@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff Okay, I’ll bite! But first, let’s remember that the (adaptive) immune system as a defence against pathogens predates the evolution of viviparity by some 300 million years. So I’m going for snotty colds too. Now, let’s talk a bit about the immune system in pregnancy... 1/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff This is an area of investigation that has historically been hindered by two things. First, the origin of immunology was in trying to perform skin grafts, so we have often looked at pregnancy through the lens of transplantation, considering the fetus as an organ transplant. 2/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff Second, in humans we have learnt about the immune system by getting cells from the blood. 3/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff This is convenient, but it has often led us to think that things we have found special properties of the immune system in the uterus that allow fetal “tolerance”, when actually many of the things we find in the uterus are features of tissues in general. 4/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff I often wonder how different our understanding of the immunology of pregnancy would be if we had first discovered the immune system in the context of another mucosal site, like the gut. 5/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff But as it happens, the birth of immunology was in the context of skin grafts for badly burned airmen in WWII. 6/ 
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff I have many gory stories on this topic but I’ll save those for another time. For now I’ll just say that Chapter 1 of @dandavis101 book “The Compatibility Gene” is a really good intro to this. 7/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 Peter Medawar, who worked on the skin grafting problem, realised that the immune system could also pose a problem for pregnancy, since the fetus is genetically half dad. Immunologically, we would say that it is semi-allogeneic. 8/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 Here’s Medawar having a sneaky fag while he does a skin graft on a cow. As you do. 9/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 He wrote a paper about this in 1953 that everyone still cites. 10/
pubmed.ncbi.nlm.nih.gov/15013633/
pubmed.ncbi.nlm.nih.gov/15013633/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 Often, students begin their essays by talking about this paper. This is a fun intellectual exercise (for Medawar too – he never did any actual experiments in this area!) but I often caution them that if you begin this way, you have to engage Medawar on his own terms. 11/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 This is to consider the fetus as if it were an organ graft. This is clearly inappropriate for a number of reasons. The main one is that, unlike in an organ transplant, the fetal and maternal circulations do not mix. 12/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 Instead, at the interface between the mother and fetus, everything is mediated by the placenta, a very immunologically interesting organ, which we will come back to later. 13/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 Another point that I think is often worth making is that, even if a pregnancy fails we do not see the massive infiltration of T cells that we see in graft rejection. So the failure of pregnancy is immunologically very unlike the failure of an organ transplant. 14/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 Medawar was very concerned with how the fetus avoided recognition by T cells. We now understand quite well how it does this, and that there is layer upon layer of mechanisms that prevent T cell recognition. 15/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 One of the key features is that the placenta simply doesn’t express most of the molecules (MHC) that T cells recognise. For the interested, this is a really good review that will tell you about ALL THE MECHANISMS. 16/
pubmed.ncbi.nlm.nih.gov/23237963/
pubmed.ncbi.nlm.nih.gov/23237963/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 But part of why I don't always think we should engage with Medawar on his T cell-based, organ graft-thinking terms is that to do so is to distract us from the more interesting (and probably important) immune cells in the uterus... innate lymphoid cells! 17/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 At the time of implantation, the lining of the uterus is full of immune cells that look a lot like natural killer (NK) cells. 18/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 They’re actually quite different from NK cells, but back when they were discovered our techniques weren’t sophisticated enough to tell that, so they were called “uterine NK cells” and the name stuck. 19/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 I’ve actually argued that they should be rebranded “innate helper cells of pregnancy” because we now know that they’re not actually NK cells and that’s a better description of what they do. 20/
pubmed.ncbi.nlm.nih.gov/31630394/
pubmed.ncbi.nlm.nih.gov/31630394/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 They’re certainly very bad at killing and there’s no evidence that they ever kill placental cells. 21/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 But there is evidence that they help the placenta implant. We know this both because they produce factors that achieve this and because combinations of genes that lead to underactivated NK cells are associated with disorders of pregnancy such as pre-eclampsia and miscarriage. 22/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 I think I’m going to have to leave it here for tonight, but if I have time tomorrow I will come back to talk a bit about how comparing immune cells in the uterus with those in the blood can be misleading. 23/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 But before I go, this feels like a good place to mention that NK cells in the blood are not at all like uterine NK cells. It’s still not clear if the two are related (this is an area I could talk about ALL NIGHT!) but they are certainly not the same. 24/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 However, this hasn’t stopped for-profit clinics offering to measure people’s blood NK cells in the hope it tells them what’s going on in the uterus. There is no evidence that it does. 25/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 At the last Cochrane review, there was also no evidence that treatments that target the immune system improve the outcome of pregnancy. tinyurl.com/y2bdwoyt 26/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 (For easier reading, the HFEA summarises their position on the evidence here: hfea.gov.uk/treatments/exp…) 27/
@notimmuneatall @AcademicChatter @OpenAcademics @mothersinsci @ImperialImmuno @AntoniaCuff @dandavis101 This is another area I could talk about ALL NIGHT but I have a long day in the lab tomorrow and really must head to bed. And I haven’t even touched on how (and why) the immune system elsewhere in the body changes during pregnancy. I will try to say more tomorrow... 28...
