🤰🔬Exploring pregnancy’s power to suppress autoimmune disease: Insights from multiple sclerosis research

Keywords

Multiple Sclerosis, Pregnancy, Autoimmune Diseases, Immune Tolerance, GDF15, Neuroimmune Crosstalk, Reproductive Immunology, Maternal Health, Research Challenges, MS Treatment

Summary

In this episode of the Young Immunologist podcast, Nóra Balzer interviews Jana Sonner, a postdoc at the University Medical Center in Hamburg, discussing the intersection of multiple sclerosis (MS) and pregnancy. They explore how autoimmune diseases typically affect women during their reproductive years, the unique immunological changes that occur during pregnancy, and the implications for maternal and fetal health. The conversation delves into the mechanisms of maternal immune tolerance, the role of GDF15, and the latest research findings on MS and pregnancy. Jana emphasizes the need for more research in reproductive immunology and the importance of including pregnant women in clinical trials to improve treatment outcomes.

Takeaways

• Pregnancy can suppress disease activity in autoimmune diseases.
• Autoimmune diseases often onset during women's reproductive years.
• MS does not typically affect fertility or pregnancy outcomes.
• Disease-modifying therapies may pose risks during pregnancy.
• Maternal immune tolerance is crucial for pregnancy success.
• GDF15 plays a role in immune regulation during pregnancy.
• Peripheral immune system adapts significantly during pregnancy.
• Exclusive breastfeeding may lower postpartum relapse risk in MS.
• Research in reproductive immunology is still underfunded and underexplored.
• Inclusion of pregnant women in clinical trials is essential for better treatment.

Please find some links to work both on MS in general and pregnancy and MS

• https://www.nejm.org/doi/10.1056/NEJM199807303390501?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200www.ncbi.nlm.nih.gov
• https://link.springer.com/article/10.1007/s00281-016-0584-y
• https://www.nature.com/articles/s41583-024-00823-z
• https://www.nature.com/articles/s41577-022-00718-z

Contact details

• Contact: Dr. Jana Sonner, jana.sonner@zmnh.uni-hamburg.de
• Webpage Institute of Neuroimmunology and Multiple Sclerosis (INIMS): https://www.inims.de

Chapters

• 0:00 Introduction to MS and Pregnancy
• 2:55 Understanding Autoimmune Diseases
• 5:44 Impact of Autoimmune Diseases on Pregnancy
• 9:09 Exploring Multiple Sclerosis
• 11:52 Maternal Immune Tolerance During Pregnancy
• 15:02 Peripheral Immune System Adaptations
• 17:46 The Role of GDF15 in Pregnancy
• 21:06 Neuroimmune Crosstalk and MS
• 23:53 Latest Research Findings on MS and Pregnancy
• 27:03 Future Directions in Reproductive Immunology
• 30:03 Challenges in Reproductive Medicine Research
• 32:52 Advice for Aspiring Researchers in Reproductive Immunology

Transcript

Nóra Balzer (00:02.524)
Hello everyone. Welcome to the Young Immunologist podcast, Immunochat. And today we are talking about MS and pregnancy, the immunology of pregnancy with Jana. Jana, thank you very much for joining our podcast. Would you please introduce yourself?

Jana Sonner (00:21.721)
Yeah, thanks, Nora, for giving me the opportunity to speak here to our future scientists, probably. I'm a postdoc at the University Medical Center in Hamburg. And I initially earned my PhD in Heidelberg at the German Cancer Research Center, where I was first focusing on brain tumors and brain tumor immunology. But then I also became interested in neuroinflammation in general and also multiple sclerosis. So this is essentially my background.

And since I wanted to dive deeper into this, I joined the Institute of Neuro-Aminology and Multiple Sclerosis in 2019 here in Hamburg. And I was just really inspired by this phenomenon that during pregnancy, there's hardly any relapses in MS patients. So it's really a condition in which the inflammatory disease activity is largely suppressed. This is not

only the case for multiple sclerosis. So you can also observe it in other autoimmune diseases such as rheumatoid arthritis or also optic neuritis. But it's really that pregnancy seems to be the best therapy in these diseases, which I think is super interesting because we can learn a lot from this.

Nóra Balzer (01:39.014)
Yeah, it's super exciting that pregnancy can be somehow also considered as a treatment. But let's go one step back. What are actually autoimmune diseases and how do they typically affect women during their reproductive years?

Jana Sonner (01:56.443)
Yes, so autoimmune diseases, I mean, there are different types of them exist, but in general, it's that the body's immune system mistakes structures, which we also call antigens, which belong to the own healthy tissue as foreign and then attacks them. So it's basically a misregulated response to the cells of the own body. And there are a lot of examples. So for example, type one diabetes, where the body attacks pancreatic cells and destroys them.

or also different forms of inflammatory bowel disease, which affects the intestine. And as I already said, rheumatoid arthritis, where the body attacks the joints, where you have a lot of pain in the joints. A common one is also lupus, has or attacks a lot of different organs. So it's mostly that you have this rash on the skin, which you can see quite often, but it can also target the joints. And as I said myself, I'm interested in multiple sclerosis.

where the targets are myelin sheets which surround the neurons and which ultimately leads to neuronal loss, to degeneration and all symptoms associated with this. And the problem is that in most of the autoimmune diseases, the onset of the disease falls into the time when women start planning their families and where this is a big topic. So for example, in lupus,

The onset can already be with 15 or 20 years, but also for multiple sclerosis, the onset is normally between year 20 to 30. So really when you think about becoming pregnant, and this can then have a massive impact on the decision, but also on the pregnancy. So I think this is really important to have this in mind.

Nóra Balzer (03:43.386)
Yes, indeed, pregnancy is kind of a Russian roulette, I can say from my own experience. I have a rather common autoimmune disease. I have a low thyroid hormone production. And it's also super risky during pregnancy if you are not checking it every four weeks and then you just need to check and make it right at the level is fine.

Jana Sonner (03:56.827)
Mm-hmm.

Nóra Balzer (04:08.144)
But how do autoimmune diseases affect the pregnancy outcomes? And what are the specific challenges do they present for maternal and fetal health?

Jana Sonner (04:21.137)
Yeah, I I in person can only speak about MS because this is the disease I'm working on and I'm also not a clinician scientist, so one has to be careful when talking about this. But at least for MS there is for now no indication that the diagnosed disease affects, for example, fertility, the pregnancy itself or also labor. But also there's a lack of systematic long-term follow-ups on the babies of MS women.

Nóra Balzer (04:24.763)
Mm-hmm.

Jana Sonner (04:50.253)
It's really hard to say if there could be anything, but in general the notion is that it does not affect pregnancy. But of course, if you are diagnosed with MS or any other autoimmune disease, I guess, this may impact your decision to become pregnant because you might be insecure. Patients also suffer a lot from depression and this is probably that what makes you really consider if you want to become pregnant.

But as I briefly said in the introduction, in MS, the disease activity drops during pregnancy, but then it can have a very strong rebound after birth. So this is something where people might be afraid of. And in general, I can just say that patients should approach their neurologist before they try to conceive, because a problem could be the treatment that they are on. So these disease modifying therapies,

they might actually pose a risk for the fetus itself because it can, for example, cross the placental fetus barrier and then also affect the child in the development. And then depending on what drug you are on, there are washout times of, for example, half a year. So you need to be off drugs for half a year before you should conceive. But there are also therapies which are still considered safe even throughout pregnancy. And then the mother still continue to take these medication.

Nóra Balzer (06:16.336)
Yeah, that's interesting that different kind of medications with different kind of outcomes during pregnancy. So actually, would you just briefly explain what is MS and what is the immunopathology of MS that people who are not in this field, they can also just come with the flow.

Jana Sonner (06:38.737)
Yeah, sure. Let's go one step back. So what is actually happening? There are still different theories because there's a so-called inside out or outside in theory, depending on if you think it's first happening somewhere in the peripheral immune system or if it's the first attack basically happened in the central nervous system. But let's just start with the more, I would say more accepted theory that it starts in the periphery. So the problem is that some autoreactive T cells

Nóra Balzer (06:41.084)
Hmm.

Jana Sonner (07:07.789)
escape thymic selection. So this is a process where normally the body deletes cells which recognize proteins of the own body. But some of them can escape and then they can be reactivated if they encounter, in this case, myelin-derived antigens. And the problem is that myelin sheaths, surround the neurons in the central nervous system and they can directly be attacked by infiltrating T cells.

And they can then in a cascade, which is basically amplifying itself, also activate surrounding glial cells such as microglial cells or ester sites, which then promote the disease. And if these neurons die or are damaged in a way, they can then release damage associated molecular pattern molecules. There are different types of molecules.

And they can basically then amplify again the whole cascade. They activate the infiltrating T cells which then release more cytokines or they activate macrophages. And in general you have a very inflammatory milieu which then amplifies the whole problem basically. And you also have a lot of changes in the microenvironment in the tissue itself. For example, disbalance of ions or

neurotransmitters which then again cause damage of the neurons.

Nóra Balzer (08:35.78)
and other known genetic risk factors for MS? How is it?

Jana Sonner (08:40.561)
Yeah, it's a bit, it's still a bit under debate. So it's not a classical hereditary disease. So if you have a parent who has an MS, your risk does not really increase that much. So it's 1.5%. This is the number that you will usually get. So there are some genes which have been linked to MS. So I think it's about 200. And most of them, and this is, think,

Quite interesting, they belong to the family of MHC molecules, so the molecules which present the antigens, or for example genes involved in cytokine signaling. So this already indicates there seems to be a dysregulation in the immune response, which is the primary trigger. But then there are other risk factors which need to be taken into account. And normally even if you have a modification in the gene, doesn't mean that you for sure will get MS.

But then there are, for example, viral infections. And one which was quite popular or is quite popular at the moment is Epstein-Barr virus, which there's going on a lot of research on this one at the moment, because it might be that it's kind of a molecular mimicry. So it has patterns which look similar to myelin antigens, which then in the periphery can activate T cells. And this is still under debate, but it could be

basically how it figures the disease. And others are, for example, vitamin D or also smoking and obesity, which increase your risk for developing MS.

Nóra Balzer (10:19.95)
interesting. So it's a mixture of genetic and environmental risk factors that can cause MS. guess, yeah, still a lot of research needs to be done. But yeah, let's go back to pregnancy with MS and also when a woman gets pregnant, how the immune tolerance works. So can you explain us the concept of phyto maternal immune tolerance? And how is it working in and

Jana Sonner (10:28.229)
Exactly.

Jana Sonner (10:32.475)
Yeah.

Nóra Balzer (10:49.742)
Why is it so critical for pregnancy success?

Jana Sonner (10:54.053)
Yes, yeah, let's switch gears a bit and go to the topic of this podcast, which is pregnancy. So in general, the idea is that there are physiological mechanisms that prevent that the mother's immune system rejects the fetus because in a way the fetus is a semi allograft because it also carries antigens which are of parental origins. So this can be recognized as foreign.

Having this mechanism is really key to maintain the pregnancy and to not reject the fetus. So I thought maybe we first talk about what is happening locally. So what is really happening in the placenta, in the fetus with contact to the mother. So in a way, the placenta is a physical barrier which separates the maternal and the fetal blood. So the idea is that you have minimal contact between the maternal immune cells and fetal tissue because this already minimizes.

Nóra Balzer (11:33.168)
Mm-hmm.

Jana Sonner (11:52.549)
the risk that antigens are detected. And then also what has been observed locally is that so-called regulatory T cells or Treg, they vastly increase in the pregnancy and they are also key in other contexts to suppress immune response and therefore also basically protect from the rejection. And then some cells which are rather special, I think, for

This fetal maternal interface are the so-called trophoblasts, which are derived from the fetus. And they have to invade the maternal endometrium. And then they can generate a microenvironment which prevents the attack of immune cells because they release suppressive cytokines and also growth factors. And what is important, what is also a bit special about these cells is that they express very low levels of

classical MHC molecules, which already tells you, they don't really present fetal antigens so much. So this already helps to suppress the immune response. And on the other hand, what they express are so-called non-classical MHC molecules, and they actively suppress maternal immune cells. And also a specialty, I would say, in this tissue are the so-called uterine NK cells.

So they're really just in the uterus and play an important role in pregnancy and they expand very early on and they also release cytokines and growth factors which are important to control the trophoblast and also to generate this environment which is key to suppress immune responses. And this is in contrast to their usual counterparts in the periphery because they are very cytotoxic and are known for example to attack tumors. So this is really

opposite here. And then just in the late phase it changes a bit so then you have an influx of T cells which then generate a more inflammatory milieu but this is then also important to trigger labor because then you want to basically prepare everything so that the child can be delivered.

Nóra Balzer (14:09.136)
Sounds like a lot of inflammation is going on during pregnancy. I guess that the immune system needs to adapt during pregnancy. But how does the peripheral immune system adapt in these nine months? What implications does this have for the mother and potentially also for the developing baby, the fetus?

Jana Sonner (14:13.381)
Yes.

Jana Sonner (14:35.749)
Yeah, I mean in contrast to what's happening locally at the interface, there are also lot of changes which you can catch up in the systemic circulation. And one of the most obvious ones is probably that you have an increase of pregnancy hormones such as progesterone and they have strong effects on peripheral immune cells. So for example, a very classical description is that

You have a shift from more pro-inflammatory T-helper type 1 cells to a Th2 type, which is more anti-inflammatory. You also here, you have an expansion of the so-called T-Rex, which are in general, suppressive. And also, for example, macrophages, they change their phenotype and they are more in a tissue repair or immune tolerance mode, which can then also affect the mother's system.

And what has been shown and what in way makes sense if you basically dampen the overall immune response is that you are mostly more susceptible to infections because the body cannot fight the pathogen as well. So this, for example, is true for the respiratory tract. there are pregnant women have to be just a bit more careful than usually.

And then one of the factors, and this is one factor that we became quite interested in, is GDF15, which is a growth differentiation factor 15, because it also increases in the serum of pregnant women. And what is interesting in the context of my research and MS is that the highest expression really overlaps with the strongest suppression of disease activity in MS patients. So it's really strong in the third trimester.

And this is also the phase where you see the strongest suppression in MS disease activity. And it had previously been shown that women which subsequently experience a miscarriage, they have lower GDF15 levels. And this was indicating for us that it could be an important factor to confer fetal maternal immune tolerance, but maybe also suppress disease in MS.

Nóra Balzer (16:53.956)
interesting this GDF 15 because I made actually my whole PhD on pregnancy immunology research and also part of my postdoc but GDF 15 is somehow doesn't come super familiar for me. So can you help me what what its primary biological function and how is it sensed by the body?

Jana Sonner (17:16.197)
Yeah, yeah, yeah, it's a bit of a tricky molecule, which I think is still a lot of research has to be done to fully understand its function. So it's a distant member of the TGF-Beta superfamily, and it's in general considered to be a stress-induced cytokine, sometimes also called a metokine. And for example, it can be induced in response to oxidative stress or tissue injury, or also if there's an

Nóra Balzer (17:25.424)
Okay.

Jana Sonner (17:46.105)
accumulation of unfolded protein because the cell is under stress. And as I said, you have not heard about it, which is maybe not surprising because it's mostly studied in the context of metabolic regulation and cancer. And there are only a few studies in pregnancy and barely anything, for example, in multiple sclerosis. And what is quite interesting is that this molecule binds to a receptor which is called G-Fral.

It's expressed in a very small population of neurons in the brain stem. This location is a bit special, I would say, because normally you say, there's the blood-brain barrier, normally molecules from the periphery don't really have access to the brain in a healthy state. But this region has lot of capillaries and thereby the access from the periphery is quite good.

If a molecule is in the bloodstream, it can easily access the sprake region and then also engage with this receptor. And as I said, it's studied a lot in cancer because one major side effect of cancer is so-called carrexia, which is when the patients lose appetite, they lose a lot of body weight. And this is apparently in part triggered by GDF15, which is released by tumor cells. So you have a...

and a strong increase of GD15 in his blood. And this basically makes these patients lose appetite. And yeah, in pregnancy, it's a bit more tricky. I said already, there have been some association studies in the past with miscarriage. And also you might have heard about it, this very severe form of nausea and vomiting, which is called hyperemesis ravidarum. So it has recently been linked

Nóra Balzer (19:39.172)
Yes.

Jana Sonner (19:42.417)
to the fact that the fetus can produce a lot of GDF15 and the mother is basically not prepared for this. And then it might, the body's response might be this hyper emesis, Gravidarum, but still there has to be a lot of research that has to be done in the future to really understand how is this working because normally pregnant women don't lose appetite, for example. So this is not something.

Nóra Balzer (20:06.42)
No, that's something I can't support.

Jana Sonner (20:09.583)
Yeah, so they don't lose body weight. So there seems to be a different regulation here, although we have this very high levels. And this remains a bit of a mystery. So how does the body differentiate here? And in the context of immunosuppression, there have been also a few reports which described that this molecule can be immunosuppressive.

but it's still not fully understood because immune cells, for example, they don't express G for the receptors. So there seems to be another mechanism which maybe indirectly mediates this immune response. And this is then something that we are studying at the moment.

Nóra Balzer (20:48.72)
Yeah, interesting. However, when I'm thinking about it at the beginning of the pregnancy, women tend to lose some weight because due to this hormonal changes and the beginning of pregnancy, just feel vomiting happens. Yeah, nauseous. Yeah, exactly. So yeah, maybe I can relate to that. But do you already have like a curve? How is GDF 15?

Jana Sonner (21:06.873)
Nauseous also. Yeah.

Nóra Balzer (21:16.782)
changing during pregnancy and what kind of effect does the change have?

Jana Sonner (21:23.473)
Yeah, I mean, this is something that we would like to look at more in the future because it's still not studied mechanistically. So what we know already from a cohort that we had looked at here in healthy pregnancies basically is that there's a continuous increase basically. So you can catch it up already in trimester one, but then it goes up like sky high in trimester three and then it vastly drops after giving birth.

But of course, as you said, maybe in the first trimester you have this adaption, so you have an increase of GDF15 and your body is still responsive to it. But then maybe once you get used to it, in a way, there is a bit of a desensitization towards this molecule with respect to appetite. So it could be that either the receptor is shattered or that the down-sym signaling is changed in a way that you are not responding to this anymore, because it would be quite harmful for you and...

developing features if you are not eating. But yeah, it's super fascinating how this is working.

Nóra Balzer (22:26.628)
Right.

Nóra Balzer (22:31.064)
It is and I'm just really thinking what does that mean for us pregnant women? So how can we implement your findings regarding GDF 15 into the clinical practice?

Jana Sonner (22:44.687)
Yeah, mean for pregnancy it's a bit difficult because I don't know you could envision that you block the molecule basically if this is of major concern for you because you suffer from this very severe form of hyper emesis and there are in the context of cancer for example there are now blocking antibodies available which they use as kind of new checkpoint inhibitors but in this case it's more to

Nóra Balzer (23:08.134)
Mm-hmm.

Jana Sonner (23:11.737)
make the immune cells infiltrate the tumor and not so much to cover the topic of appetite. But of course, this is something which might be of interest, but for this we need to better understand it. So as you said, you have this adaption period and then maybe later on it's not so much of a problem anymore. So maybe you just need to do something in the first weeks of pregnancy. Yeah, but it's tough because doing clinical trials in pregnant women is not something that

has done a lot. yeah, maybe we can come back to this later on, but it's easy that they are mostly not studied. Yeah.

Nóra Balzer (23:42.49)
Yes.

Nóra Balzer (23:50.382)
Indeed.

Yeah, that's true. And that's also the reason that usually the medications that you can use in many kinds of autoimmune diseases are the ones which are super old and outdated and not the newest and best medications for your disease. Right. So it's just like learning by doing.

Jana Sonner (24:13.989)
because there's just no data available basically.

Nóra Balzer (24:22.512)
But many things happen in the head, especially also in MS. So could you explain as the general concept of neuroimmune crosstalk and what does that mean in this specific context?

Jana Sonner (24:39.949)
Yeah, I mean, maybe for this we need to go a little bit back. So as I already said that GD15 is sensed by this receptor on the neurons. So it's that the brain basically senses something which is happening in the periphery. So there's also recently been introduced the term of immunosception. So sensing the immune system. So you have kind of a dysregulation in the periphery and then

Nóra Balzer (24:49.37)
Mm-hmm.

Jana Sonner (25:08.857)
neurons catch it up. So in our case, for example, you have an increase of GD15 in response to either pregnancy or also neuroinflammation itself. And then these neurons, they respond to it and they themselves, and this is what we are looking at and what we have found to be a super strong effect is that once you activate these neurons, they shut down the peripheral immune response. And we have done this in different scenarios.

We got inspired by pregnancy, but then we tried to use this in a therapeutic setting. So we used gene therapy. We used also recombinant GD15, which has already been used in clinical trials. And when we give this to animals which undergo a model of MS, which we use to study the immunopathology, these mice are basically completely protected. And also if you would...

genetic trick basically activate just these neurons, these mice are completely protected. So I think this is super interesting because it's a very small fraction, as I said already, it's a few hundred or thousand neurons maybe, and they are extremely powerful and we need to really better understand how they do it, but they can basically modulate the T cells in a way that they are not able to enter the central nervous system anymore. And maybe, and this is something which we have to look at,

could also be important for maintaining the pregnancy because it could also affect immune cells that would normally attack the fetus and then thereby prevent rejection basically. But yeah, this is for me in general a super fascinating topic, which this is kind of a prime example, but there have already been other studies where specific neurons, they induce the, for example, a secretion of neurotransmitters, which can then...

also modulate immune cells.

Nóra Balzer (27:06.947)
Yeah, indeed. It's super fascinating that with pregnancy you can somehow protect people from MS symptoms. So I'm just really thinking about if we could mimic pregnancy, like anti-baby pillar, that would be exciting. But I'm in general super excited when I talk to researchers.

Jana Sonner (27:18.555)
Yeah.

Yeah, it seems.

Jana Sonner (27:27.739)
Yeah.

Nóra Balzer (27:34.956)
who make their research in pregnancy and also with a combination of autoimmune diseases. Because that's really the way, the really long, long run to help on those women and people. And so give us some news. What are some of the latest research findings regarding MS and pregnancy? How is it at the...

PubMed nowadays.

Jana Sonner (28:04.337)
Yeah, I mean, this is I briefly referred to in the beginning, this observation that pregnant MS women are mostly protected. This is 25 years old now, so basically this first study which analyzed this. And based on this, have also been trials, as you said, to use hormones or pregnancy hormones to mimic pregnancy. So for example, they were using Estradio,

And they saw some beneficial effects in MS patients, but it was not enough. And it showed us that there's so much more to learn and it's not just these hormones which mediate the protection. And what is rather recent is that there have been some more comprehensive meta-analysis of different studies, which looked at, for example, the postpartum relapse risk, because this is, I was briefly introducing it.

Once you deliver, then you might suffer from an even stronger relapse than pre-pregnancy. And it looks like that shortly after pregnancy, so normally three to six months after pregnancy, you might have a stronger relapse activity, but this then reaches pre-pregnancy levels after a few more months. So it's not that pregnancy increases overall your disease or, yeah.

the neurological disability. And what I found quite interesting or find interesting is that exclusive breastfeeding apparently drastically lowers the risk for relapses postpartum. And it's still not fully understood why this is the case. It's in general highly recommended to do it. It might be, for example, that there's microbiome components which are transferred or immunity which is transferred to the baby.

What you need to take maybe into consideration when you look at this data is that there might be also a bit of a bias because patients who do suffer from a very high disease activity before pregnancy, they normally tend to go back to their medication as early as possible after delivering. So they might not be the ones breastfeeding because then they are afraid again of transmitting the medication to the baby. So.

Jana Sonner (30:30.491)
You always have to be a bit careful when you analyze this kind of data because it could also be because of this that only the ones who are not so active in their disease, they continue to do the breastfeeding.

Nóra Balzer (30:44.058)
Right. That's really a thing with human studies in general. it's not exactly...

Jana Sonner (30:52.165)
Yeah, you have a lot of confounding factors and you can't disentangle it at the end.

Nóra Balzer (30:58.426)
Yeah mice are much easier in that way.

Jana Sonner (31:00.593)
Yeah, but then you're also a bit limited, so I think you really need both.

Nóra Balzer (31:07.329)
Exactly. Everything has its pros and cons. research questions like yours are not a short-term sprint but more a long-term marathon. So what do you envision for the next five to ten years? Are there any systematic approaches to find new targets?

Jana Sonner (31:19.301)
Yes.

Jana Sonner (31:28.601)
Yes, good question. I think what we really move the field forward is using longitudinal samples. So as I said already, I think we need these samples from human pregnancies and they can tell us a lot. I think now with all the omics technologies, we have a good base to find new things. for example, what we have here in Hamburg is a pretty unique cohort of

and as women who want to get pregnant. So once they have the wish to become pregnant, they will tell the neurologist because as I said, anyways, they would need to discuss their treatment with them. And then we can draw samples from these patients. So we can have a PBMC, we can have plasma. And then they also come in every trimester and also after delivery. And then this is a super valuable.

basically, because now we can use these samples to do, for example, a proteome screen, which means we look in the serum which molecules are modulated. Is this, for example, different in patients who have a relapse versus the ones who do not have a relapse? And what molecules basically follow the pattern of immunosuppression? So as GDF15 was a prime example, we envision that there are much more molecules to be found.

could mediate immunosuppression in the context of pregnancy itself, but also pregnancy-induced immunosuppression in autoimmune diseases. And then if we combine this, for example, with single cell technologies to look at what is happening on the cellular level, how are T cells change, how are T cell receptor change, I think this will really be key. It's a challenge to then bring all the data together because it's different modalities and you need a lot of

bioinformatics, but I think we are really ready for this now and we should use the chance to analyze this data and then of course validate it. So it will take probably longer than five to 10 years, but at least to have a discovery which is worth to follow up.

Nóra Balzer (33:41.048)
Indeed, think such a longitudinal study is really the one that science would need nowadays, especially in pregnancy. And if you have the human cohort for that, that's just amazing. So go for it, don't give up. So what are the main challenges of performing research, especially in reproductive medicine?

Jana Sonner (33:55.503)
Yeah. Yeah.

Jana Sonner (34:05.009)
Yeah, I think it's a bit that the topic has been neglected for quite a while. And for a long time, it has been considered to be an issue that is only relevant for women because they are the ones who do get pregnant. And the women are usually not the ones who decide who gets the money. So they're not the ones who decide who will get the research grant. So I think there has been a bit of a bias if money is available to do this kind of research.

And then also it's still a topic which mainly attracts women. mean for this we need to be honest if you have a look at who is working in this field it's mainly women and I think they are still facing problems to fill a position at prestigious research institutes, and also despite the efforts of conference organizers to

to give everyone the chance to speak. I there is also still a bias in who is presenting or maybe also the women are not so much the ones who scream, yeah, I want to give the talk, I want to introduce this topic. So I think this is still a bit of a challenge to bring this out to society. But I also, and hopefully many more, but yeah. So when you talk,

Nóra Balzer (35:25.188)
Except you and me. Exactly.

Jana Sonner (35:32.983)
or now also when you attend meetings, think it's slowly changing and there's also an increased awareness of pregnancy complications, whatever is related to this and also what it means to the overall society and not just for women. But as we already said, I think what is really needed is to include pregnant women in clinical trials. And I think there has been this quite famous slogan that

means protect pregnant women by research and not from research, which means you should really include them to also give them a chance to benefit from all the new developed therapies.

Nóra Balzer (36:15.41)
yeah, it's such a saying. I love that. True.

So what would you suggest for scientists or scientists to bees who want to contribute to the field of reproductive immunology, which term I think I used for the first time, reproductive immunology, to support women in childbearing age with autoimmune diseases?

Jana Sonner (36:36.945)
Yeah.

Jana Sonner (36:43.981)
I think there are a few things which is probably not very specific for this research topic, but which I would tell anyone who wants to start their research in science. So I think you really need to find a topic for which you have an intrinsic interest, for which you are passionate about. So I personally believe that it should not be the major point of your decision, whether it's a prestigious research institute or topic, or if there are a lot of

fancy techniques in this lab. So it's really something that you want to work on because you will carry the project and you ideally also continue working on this topic after your PhD, for example. So you will need to find something for which you have the spirit. And also what I learned is that it can be really key to find a good mentor, which I know it's not straightforward.

to figure this out when you apply for positions. But I think it really helps to talk to people in the lab, to former students, if you somehow can access them. And I think for this very specific topic, it's still a niche. So it requires expertise both in reproductive medicine and immunology. So as I said, it's an interesting term, reproductive immunology. And I think for this, it's really important that you

build a good network and I think for this it's very helpful if you have a good mentor who knows the people in the field who can bring you in contact with them. And yeah also as we said already longitudinal human cohorts are so important I think especially for this to really understand and they are extremely valuable and try to somehow get access. It's not that you need to have them yourself because this is very tricky.

because you need doctors, need the infrastructure, but you should try to get your hands on it.

Nóra Balzer (38:49.53)
Right, Jana, thank you very much for sharing your thoughts. My favorite sentence is still that protect women. Once again, do not protect. Yeah, exactly. Protect women by research and not from research. Thank you very much for sharing all your thoughts. I wish you the best luck for your research.

Jana Sonner (39:00.987)
by research, not from research.

Nóra Balzer (39:17.364)
and we will put all citations in this topic into the show notes and maybe we can also put your contact details. If someone is interested in your research and want to continue his PhD or postdoc in this field, Reproductive Immunology is the new hit, then they can just approach you. Thank you very much. I wish you a great day. Bye.

Jana Sonner (39:42.833)
Thank you, Nora. Bye bye.