Part 2

On why comparing immune cells in the uterus with those in the blood can be misleading… 29/

I already said a bit on this back in Part 1. In particular I mentioned that the accessibility of the blood can lull us into a false sense that measuring immune cells in the blood will tell us something about what they are doing in the uterus. 30/ https://twitter.com/VikiLovesFACS/status/1290411571320098817?s=20

As @AshleyMoffett used to say, this is like counting red minis on the M25 and expecting it to tell us something about the number of black cabs in central London. 31/

But other, subtler, mistakes emerge when we use blood immune cells as our go-to comparator. 32/

For example, Tregs are much denser in the uterus than they are in the blood. So it might be tempting to suggest that they have an important role in mediating tolerance to the semiallogeneic fetus. Maybe they do. 33/

But if we look at the liver, gut and lung we see something similar. So maybe all we’ve done is discover a general property of immune cells in tissues. 34/

We see something similar with TGFb, which is highly expressed in the uterus and has been suggested to mediate the development of uterine NK cells. 35/

But TGFb also mediates a similar process in the development of specialist local ILC populations in other tissues, such as the liver and salivary gland. 36/

A question I like to ask, as we look for immune factors that are involved in the success of pregnancy is: what would happen in another organ, if we took this away? 37/

For example, Crry knockout mouse embryos, which lack a complement regulatory factor (somewhat like DAF in humans) die at about embryonic day 10.5 due to complement-mediated inflammation. That tells us that Crry is really important for fetal tolerance, right? 38/

But if we lose complement regulatory factors in any organ we expect a complement-mediated immune response. 39/

In fact, this is one of the problems with trying to transplant pig organs into humans… they don’t have the right complement regulatory factors and undergo complement-mediated hyperacute rejection. 40/

We see something similar with Tregs. In mice, depleting them during pregnancy can cause fetal loss. So they’re important for fetal tolerance, right? 41/

We see something similar with Tregs. Depleting them during pregnancy can cause fetal loss. So they’re important for fetal tolerance, right? 42/

But depleting Tregs also causes massive, fatal, immune reactions in all organs within about a week. So what we’ve really discovered is that Tregs are important for tolerance in all tissues. 43/

None of this is to say it’s not important to know about these things. But we have to be careful of claiming to have discovered something about fetal tolerance, when actually we have discovered something about tolerance in general. 44/

As it happens, there is a lot that is special about the placenta, immunologically, that is important for tolerance. I’m going to recommend this paper again. 45/ https://pubmed.ncbi.nlm.nih.gov/23237963/ 

It’s super-interesting, particularly if we could harness some of these mechanisms to induce tolerance in clinical situations where it would be useful. 46/

But because there are so many layers of redundancy here, most failures of pregnancy – even if we think there may be an immune component involved – are probably not failures of tolerance. 47/47