OK, so we all know the basic story of the immune system: A virus or other pathogen enters the body, the immune system develops an antibody to it and mass-produces it, the antibody neutralizes the invaders, and the immune system keeps the plans for the antibody in case the same pathogen invades again.
But there are a lot of gaps in that basic story that need explaining. First of all, how does the immune system manage to develop molecules of the appropriate shape? Humans do that too, in drug development, but it’s still extremely difficult. Granted, the body’s immune system is massively parallel in its work, but then again, it’s hard to imagine that cells are much better at this than computers.
Then, once you’ve developed the antibody, how is it mass-produced? Antibodies are proteins, right? But doesn’t every protein has a gene that produces it? I presume that the immune system isn’t writing new DNA sequences from scratch to produce each new antibody. What other ways are there of manufacturing proteins?
And then, after the invader is fought off, the immune system stores the plans for the antibody, so it can be quickly ramped up if needed: This is of course how vaccines work. But how is this information stored? DNA? Something else? It must be stored in many different cells, so that many cells can produce the large quantities of antibody needed, which means that the information must be in some easily-copied form. But nucleic acids are the standard medium for easily-copied biological information storage.
And if all of this is done via DNA, would that suggest that resistance to diseases would be heritable, Lamark-style?
No, that’s pretty much what happens. There are segments of the DNA of immune system cells that mutate at orders of magnitude above the standard rate. They evolve new genes to produce new antibodies.
Nope, because the germline cells aren’t the ones doing the mutating.
Huh, I really ought to know better than to reject an obvious solution just because “nah, that can’t be it”.
So, once one lucky immune system cell comes up with a sequence that makes a working antibody, how does that spread to enough cells to mass-produce it? Does that cell reproduce to sufficient numbers, displacing the other cells that weren’t so lucky, or do they exchange genetic material?
This is a topic where a handful upper-level undergrad immunology courses will barely scratch the surface. I’m probably going to get to the limits of my knowledge – how to get a critter to make an antibody to use as a detection reagent – real quick.
ETA: One memory B cell divides to produce large numbers of antibody producing cells which produce sufficient quantities of the antibody to fight off the infection.
To be precise, it’s only one particular cell, and its descendants, that will make a new gene (for each antibody chain) that will bind to some antigen that the body recognizes as “foreign”. The system as a whole makes many antibodies because there are many different antibody producing cells.
This process is called “B cell maturation”. Immature B cells make antibody genes by randomly picking from sets of partial segments encoded in the genome (these are the V, D, and J segments). These are recombined into a single gene coding for the heavy or light antibody chain.
During B cell maturation, immature B cells with their randomly produced antibodies will interact with antigen-presenting cells. If they bind to an antigen, they receive signals to divide and grow. But if they also bind to any antigen in the host, they are killed off. This means there is both positive and negative selection for antibodies that bind to a specific foreign antigen.
Later on, somatic hypermutation produces many variants of the immature antibody, and selects for B cells that produce antibodies that bind even better to a particular antigen.
The population of B cells that produces an antibody will stay with you for most of your life. When a particular B cell detects something that binds to its antibody, it divides to produce a large number of antibody producing cells to fight off an infection. After the infection, most of those cells die, but some remain as memory B cells which wait for the next infection.
The driving force behind the evolution of the immune system is the fact that pathogens have a short generation time, measured in minutes rather than years. Pathogen evolution is orders of magnitude faster than host (e.g. mammalian) evolution. This means that resistance cannot all be hard-coded into our DNA by evolution: if it were, pathogens would quickly evolve to evade it, and we would always lose that evolutionary arms race.
Early in life, we generate a huge and random diversity of specificities to almost every conceivable “shape” (epitope) of antigen. This is achieved by carefully orchestrated mutation of the parts of the DNA that code for receptors and antibodies within lymphocytes (T- and B- cells) in a process called V(D)J recombination. The DNA in each T- and B-cell recombines randomly and differently; after this mutation, each individual cell now stably produces receptors or antibodies with one particular specificity.
Next, at a specific time (still early in life), this diverse population of T- and B-cells is carefully exposed to every type of protein that is produced by the host, i.e. all of the “self-antigens”. Any cell found to react to a self-antigen is killed, a process called clonal deletion. This is how we achieve immune tolerance so that the immune system does not routinely attack the host’s own tissues.
After clonal deletion is complete, the immune system now goes “live”. There remains a huge diversity of T- and B-cells, each with a different random specificity, but none reactive to host tissue. The diversity is so great that if a pathogen invades the body, there will almost certainly be a few cells with the specificity to react against some non-self antigens found on or in the pathogen. However, because of the need to maintain such great diversity, upon first exposure to a pathogen there will only be a few cells that react. The first encounter causes these reactive cells with specificity for the particular pathogen to proliferate massively, but this takes time, that’s why fighting off a first infection often takes a few days. But reactive cells are also stored in immunological memory, which means that clones of these cell are primed to respond and multiply much more quickly to the second exposure to the same pathogen. Furthermore, these reactive cells undergo a further process of fine-scale diversification by carefully orchestrated DNA mutation called somatic hypermutation that allows them to fine-tune their specificity the foreign antigen.
There’s another really cool part of the story: antigen “encryption” by the immune system.
In addition to the antibodies produced by B-cells, part of the adaptive immune response is mediated by T-cells that recognize antigens through receptors on their surface. These T-cell receptors have the same range of random diversity in antigen specificity (generated by V(D)J recombination) as antibodies. However, T-cell receptors do not recognize “raw” antigen. They recognize carefully processed antigenic peptides that are randomly chopped up and “presented” to them on the surface of Antigen-presenting cells. These peptides (pieces of antigen, whether self proteins or chopped up parts of pathogens) are held in place on the surface of Major Histocompatibility Complex (MHC) cell-surface proteins, and the epitope (shape) that the T-cell receptor recognizes is the complexed shape of the antigenic protein plus the MHC protein that’s gripping it. In effect, the antigen is encrypted by the MHC molecule when presented to the T-cell receptor.
Now, the MHC region of the genome is one of the most diverse (polymorphic) in the genome - i.e., there are a wide variety of MHC “haplotypes” present in the population. Here, we are talking about hard-coded DNA variation, different people in the population carry different variants at this locus in the genome, and pass on their particular variants to their children.
What this means is that two individuals with different MHC haplotypes will “encrypt” the exact same pathogenic antigen in different ways, to produce a different epitope (shape) for the T-cell receptors to look at. All of this makes life much harder for a pathogen. Even if a pathogen can learn to “display” only epitopes that look similar to host proteins on its surface, the pathogen’s proteins will be chopped up endless different ways, and then encrypted in different ways by different people in the population according to each person’s particular MHC haplotype.
MHC “encrypted” presentation of antigens is the reason for the need to tissue-type people, because the host proteins are also encrypted in the same way during the process early in life when the immune system learns tolerance for self. Self-antigens that are encrypted by a different MHC haplotype will be treated as foreign. Thus, a “tissue match” is somebody with a similar MHC haplotype.
The other interesting thing about the MHC region is that there is obviously an evolutionary advantage to having a different MHC haplotype from other people in your local population. If pathogens have not yet encountered your particular encryption key, they are unlikely to have evolved to subvert it. Thus, the MHC region is subject to strong balancing selection, the unusual form of natural selection that favors diversity.
In my experience, immunology is often poorly taught. Courses can get bogged down in the intricate and often tedious details of innumerable types and sub-types of cells and clinical aspects, while failing to communicate the evolutionary context and the overarching principles that explain why things work the way they do.
There’s been some talk of a gene that confers resistance to HIV (I think it’s speculated that it originally evolved in response to bubonic plague, which it also protects somewhat against). Would it be right to guess that that gene is in the MHC region?
No, it’s not in the MHC region. The mutation does not enhance the immune response to HIV, rather it prevents HIV from getting into cells.
I don’t know much about it, but the most common form of heritable resistance to HIV appears to be the CCR5-Δ32 deletion, resulting in a non-functional CCR5 receptor. This is a cell-surface receptor that some forms of the virus exploit to gain access to the interior of the T-cells where they live.
Trying to research the answer I come up with the onset being with jawed fish and with “the emergence of the recombination-activating gene (RAG) transposon, and two rounds of whole-genome duplication.” That article notes adaptive immunity also comes with substantial costs (e.g. risk of autoimmunity) and hypothesizes that the pressure was the few offspring that larger jawed predators gave birth to.
Another article however suggests that the adoption of a more complex microbiota and the need to tolerate it as “self” was more likely the driving pressure.
The key event in the evolution of adaptive immunity was the “acquisition” of the RAG recombinase genes that generate diversity in V(D)J recombination. The RAG genes and their target sequences derive from transposons that jumped by chance into favorable positions in the genome relative to the ancestors of immunoglobulin and T-cell receptor genes. This happened a long way back in vertebrate evolution, in our common ancestor with the jawed fish.
It’s interesting that jawless fish have an adaptive immune system that generates receptor diversity in a completely different way (without RAG genes), i.e. their adaptive immune system is convergent evolution.
I’m a little too rusty on the innate immune system to attempt to discuss its evolution.
ETA: I see you ninja’d me on some of that while I was writing it. Yes, it’s the RAG genes that were critical.
I can’t use the phrase “rusty” as that implies that there is something there that worked once and would now if only I had kept it well oiled …
Agreed on how immunology is taught and my head spinning keeping the sub-classes only partially confused is a case study of it!
Innate immunity was at most grazed over yet it is a big area of recent research especially in regards to dealing with multi-drug resistant organisms.
I’d be very curious to find out if the jawless fish that convergently developed an adaptive system somehow also only gave birth to few progeny or if they instead began to develop a greater diversity within their microbiomes. I must admit the concept of the adaptive system co-evolving with gut microbiomes, more out of the advantages gained from having tolerance to a diverse microbiome with the superiority over a pure innate system being relatively gravy, appeals.
Which makes perfect sense … but … there are lots of species on this planet that do not have adaptive immunity, pretty much have resistance hard-coded into their DNA by evolution, and they somehow have not lost the evolutionary arms race. It’s a pretty broad and varied swath of evolutionarily successful organisms. Don’t consider any Kingdom except for Animalia and it’s still only something Chordata (and not all of that Phylum) came up with.
And among that varied swath of others, some extremely short-lived, some very long-lived (the hydra considered by some to be immortal), some large, some small, some solitary, some social, some large predators (extreme case being the Colossal Squid), some small prey, were other items that convergent evolution came up with … similar eye structure to mammals in the octopuses for example, and in the same group intelligence likely higher (depending on how defined) than most mammals. All dealing with pathogens that evolve orders of magnitude faster than they do and many of them. But all of whom only have that which is generally referred to as innate immunity.
Of course one question is how innate (relatively hard-coded) immunity has been enough for them to carve out sizable niches competing with vertebrates that have adaptive immunity. (And what can we learn from those tricks?)
But the other is that such argues that since evolutionary success does not per se require adaptive immunity then adaptive immunity must have had other benefits within the context of jawed chordates.
One response: survivorship bias in your survey of life on the planet. The vast majority of species that have existed are extinct. Many may be extinct because they lost the arms race with pathogens. So it may still be true that the adaptive immune system confers a big advantage.
Still, of course, we need to understand and explain what’s happening with species that do seem to survive just fine without. At some level pathogens can’t just ruthlessly kill all potential hosts, or they have nowhere to live. So it may be that to some extent pathogens and hosts have evolved toward something more like symbiosis.
Have many more species of Echinoderms or Arthropods or Nematodes or Cnidarians for that matter gone extinct since the dawn of jawed vertebrates than have vertebrate species?
Certainly the second part of your hypothesis does occur. We see it with pathogens that infect humans with great frequency. A pathogen that kills too often too quickly ends up evolving towards a less rapidly fatal version as the latter will infect more other hosts. Excessive virulence can be selected against.
But still your final point is most cogent: some large number of non-vertebrates have survived and adapted to a constantly rapidly changing environment of potential pathogens and parasites using innate immunity alone. We still need to understand and explain what’s happening with those species. Innate immunity apparently has some mad skillz that I certainly do not comprehend the depth of.
thanks for this thread!
I had no idea antibody production was so sophisticated or complex. The idea that in addition to all the antibodies, each body has a unique (or at least special) encryption to identify itself to the antibodies is cool.
How these things develop during gestation without destroying the body is in itself incredible.