Pandemic Diary 2020-07-02: Thymus theories

This post is pure conjecture. I’m not an immunologist or virologist or doctor, nor am I particularly informed in any of those fields. Still, I’ve been obsessed to the point of paralysis by the COVID pandemic, and I try to make sense of things. I offer this in hopes that people more informed than me will tell me why it’s full of shit, not because you should expect it should be right. (And, though it’s all probably wrong, I don’t think these ideas are original. I’m just giving order to thoughts gleaned from conversations in the ether.)

So. Here’s the “theory”. Recently evidence has emerged that T-cells play an important role in COVID recovery and immunity (ht Andy Slavitt). T-cells (as I understand things!) comprise a distinct though related line of defense from antibodies and the B-cells that produce those. The adaptive immune system, in my imagination, is like a mind that works to sense and remember invaders, and produce a response that must be carefully calibrated to repel them without causing too much “collateral damage” to the body. T-cells have a variety of roles in that mind, serving as repositories of memory and helping to coordinate the antibody response. But they also function as killers.

While antibodies mark and disable invaders floating around in your blood, killer T-cells “look inside” the cells of your body for untoward activity that might indicate infection. (Our cells have a kind of billboard upon which they display information about what they are up to, for these cells to observe.) When these killer T-cells decide they have sufficient evidence that a cell has gone rogue, they induce the cell to kill itself. This is a rough sort of justice. Antibodies are officer friendly, attacking bad guys but leaving the host unharmed. Killer T-cells are secret police, disappearing cells whose continued survival they deem not in the interest of the community. Killer T-cells attack not outsiders or invaders, but your own tissue, as a necessary evil to root out infection.

White blood cells are developed into T-cells by an organ called the thymus (after which they are named). One a priori clue that T-cells might have some role in COVID-19 is the age profile of the thymus. The thymus is most active in young children. It’s function declines with age, particularly after puberty, when it begins to “involute” or atrophy. While the thymus functions to some degree even in the elderly, it decays continuous over our lifespans, getting worse and worse. In male rodents, castration can slow this puberty-accelerated atrophy, and interestingly there’s evidence that human castrati have unusual longevity. (I still don’t recommend the procedure.)

Young children do very well with COVID-19, while the risk of a difficult outcome increases monotonically with age. This seems suggestive that the thymus and its T-cells might have a role in repelling the disease.

Two other pieces of evidence seem to fit. A recent French study found that asymptomatic close contacts of infected individuals often showed a T-cell response with no detectable antibody response in blood (ht TWiV, a great podcast!) What this might mean is that, in the very best kind of response to the infection, where you don’t get sick at all, your T-cells just quickly dispatch infected cells without much of an assist from antibodies at all. A Chinese study comparing the antibody response between asymptomatic and clinically-ill infecteds found, perhaps counterintuitively, a stronger antibody response among the sick than among those with no symptoms. Again, this seems consistent with the idea that a quick T-cell response is what’s most capable of forestalling the disease. Antibodies, in this conjecture, represent a second-best response, appearing if the T-cell response fails to make quick enough work of the infection.

It’s all about kinetics, about speed, in this “theory”. It’s a race. Bad outcomes come from a too-slow T-cell response. If your immune system develops COVID-19-attacking T-cells too slowly, you get a big but perhaps not-super-effective antibody response because nothing else is restraining the infection. Eventually, even older, slower thymuses do produce, but by the time they do, the infection may have run wild, so your own killer T-cells may end up deciding to attack a whole lot of your own tissue. This seems consistent with the observation that, once the infection becomes severe, immunosuppressants help prevent bad outcomes.

So that’s the conjecture, definitely overfitted to stuff I hear, probably bullshit, for what it’s worth.

What would be the implications if there were something to this? On the optimistic side, if the French study generalizes and an effective T-cell response often forestalls a discernible antibody response, that’s “immunity not reflected by serology“, which could mean that the infection fatality rates we’ve estimated from serology studies are overstated, and the disease may not be as commonly fatal as we think. On the less optimistic side, it means that an observed antibody response might not be strong evidence of vaccine effectiveness (e.g. here). It also calls into question the likelihood that convalescent plasma therapy and monoclonal antibodies will be great. Obviously, I hope these less happy implications are wrong.

Under this conjecture, if there were some way to accelerate thymus function or reverse its deceleration, that might be useful as a prophylactic. If thymus health can be evaluated more individually than “it gets worse with age”, maybe that would predict risk of a hard disease course. But it’s no great insight that bad health of an organ of the immune system would predict difficulty at repelling an infection, or that improving the health of such an organ might help. If there are thymus-stimulative treatments out there, probably they are already being tried.

These “thymus theories” are how I’m currently, tentatively, making sense of things for myself. But I’m not sure they are right, and even to the degree they might be, I’m not sure they buy us very much.


5 Responses to “Pandemic Diary 2020-07-02: Thymus theories”

  1. Detroit Dan writes:

    Interesting. Here’s something a quick search turns up:

    Hopes that the COVID-19 pandemic may end sooner than initially feared have been fuelled by speculation about “immunological dark matter”, a type of pre-existing immunity that can’t be detected with SARS-CoV-2 antibody tests.

    Antibodies are produced by the body’s B-cells in response to a specific virus. Dark matter, however, involves a feature of the innate immune system termed “T-cell mediated immunity”. T-cells are produced by the thymus and when they encounter the molecules that combat viruses, known as antigens, they become programmed to fight the same or similar viruses in the future.

    Studies show that people infected with SARS-CoV-2 indeed have T-cells that are programmed to fight this virus. Surprisingly, people never infected also harbour protective T-cells, probably because they have been exposed to other coronaviruses. This may lead to some level of protection against the virus—potentially explaining why some outbreaks seem to burn out well below the anticipated herd immunity threshold.

  2. Detroit Dan writes:
  3. japhy writes:

    Melatonin also decreases with age.

  4. albatross writes:

    One important difference, as I understand it: If you have an effective antibody response, future attempts to infect you will just bounce off–every time you’re exposed to the virus, the virus particles are quickly coated by antibodies and disposed of by the rest of your immune system. If you have an effective cellular response (cytotoxic T cells and other stuff), you can get infected, but then your body very effectively controls the infection, so you may not get very sick, but you may still transmit the virus. (The virus gains entry into some cells and starts replicating, but those cells quickly get zapped by the cytotoxic T cells, so it can’t spread very well.)

  5. Detroit Dan writes:

    More here: More on T Cells, Antibody Levels, and Our Ignorance, by Derek Lowe.

    Many readers will have seen, for example, this new paper from The Lancet on a large study in Spain. Testing tens of thousands of people across the country continues to show that (on average) only about 5% of the population is seropositive (that is, has antibodies to the virus)… the Spanish survey may appear to show that 95% of the country has not yet been exposed to the coronavirus, but that’s almost certainly not true.