evolutionary ancestors. How did we get from a few mobile cells in a transparent, microscopic body to the 1.8 trillion immune cells that move throughout our bodies every day? In other words, how has the immune system evolved over time?
Single-Celled Organisms
While single-celled organisms may not possess what we traditionally consider an immune system (i.e., one made up of specialized immune cells), they do possess a whole host of innate defense mechanisms to protect themselves from pathogens.
One example in which they do this is via phagocytosis, a process in which a cell engulfs and degrades an extracellular pathogen. Both specialized mammalian immune cells and many single-celled organisms possess this ability. In fact, an organelle called the mitochondria, nicknamed the “powerhouse of the cell”, was theorized to have originated from the phagocytosis of an ancient bacteria by a larger single-celled organism!
Invertebrates
It turns out a backbone isn’t the only thing invertebrates lack – they also lack an adaptive immune system! Thankfully, they make up for it with a diverse range of innate immune mechanisms to defend themselves from pathogens.
As mentioned previously, where an adaptive immune system recognizes specific pathogens, an innate immune system is a generalized, non-specific immune response. As such, rather than detecting specific pathogen characteristics, it relies on sensing danger signals that indicate the presence of an infection, namely pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). These signals are recognized by pattern recognition receptors (PRRs) expressed on the surface of cells, and emerged alongside the evolution of early invertebrates. For example, PRRs have been detected in different species of sponges, some of the most primitive invertebrates (and by extension, animals). Later invertebrates have evolved their innate immune systems to possess more complex PRR systems and specialized immune cells. For example, fruit flies (Drosophila melanogaster) have three types of immune cells, with one population, plasmatocytes, possessing the same phagocytic capabilities as both amoeba and some human immune cells. Interestingly, while innate immunity is not generally considered to have memory, recent research has shown that many invertebrate immune systems can possess some aspects of immune memory.
Jawless Vertebrates
Jawless vertebrates comprise the next evolutionary step from invertebrates, and it is here that we begin to see the earliest origins of adaptive immunity. Modern examples of jawless vertebrates, such as the hagfish and lamprey, possess hallmarks of adaptive immunity, such as the production of antigen-binding molecules similar to human antibodies. What puzzled scientists was that the genes that define human adaptive immunity, as well as the organs (thymus, spleen) that allow for the production of these molecules, were absent in these organisms.
This all changed in 2004, when scientists discovered the presence of a family of variable lymphocyte receptor (VLR) genes. VLR genes contain the information needed for the production of VLR proteins, which recognize specific antigens. What allows these proteins to be specific to pathogens is that they are susceptible to becoming randomly modified by the insertion of repetitive sequences. The end result is the generation of trillions of different VLR proteins, all of which could potentially recognize different antigens. While distinct from antibodies, this process is likely the earliest origins of a mammalian adaptive immune system.
Jawed Vertebrates
Jawed vertebrates are where the adaptive immune system, as it is defined in humans, finally emerges. Rather than the modification of VLR genes resulting in trillions of VLR proteins, jawed vertebrates rely on a system called variable-diversity-joining (VDJ) rearrangement to create trillions of T cell receptors (TCRs) and B cell receptors (BCRs), the evolutionary equivalent of VLR proteins. One event that made this possible was the RAG transposon event.
The RAG transposon event refers to the invasion of a segment of DNA into our genome that allows for the production of the proteins RAG1 and RAG2 (i.e., the RAG1/2 gene). When and how this gene invaded our genome (the collection of all the genes in our body) is unknown. It was initially thought to have entered our genome in a vertebrate ancestor, possibly through a virus, but recent evidence has identified RAG genes in sea urchins, meaning it could have invaded much earlier. As to why it only became active in jawed vertebrates, we still do not know. Either way, it is difficult to underscore how essential RAG1 and RAG2 proteins are to our adaptive immune system. They are so essential that deleting them from mice results in the deletion of the entire adaptive immune system!
From here on, the jawed vertebrate immune system was further sculpted by evolutionary pressures to where we are now, characterized by the development of different antibody subtypes and changes in the structure of the organs where the adaptive immune system predominantly resides.
What’s next for the human immune system?
While one might expect the human immune system to have stopped evolving, human populations continue to adapt to new pressures through genetic variation, environmental exposures, and social factors that shape immune function.
For example, it has been established that two groups of long-extinct distant human ancestors, the Neanderthals and Denisovans, often interbred with modern humans (i.e., Homo sapiens), and modern technology has enabled us to understand how this has shaped our modern immune system. Crucially, Neanderthals and Denisovans differed subtly from modern humans in the ways their immune systems communicated and recognized pathogens. Examples include Neanderthal- and Denisovan-specific variants in genes coding for cytokines and transcription factors, molecular messengers and regulators of the immune system, and even in some PRRs. When considering that different ethnic groups possess varying amounts of Neanderthal and Denisovan DNA, it becomes all the more important that research into the immune system is inclusive of people of all different ethnic backgrounds.
However, genetics are not the only driver of human immune evolution. Throughout history, as major pandemics have swept the world, the immune system of subsequent generations have become defined by the genomes of the survivors. For example, the frequency of the gene ERAP2 increased in human populations after the Black Death because it conferred protection, even if it is now linked to increased risk for autoimmune disease. Only time will tell whether modern pandemics, such as the recent SARS-CoV-2 pandemic, will have the same effect.
So, the next time you get a chance to look at a lymphocyte under the microscope, just remember that you are facing a miraculous product of cell engineering, shaped by millennium of evolutionary pressures.
Christopher Ryan Tan
