Immunity II: In His likeness
Which all things could plausibly be ‘antigens’ ?
The distinction between ‘mine’ and ‘yours’ is not, as it seems at first glance, trivial. Considering the life forms have co-evolved for billions of years, they are really less dissimilar to each other than you would think.
At the scale we view the world, the differences are quite obvious. You are, at least from a purely anatomic perspective, quite unlike a bacterium. You have acquired evolutionary traits like ‘division of labor’ between organs, lost most of the metabolic capacities (yes, lost; any random bacterium has a much richer set of enzymes than human beings), and generation time (i.e. the time taken for a newborn to reach reproductive maturity and produce an offspring of its own) has lengthened by several magnitudes.
But biology still operates at the level of chemistry; and at that scale, things have hardly changed. You are more similar to a bacterium than a bacterium is to a rock. You are still made of proteins, carbohydrates, lipids, the very molecules that go into making a bacterium. Rocks, on the other hand, are solid chunks of a mix of metals (mostly their oxides and complex conjugates), which is unlike anything found inside you. (You have metal inside you, yes, in bits and pieces, usually attached to some protein, like iron in the middle of the hemoglobin molecule; you don’t have anything like ZrSiO4 in you).
So you would expect rocks to elicit a stronger immune response in you than bacteria, right?
Wrong. Metals hardly produce a immune response, if any ( to be sure, they do excite a few T cells, but that’s that). In fact, millions of people with a joint replaced live in perfect harmony with metals inside them. There has been no cases of a artificial metallic limb being ‘rejected’ by the immune system (although, on a few occassions, the immune system does ‘loosen’ the artificial joints a little¹). Nothing remotely as severe as rejection of a grafted kidney.
But maybe this is because metals remain as atoms, or at most — simple oxides no more than a few hundred in molecular weight. In which case, the large crystal lattice of titanium, millions in molecular weight, should make my immune cells go crazy, right? Wrong again. Titanium implants do manage to produce an immune response, but nothing of clinical significance (and most of the outrage is targeted agianst the admixed vanadium)².
Which only begs the question.
Let’s move onto a different class of molecules — something more to the liking of our atomic composition; something made of carbon and hydrogen.
There’s really nothing about aniline that would incite curiosity even in the terminally neurotic; aniline is a benzene ring (a ‘phene’, if you will) plus a run-off-the-mill amino group. And its one of the most abundant toxins in the post industrial world; aniline is the mother tincture of many of the dyes in our everyday clothing. One can be exposed to any quantity of aniline, to the point of even death, without showing any immune response. It seems the immune system, whose only job is to protect our carnal beings, is not very good at its job.
But let’s continue our journey upwards: three benzene rings put together (‘anthracene’) elicits a discernible, albeit limited, immune response. You get a mild skin rash, and that is about it. Nothing specific to protect you against increasing doses of anthracene. The system still has not registered the offending molecule as ‘sufficiently foreign’.
Is there a pattern here?
To elicit a targeted immune response, it is not enough for a molecule to be large. Titanium lattice is noticeably, but it is made of repeating units of the same atoms, and is thus ignored by the immune system. Smaller molecules like aniline, although made of different kinds of atoms, are still overlooked due to their very small size.
A key insight from the early days in immunology was a peculiar obervation: that when small but complex molecules are conjugated to a known, innocuous protein (like albumin), it suddenly drives a targeted immune response, i.e. you can have antibodies against aniline which will actually protect you. Such small molecules, that can capture the attention of the immune system only when bound to a larger protein, are called half-antigens (‘haptens’, if you will).
The trigger, in this case, seems to be not aniline itself, but the minor changes in conformation of atoms in albumin, which have been brought about by binding aniline. It says more about the immune system’s inkling towards albumin, a known protein, than aniline. It seems even a minor conformation change in an atom of albumin shalt not be tolerated. This is the very reason why my immune system will reject somebody else’s kidney, which have very similar but ever-so-different molecules from mine; whereas, the same immune system will happily ignore grossly dissimilar molecules like titanium lattices.
These initial observations were later confirmed by the fact that differences, even in one or two amino acids, in otherwise known, housekeeping proteins — could elicit a severe immune response. The very reason we can generate antibodies against bacteria and virus is that, on the whole, they are not very unlike us. The day an alien bacterium with a molybdenum based life form invades the earth, we would succumb even without mounting an immune response, for the simple reason that those creatures would be too dissimilar for the immune system to react.
All of which are telltale signs of a active, methodical, almost intellectual — machinery — running the immune system.
