Episode 67 – What is Autoimmunity?

00:00:01 Announcer Welcome to the Standing up to POTS podcast, otherwise known as the POTScast. This podcast is dedicated to educating and empowering the community about postural orthostatic tachycardia syndrome, commonly referred to as POTS. This invisible illness impacts millions and we are committed to explaining the basics, raising awareness, exploring the research, and empowering patients to not only survive, but thrive. This is the Standing Up to POTS podcast.

00:00:29 Jill (Host): Hello fellow POTS patients and exquisitely lovely people who care about POTS patients. I'm Jill Brook, and today we have an episode of The POTS Basics where we're going to discuss autoimmunity with Dr. Cathy Pederson. I think you know by now that Dr. Pederson is a neurobiology professor, POTS researcher, POTS parent, President and founder of Standing Up to POTS. So today I'm going to introduce her as the 2022 Keynote Speaker for the Ohio Academy of Sciences, which is a huge honor but also a wonderful windfall for us, POTS community, because her keynote address is going to be about POTS, and it will reach scientists, doctors, scientists-to-be, and doctors-to-be! So, Dr. Pederson, I know you were speaking about POTS to NPR yesterday, you were speaking to a Cleveland Evening News program last week. You are a firehose of POTS awareness lately. So, thank you for making time to discuss autoimmunity with us today.

00:01:38 Dr. Pederson (Guest): You know I love to be here. But yeah, it's been a crazy couple of weeks, that's for sure.

00:01:43 Jill (Host): Well, we're excited to see what comes when everybody finally hears about POTS. Our topic today is autoimmunity, which is a word that we hear so often connected with POTS. But it's a pretty complex topic in its own right, and there are people who dedicate their entire careers to just autoimmunity or just one type of autoimmunity. So, we thought we should try to understand it pretty well today. What in the world is autoimmunity?

00:02:14 Dr. Pederson (Guest): This is a great topic, I think, and we're going to come around to the end, where we talk about what some evidence is that's mounting that might indicate that POTS is an autoimmune disorder. And, it is something for us to think about. Now, the research isn't quite there. We'll come back to that at the end. I don't think we can say strongly, "Yes, POTS is an autoimmune disorder." But there certainly is research in that direction. So what is autoimmunity? It's when your own immune system betrays you, and instead of fighting the pathogen, like a bacteria or a virus or a fungal infection - something like that - instead, it starts attacking your own healthy body cells. So we call them host cells. Those are your cells that are just hanging out doing whatever it is that they're supposed to be doing. So, the... the immune system has gone wrong. I want to back up for a second, though, and just talk very basically about the immune system. It's really complex. My students hate the week or two that we cover it in Human Anatomy and Physiology because it is so complicated. So, I'm going to just give broad strokes here, OK? But as far as protecting ourselves from pathogens, there are three main layers of defense that we have. So the 1st layer is called "nonspecific defenses." And we're actually born with these. So, one example would be your skin, right? You have lots of pathogens that are on the outside of your body that never get in because you've got this physical barrier called the skin that's protecting you. Another example of nonspecific defenses that folks are aware of would be inflammation, and a third one would be fever. There are others, but those are the ones that folks would know about the most. So, those are called nonspecific defenses. We're all born with these defenses. They really don't change through our lifetime. The other two are called "specific immunity" and there are two branches. And again, I'm not going to get into the details of this, but for those in the know, it's humoral immunity - and those are the plasma B cells that secrete a whole bunch of antibodies, these proteins, to help us fight infection. And then there's cellular immunity, which uses cytotoxic T cells are what they're called, that can actually go out and attack your cells that have been infected by a virus, whether that's the virus for mono or a COVID virus or the flu virus, and it tries to get rid of the infections that way. So, we have nonspecific defenses. We've got this humoral immunity and cellular immunity. The nuts and bolts don't matter, but all of these work together to sort of protect you against any pathogens that you might see. Now, here's one key of the immune system. The main thing, and we don't think about it this way, is that it has to be able to tell which cells are your host cells or your body cells, and which cells are the invaders, the pathogens. So how can it tell your liver cell from a bacteria, or a muscle cell from a virus? And, it turns out there's a secret code....

05:41 Jill (Host): [Laughs]

05:42 Dr. Pederson (Guest): ...and these are called major histocompatibility complex - these are type 1 receptors - that are on the outside of every cell membrane in your body.

00:05:54 Jill (Host): Wait, can I make sure I understand this?

00:05:56 Dr. Pederson (Guest): Yeah.

00:05:58 Jill (Host): So, you're saying that in order for the body to be able to tell ‘self’ from ‘other’, there is basically something stuck on to the exterior of every cell that has a secret code in it?

00:06:12 Dr. Pederson (Guest): Exactly right, yeah. So, it's called this MHC receptor, and they're on all of your... well, OK. Here's the professor, right? My students, if they were listening to this, would say, "But you said they’re on every nucleated cell." So, the obvious thing to me, but maybe not to our listeners, that's excluded there are red blood cells. So this is why we can give transfusions, right, because these special markers that say I'm Cathy Pederson and you're Jill Brook, and our listeners are different from us, are not found on those red blood cells.

00:06:47 Jill (Host): So, I think what you're saying is that if I got a liver transplant, I would need to worry about my immune system rejecting that liver. But when I get somebody else's red blood cells, I don't need to worry about that because there is no special code on those.

00:07:04 Dr. Pederson (Guest): Perfect, that's exactly right. And you hear about people when they're getting some kind of a transplant - a liver transplant or a heart transplant or kidney transplant - you know how they talk about matching and then they want them to match on as many points as they can? This is a big part of what they're talking about.

00:07:22 Jill (Host): OK.

00:07:22 Dr. Pederson (Guest): These receptors, these MHC receptors.

00:07:25 Jill (Host): And then the whole reason that transplant patients are immune compromised is because they oftentimes have to give them immune suppressants to keep them from rejecting the new organ, right?

00:07:37 Dr. Pederson (Guest): That's exactly right. So, we're trying to hide that new organ with this different MHC tag on it from their immune system.

00:07:47 Jill (Host): So that's interesting. I never thought of that as a problem that was kind of related to autoimmunity. But they're both problems of identifying ‘self’ versus ‘other’.

00:07:58 Dr. Pederson (Guest): That's exactly right.

00:07:59 Jill (Host): OK.

00:08:00 Dr. Pederson (Guest): You just never know what you're going to learn about on so this show.

00:08:03 Jill (Host): [Laughs]

00:08:04 Dr. Pederson (Guest): [Laughs] Yeah, so I think that's great. So, that's the problem, though, is this idea of how can the body tell if it's a pathogen, a bacteria, or virus, or if it's something else? Now, I have to be honest and say there are a number of ideas on how autoimmunity comes about, but I don't know that we know for sure. OK? So here's one idea. So, these T cells, the ones for cellular immunity - so maybe you've heard of helper T cells. They turn on the immune system. They actually turn on both sides of the immune system. And we have these clones of cells. So anyway, the early version of these cells - they're born in your bone marrow, and they go to an organ that most people have never heard of, called the thymus. And the thymus in adults is down around the heart. In kids at the top of the heart, but it actually extends up into the neck. And the older we get, the smaller the thymus gets. And the job of the thymus is to help these T cells know what is us and what is not. Think about a baby. They catch everything, right? They've not seen any of these infections before. You think about a kindergartner. Oh my goodness, their noses are always dripping. They're cute - it's a good thing they're cute - but they're always catching these infections. So the thymus s is helping with this. In a normal, healthy person, only about 3% of the T cells that are in that thymus trying to mature and move out into the blood, make it. So one theory is that some of these T cells that should never have been released somehow get out into the blood, and they're ready to attack tissues that they shouldn't, right? So they never should have been released from the thymus. That's one idea.

00:10:09 Jill (Host): Oh interesting, OK.

00:10:10 Dr. Pederson (Guest): And these aren't mutually exclusive. Another idea is that the antibodies... that these are proteins that are made by these plasma B cells and humoral immunity. And they're they're great. They help us to fight infection when you have COVID or the flu, or a cold, folks, you need to eat protein. You need protein because protein allows you to make more of these antibodies to fight off that infection. And so anyway, maybe these antibodies get tweaked a little bit so now that they're attacking your normal tissue instead of going after that bacteria or virus or whatever their initial target wants. And then a third one, and we'll probably come back and talk about this a little bit more later, is this idea of mistaken identity. So we know that helper T cells sort of turn on the immune system. There's another cell type that likely helps us to turn it down again. They're called suppressor T cells. But what happens if we don't turn it off? What happens if we allow this this reaction to the flu or to COVID or to mono or to Lyme disease to work longer than it needs to? Now that pathogen is gone, but our immune system is still working. And what if like in MS - multiple sclerosis - the protein that they were going after on the bacteria or the virus is close to the myelin in your brain? That's what gets attacked in people that have multiple sclerosis. This idea of mistaken identity where the attack turns just a little from the pathogens’ protein, and now it's going after some protein that's on myelin in your body, or a certain receptor in your body, or whatever the case may be.

00:12:00 Jill (Host): And that one, I think, is where an interesting couple of studies have come in in the nutrition world - and I think we're going to have a whole separate episode about nutrition strategies for autoimmunity - but there are some studies now finding that there's some pollutants out there in the world, that sometimes when they get into our bodies, they can attach to some of our proteins and then change the shape of those proteins and make them no longer look like self. And that was one theory that I just became familiar with in the last couple of months. But what was driving that in their hypothesis by Dr. Datis Kharrazian and colleagues was that it's environmental pollutants that are doing that, and that our immune system is actually just doing what it's supposed to do, which is attack proteins that it doesn't recognize. It just never foresaw that we might have things like microplastics or fire-retardant chemicals attaching to some of our proteins.

00:13:03 Dr. Pederson (Guest): Right. That's been around for a while. So, BPA is one of those - Bisphenol A - and that's a big endocrine disruptor as well. So, it disrupts the hormones in the in the system. DDT way back in the 60s and 70s - it's banned now in the United States - is another one that gets in, and both of those get into your fat. They stay in your system for a long time. So you don't just drink plenty of water and wash them away. And so it's a lasting impact. Absolutely. Scary stuff.

00:13:34 Jill (Host): Now that we've talked a little bit about what autoimmune conditions might be, can you give us examples and why are there so many different ones?

00:13:44 Dr. Pederson (Guest): Absolutely. You know, in preparing for this episode, I found that there are about 80 different autoimmune diseases. And so, like POTS, these are chronic. They're often debilitating. They can be difficult to treat. And that in the United States, they seem to affect between 7-8% of the population, which is about 24 million people. So that's a lot of folks that we're talking about that are suffering in a way, very honestly, that's very similar to our own community with this chronic, debilitating, painful, often condition. So there are a number of these. One is Hashimoto's thyroiditis - that's really common actually. And it's where the thyroid's being attacked. And sometimes the thyroid hormones are really high, sometimes they're really low. And it has a lot of effects on your physiology. Another one is Graves' disease or hyperthyroidism. That's another one that's actually attacking the thyroids. Our thyroid gland is under attack here. Think lots of our listeners have heard of rheumatoid arthritis, and some of them may even have that. That's where now the immune system is attacking connective tissues in our joints. Type one diabetes, I think many, many folks are familiar with this, may know someone with it, but may not realize this is an autoimmune disorder. So that's the one where the pancreas isn't making enough insulin, so they need the insulin pump or insulin shots in order to function and feel good. Multiple sclerosis, I mentioned a few minutes ago. That's where the proteins in the... on the myelin in the brain and on your peripheral nerves are being attacked. And then the other really big one is lupus, and that attacks a lot of connective tissue. Again, sort of like POTS. Many many, many systems are affected. And not everyone has it, but if you see that butterfly rash on the face, that's sort of a characteristic of lupus. So, there are lots and lots of these where the nervous system is being tricked, as you pointed out, where it thinks it's fighting something that's foreign and it's actually attacking our normal healthy body tissue.

00:16:08 Jill (Host): So, each one of these 80 or so different autoimmune diseases is just characterized by which different type of healthy self tissue is getting attacked. Is that right?

00:16:18 Dr. Pederson (Guest): That's exactly right.

00:16:20 Jill (Host): And is it correct that just because you get one doesn't mean you can't get another one too, right?

00:16:29 Dr. Pederson (Guest): That's right, yeah. And that's something I didn't really think about even myself until several years ago, but often people that have one autoimmune disorder go on to develop another one over time. So it's not uncommon for people to have two.

00:16:45 Jill (Host): My own 23andMe genetic testing came back as being at high risk for autoimmune disease and it would eventually result in diagnosis of three of them so far. But, the funny thing about it was it was the same gene that I apparently had in common with Marie Antoinette. So, some common ancestry of... of not the luckiest kind. So anyway, that was my fun little... [Laughs]

00:17:14 Dr. Pederson (Guest): So you know, autoimmune disease inside and out.

00:17:17 Jill (Host): Well, I know it as well as I would like to know it, and hopefully there's not too many people getting four or more. I'm going to try to cap it at three. I know that there's not a ton of great research on this, but which autoimmune disorders are most commonly seen in POTS patients? I know that it's been found that POTS patients are more likely to have autoimmune conditions than the general population, and is it certain ones?

00:17:45 Dr. Pederson (Guest): The literature on this is sparse and it's diverse. So... so the papers that are out there that sort of talk about this, they don't agree. So, let me tell you about one paper. It's a review article by Venino and his colleagues that came out in 2018. [Transcriber’s note: you can read the abstract for that article here: https://pubmed.ncbi.nlm.nih.gov/29909990/ ] And one of the major findings was actually that about 20% of people with POTS do have an autoimmune comorbidity. So, you're not alone in the fact that you have POTS and then you have other autoimmune disorders. And in your case, Jill - we've talked before - yours probably has an autoimmune etiology, although that's more difficult to prove right now. In that particular study, which again was sort of surveying a bunch of other studies that are out there, the top 4 autoimmune disorders that they saw in people with POTS were multiple sclerosis, lupus, Sjogren's, which I didn't mention before. This is really a not very common autoimmune disorder that seems to pop up a lot more in POTS patients than in the general population. And so Sjogren's often is... I guess the symptoms that people notice first is that they get really dry on their mucous membranes. So really dry eyes, really dry mouth, all the time. They're also more prone to small fiber neuropathy. And so lots of our listeners probably have small fiber neuropathy as well. You don't sweat very much, got dry eyes and mouth, maybe it's something to ask that health care practitioner about. Ad then the last one in that paper that really popped was celiac disease. And again I think lots of folks are familiar with that. That's the one where gluten really makes them really, really sick. So if they eat things that have wheat in it or regular flour in it, they get very very ill. One of the first papers I saw was Dr. Blitshteyn, who has been a guest on our show, and Jill, I think you worked on this paper. So I'm not even going to pretend to tell it I'm going to tell it. To throw it back to you.

00:20:02 Jill (Host): Sure. So this was back in 2015 when there was kind of only the beginning of talking about POTS as potentially having an autoimmune angle. So, I think she was just curious to see how common were autoimmune markers and autoimmune disorders in her POTS patients. So, all she did was she looked at her most recent 100 POTS patients to see if they had something called "antinuclear antibodies" - ANA - that's a blood test that sometimes can be indicative of autoimmunity. And then she looked at a few other markers of autoimmunity and looked to see if they had comorbid diagnoses of autoimmunity. So, to be clear, she wasn't testing everybody, she was just looking in their records to see if some doctor along the way had diagnosed or found some of these things. And so, the reason that matters is because, of her 100 patients, the mean age was only 32. We know that a lot of these autoimmune disorders can take many years, just like POTS, to get a diagnosis. And so in such a young cohort, what she found was a surprisingly high rate of autoimmune markers and disorders. So, for example, she found that 25% had the positive ANA, 7% had at least one positive antiphospholipid antibody, and 31% had some marker of autoimmunity. So, then what we did was we looked for statistics in the general population of, OK, how common are these disorders? And what we did is if we found a few different studies that had conflicting numbers for prevalence, we just took the highest one. So in the very most conservative way possible, she wanted to compare what her POTS patients looked like compared to the general population in terms of prevalence of these things. And so for example, she found that 11% of her POTS patients had Hashimoto's thyroiditis versus up to only 2% in the general population. So that means that the POTS patients had 6.1 times the odds. Rheumatoid arthritis, she found that 4% of her POTS patients had it versus only up to 1% in the general population. So it was a 4.1 odds ratio. For the lupus, she found 2%, and in the general population it's only .12%. So that was an odds ratio of 17. And then for common variable immune deficiency, she found 2% in her population versus .004% in the general population. So that was an odds ratio of 510. What struck me is even though her prevalences were much, much higher than the general population, a lot of these percentages were still pretty low. But those were some of the earliest findings.

00:23:14 Dr. Pederson (Guest): But what that means is again, these other autoimmune disorders are more prevalent in POTS patients, is what you're saying, than they are in the general population, even when you're taking the highest estimate for what it is in the general population.

00:23:30 Jill (Host): Even when your cohort is only 32 years old, on average. OK, so speaking of age, what is the demographic that tends to get autoimmune conditions?

00:23:42 Dr. Pederson (Guest): Yeah, so we know that about 75% of them are women and that matches closely with the POTSs numbers. It's depending on the paper, between 80 and 90% of POTS patients are women, which of course also means that 10 to 20% are men, but the 75% autoimmune is in there pretty close. What's interesting, I think, is that minority groups actually have higher rates of autoimmune conditions than Caucasians. So autoimmune conditions are more common in LatinX, in African American, and in Native American populations. When we look at the women - 75% that are women - most of those are childbearing age. So that goes right with what you were just saying, Jill, when you're talking about women who are 32, that's right in the middle of childbearing age, and so this makes people think that the sex hormones must play some role - estrogen and progesterone must play some role and that some of the triggers for autoimmune disorders come when we have big shifts in these hormones. So, during pregnancy as an example. And during pregnancy, as you go through that pregnancy, the levels of estrogen and progesterone climb tremendously as the placenta is making more and more of it. Another related change is in childbirth. And so when that baby is delivered within the next hour or so, they have the delivery of the process. So the placenta was making huge amounts of female hormones and now the body almost goes into withdrawal because literally we're tearing that placenta away and delivering it out of the body. So just like there is a huge upswing in pregnancy, there's a rapid bang decline after childbirth. And so we hear about postpartum depression that can be linked to this, but so can autoimmune conditions. And then the third time in a woman's life when she is most likely to develop an autoimmune condition is as she goes into menopause. And again, that's where you've got that dropping off of hormones. As the ovaries in this case stop working.

00:26:30 Jill (Host): Interesting. So I know we're going to talk about therapies in a minute, but I'm not aware of any therapies that have to do with playing with people’s hormones, and it sounds like that could be an interesting area of research.

00:26:34 Dr. Pederson (Guest): Yeah, I don't know if that would help it after the fact. I don't think that would help the immune system.

00:26:47 Jill (Host): OK.

00:26:48 Dr. Pederson (Guest): But if there's a way to buffer it out so that we prevent the immune system from gearing up in the wrong way, that's where it would be helpful.

00:26:57 Jill (Host): OK. Well, so this brings us to do we know what causes autoimmune conditions?

00:27:06 Dr. Pederson (Guest): It's not a definitive answer. Again, I'm going to hedge around here a little bit. I think there are three general categories that most people would agree contribute to autoimmune disorders. The first one is is genes, your genetics, your heredity. And so you mentioned 23andMe a few minutes ago. We know that there are. Families that have autoimmune disease run through those families and they may not all have rheumatoid arthritis as an example, but a lot of folks in that family lineage have some sort of autoimmune disorder. There are others that we do have some genes that have been isolated that they can go and look at a little bit, but not very many. So a lot of it is really looking at the pattern and the family. So, genetics is one category that can trigger an autoimmune condition, and I ought to say that even if you've got the genes, just like you have the genes for cancer, you may be able to slow it down or stop it with lifestyle sorts of things, being very careful to exercise and try to eat as cleanly as you can, that sort of thing. The second category is infection, and that's that idea of mistaken identity that we were talking about at the top of the show. So, some sort of famous infections for this, mono is one, and that's what my daughter had. She got mono when she was 10 and is 20 now and still isn't better. Lyme disease is one of these. COVID, I think is evolving into one of these. So there are many infections. And in fact I read a paper that showed that 20% of the really serious COVID cases, so these would be the folks that are in the hospital on the respirator or the people that died - so 20% of serious or fatal cases - when they tested their blood had some sort of auto antibody. Auto means ‘self’. Antibody is that little protein that's supposed to be going out after COVID, in this case, sort of binding them together and waiting for help to come. And so what we see in - and the idea is that maybe the organ damage that we see in those severe COVID cases - yeah, it's partially the virus, but it may also be that somehow our immune system is turning on us and accelerating that problem as well. So I thought that was really interesting. Science moves slowly, though we're only a couple of years into the pandemic. It'll be a long time before they can say that that's true for sure.

00:30:05 Jill (Host): Yeah, and that is so interesting, and it goes along with what we've been hearing from some of the mast cell researchers, too, that we can't definitely tell at this point how much damage is being caused by the virus versus our immune response to the virus. And that's an interesting idea.

00:30:26 Dr. Pederson (Guest): Absolutely, absolutely. And it's scary in some ways, 'cause you feel like, let's beat the infection and we've got it won. How do you beat your immune system, which is working overtime trying to protect you? Yeah, it's difficult. The third category, then, is environmental exposure and this is what you were alluding to again earlier in the episode, I think Jill, when you were talking about environmental toxins that people are eating in the food supply or microplastics - this sort of thing. And I think about environmental exposure and cancer. I think we've known for a long time that radiation can cause cancer. Sunlight can cause cancer. But we're starting to see some of the same things for these environmental exposures and this autoimmune where your immune system gets messed up a little bit and starts attacking your system. So, sunlight is one of those. Again, I think of sunlight and skin cancer. Don't necessarily associate it with triggers of autoimmune disorder, but there are some early studies that show a correlation. Now there's a difference between a correlation and a causation - that's not the same. A second one that I thought was really interesting and nonspecific is childhood poverty. Now there's so many things that go with that. It's where you're living. Are you living in a place where you're inhaling all of the factory smokestack chemicals? Or are you living in a place because it's cheaper to live there that's right near the trains where you're getting all that exhaust from the diesel or the trucks? Or are you near the electric wires? So, it's more than just the poverty, it's all the things that wrap up. What about the food supply? Again, going back to sort of your bailiwick there. If you're eating a lot of packaged food that has preservatives in it, think about food deserts that we're hearing about in the news all the time. So I think that's a really difficult one to unpack, but they do see an association - again, not causation, but an association - between childhood poverty and later development of autoimmune disorders. Pesticide is another one. So think about the farming community, people that live downstream from the big farms.

00:33:06 Jill (Host): And I think one of the hypotheses around that is the potential effect that pesticides might have on gut microbes, 'cause we're learning that gut microbes send a lot of signals to your immune system about how aggressive to be.

00:33:20 Dr. Pederson (Guest): Yeah, it's been just in the last, I don't know, 5 or 10 years that we've realized how important that gut microbiome is, specifically for immunity. So things that throw that off, whether it's pesticides or antibiotics - we shouldn't be taking as many antibiotics as we do - but there are lots of things that can throw that off, and it does indeed seem to affect the immune system. Organic mercury, so if you're eating fish that have a lot of mercury in it, exposure to cigarette smoke, even if you're not the one that's smoking - so, secondhand smoke. Again, we've heard that can lead to lung cancer. Most of us haven't heard about this as a possible trigger for autoimmune conditions. And then lack of vitamin D. And I think that Dr. Dempsey mentioned that in her episode. And this is something that we can control. Maybe, Jill, I ought to throw that back to you for a little bit better explanation there.

00:34:21 Jill (Host): Vitamin D is interesting because we know that it does so many different things in the body, but one of the things it does is it can affect the expression of a lot of your genes, like thousands of your genes. So that might play into it. We know that every cell in your body has receptors for vitamin D. I think there's been some studies showing that at latitudes with lower vitamin D levels they see more MS. We know that vitamin D affects gut health and gut health ties back into the immune system.

00:34:54 Dr. Pederson (Guest): Wow, that's great.

00:34:56 Jill (Host): Yeah, especially because I mean when we get to the treatments, I mean, as somebody who's got a few autoimmune conditions, I'm familiar with the treatments and they're not that great, and some of them have kind of scary side effects. And so if something like vitamin D can get you partially there, I think that is something we really need to pay attention to. But this brings me to their next question: rates of autoimmune disease are rising and they have been for decades, and they're rising kind of fast, especially among younger females. Can you talk about that? Do we know why?

00:35:31 Dr. Pederson (Guest): Yeah, this is a tough one, I think, bcause what we look for now and what we looked for 30 years ago might be different. And so I think sometimes these historical types of studies and comparisons are a little bit false. But yes, I will address that. So there are some studies that have looked at the antibody that you mentioned before - it's called antinuclear antibody - and lots of our listeners look at so many of their own blood tests. They may have had this blood test often on the sheet it says ANA - A-N-A - which stands for antinuclear antibody. And so this study looked across time at the population, trying to see what percent had elevations in this in a nuclear antibody. And in the late 80s or early 90s, about 11% of the population had an increase in this inner nuclear antibody. In the late 90s and early 2000s it went up modestly from 11% to 11.5%. But by the time they looked in 2011 to 2012, that's where we got a big jump. So that went to almost 16%. So it was a 4 or 5% jump, depending on which year you're comparing it to, which doesn't sound like very much, but when you multiply that times the millions of people who live in the United States, we're talking about a lot of people who potentially are seeing this increase in their antinuclear antibody. Now, I think we mentioned this a little bit before, but let me be clear on this - this is a sort of general quick and dirty test to see if autoimmune might be there. It doesn't tell you if you have an autoimmune disorder or not. It's sort of the litmus test for ‘should the doctor look further?’ sort of a thing. So it's not necessarily that all the folks that had this higher number of this ANA - this antinuclear antibody - actually had autoimmune disorder, but it is a potential one. The scariest part of the whole thing, I think, is that it was the teenagers. So the biggest increase in this ANA over that 30-year period was in 12 to 19 year olds, and certainly my daughter - again thinking about autoimmune and POTS, she developed pots when she was 10. So many of us, our listeners, either developed POTS in their teen years or maybe their children developed POTS in their teen years. So, so we're sensitive to that as a POTS community, I think. Again, not that autoimmune can't happen at different ages, not that POTS doesn't happen at different ages, but this is an area where we're seeing a big change over time. It's unlikely to be a genetic change. You know, 30 years sounds like a long time, but that's not many generations. You really need generations and generations to see a change in the alleles at the genes, OK? So that means it's more likely a change in lifestyle or environment. And so we mentioned before, I think about what I ate as a kid and the way we eat now. There's a lot more processed food. It just wasn't as available. Now, I'm an old person. I recognize that, right? Born in the late 1960s, but I just feel like the way that we cook and the way that we treat food is really different and we value shelf life, as a country, over freshness and nutrients. Anyway, I'm sure this is Jill's diatribe. I [inaudible] to do that. The other thing is that environmental piece at environmental exposure. You think about the amount of carbon dioxide, the global warming, the pesticides, all these things that we mentioned before where we really have not done a good job as a population in protecting our own environment, which may be making us sicker over time. Now, these are very hard things for me to prove, for science to prove. I'm doing a lot of what I would call magic hands with my students, where I'm just waving my hands and saying things, right? These are really hard to prove once and for all.

00:40:14 Jill (Host): And what's tough is that we had so many changes at the same time that I don't know how you ever identify which ones are most responsible.

00:40:21 Dr. Pederson (Guest): That's exactly right. In science what we want is to change just one thing at a time. And so for POTS patients, often the doctors say, "I'm only going to change this medicine," and it's frustrating to that patient and to the family, but the truth is if you change three things at once and get better, you don't know which of those did it. It's actually good science for your health care practitioner to just change - whether you're adding things or taking them away - change one thing at a time. So, these have been around for a long time. I said there are 80 different conditions, but the treatment is not very good, really, and not very specific. So again, I'm going to talk in broad strokes here, but often what practitioners want to do is start with the least invasive, the things that will cause the least amount of side effects while hopefully controlling those symptoms. And so they'll start with the anti inflammatory drugs. These are things like ibuprofen or naproxen. And these are painkillers, so it'll help to reduce the pain. Think about someone with rheumatoid arthritis, for instance, who has a lot of joint pain. But it also helps to decrease inflammation. While inflammation is part of that immune system, working to try to protect your body, they may also prescribe physical therapy. And depending on what kind of autoimmune disorder we're talking about, mobility often is an issue. And so, you know, if you don't use it, you lose it. And so trying to keep people able to move about as much as they can is actually really, really important. So those are the places that they often start, and if they don't get much impact then they'll move to something like corticosteroids. These are very, very common. These are anti-inflammatory, so they're going to reduce that inflammation. They're stronger than an Aleve or an ibuprofen. They also come with bigger side effects. So there's water retention that comes with that, weight gain, other sorts of things that are not that great. But again, the idea is to try to dampen down that immune system so that it's not attacking your own tissues. And then the last one, which definitely has the most power for the punch but also has the most side effects are the immunosuppressive drugs. And so you mentioned these before when we were talking about someone with a liver transplant or a lung transplant or a heart transplant or an autoimmune disease, they will prescribe these immunosuppressive drugs. And they work great at dampening down that immune system. They work great at slowing the destruction of your normal tissue, but the problem is - we have two problems actually. One: it increases your risk of illness and infection because you are dampening down your immune system for everything, not just for your autoimmune condition. And secondly, it really increases the risk of cancer because your immune system is one of your first lines of defense against cancer. A lot of people don't know that, but by the time you're 20, almost everybody has had at least one cancer cell. But most 20 year olds don't have cancer, right? Because the immune system kills it before it has a chance to grow.

00:44:00 Jill (Host): Yeah, so that's quite a downside. And my experience with immunosuppressive drugs was that they wanted to test my blood every month, make sure that I wasn't getting to immunosuppressed, and at times I would get too immunosuppressed and then they'd say, "Oh, goodness, don't go in public this month," and it was seemed like a fairly delicate balancing act that was certainly not ideal, which is, I think, what drives so many people in the nutrition direction, because actually autoimmunity is one place where I think the nutrition research is a lot better than average. That said, I don't want to scare people. I think they're getting a lot better, and they're getting more targeted, and they're... they're getting improvements all the time. But like you said, you have to live with that side effect of knowing that all those other things are a little more likely.

00:44:50 Dr. Pederson (Guest): Right. And they're going to put you on the lowest dose possible to try to control your immune system to minimize those other effects. But there are risks, that's our point. There's risk to taking those drugs as well as not taking them.

00:45:06 Jill (Host): OK. So, let's get to the maybe exciting newer research. What is the current thinking about autoimmunity possibly being associated with POTS or maybe even driving some cases of POTS?

00:45:22 Dr. Pederson (Guest): Yeah, there's mounting evidence in the literature now that, at least for some POTS patients, this is an autoimmune underpinning. Now, again, there hedging in the literature, they'll say there may be an autoimmune cause. Again, it's not definitive in the literature yet, but there is a lot of literature and if you go to Google Scholar and you type in ‘postural tachycardia autoimmunity’, there are lots of papers that come up. So again, in broad stroke, we're seeing that as you said, with the Blitshteyn paper from a few years ago, we're seeing an increase in those antinuclear antibodies. Again, that's that sort of quick and dirty, is the autoimmune part of that puzzle or not? It doesn't... it doesn't do a whole lot past that, but just a good quick look - blood test - quick look there. But there are other studies that are a lot more specific. And there are receptors in our brain and throughout the body that are called acetylcholine receptors. And there are various different kinds of them, but they found autoantibodies - your antibodies going against these body receptors - for the ganglionic adrenergic and muscarinic acetylcholine receptors. So to lots of folks that doesn't mean anything. What what that means is 3 different kinds of these receptors that are found throughout the brain and the body - part of our parasympathetic nervous system, that rest and digest system - are being attacked in people with POTS. So that's interesting. Other studies have found that we have these autoantibodies, again, where it's attacking our normal receptors - these are called glutamate receptors. These are important for excitation in our brain and a specific kind - they're called NMDA glutamate receptors - and this is important for long term potentiation and other things in the brain memory, that sort of thing. Again, we don't really need to talk about it. The point is that it's going after these receptors that you need and you want and that are normal and should be there in your brain. And then finally other studies have have shown elevation in cytokines. The cytokines, in particular, I think folks have heard about because COVID and the news they've been talking about cytokine storms. So maybe folks know that these are inflammatory chemicals. And again, inflammation and immune system autoimmunity may all go together. So if you wrap it all up, there are a number of receptors in our brain and throughout our body that are showing that antibodies are attacking where they shouldn't be attacking, showing autoimmunity in addition to this elevation of inflammation and these antinuclear antibodies.

00:48:31 Jill (Host): So that's pretty interesting that it's multiple autoantibodies, potentially, 'cause my understanding is that some autoimmune conditions just have one, just kind of simple, and here we are with a handful, and it might partially explain why POTS gets so complex.

00:48:52 Dr. Pederson (Guest): That's right. And realize that these are probably in different people. You'd be pretty unlucky, although it could happen, to have all of these in one person. So, we're just saying through the POTS community. So even if you had one of these that was being attacked, they would say yes, that's an autoimmune form of POTS.

00:49:13 Jill (Host): Right, and I think at this point it's not that easy to get tested for these autoantibodies. I think that some of them you can only do in a research setting. I think there's a lab in Germany that can test for some of them, if you can figure out how to have your blood drawn and sent to Germany. But I think it's not quite ready for primetime yet, but I think the research is getting there pretty fast. I think there's a lot of interest.

00:49:37 Dr. Pederson (Guest): Yeah, that's exactly right. So this is something that is not clinically available right now, is your point, but we hope that in 5 to 10 years, if the evidence is there, wouldn't it be great if we could do a blood test for these, see if that person is positive for any of them, and then start that treatment faster before there's a lot of damage that we can't go back and reverse? Yeah, there's a lot of work to be done here.

00:50:03 Jill (Host): Well, as always it's not simple and it's not there yet, but we so appreciate your taking the time to give us all of this great information. You always explain everything so nicely. It's almost as if you were an award-winning professor or something. So....

00:50:17 Dr. Pederson (Guest): [Laughs] Thank you, Jill.

00:50:19 Jill (Host): We’re very happy to have you. And hey listeners, if you are interested in sponsoring this podcast, please check out our website for details. But thank you for listening. Remember, you're not alone and please join us again soon.

00:50:35 Announcer As a reminder, anything you hear on this podcast is not medical advice. Consult your health care team about what's right for you. This show is a production of Standing Up to POTS, which is a 501(c)(3) nonprofit organization. You can send us feedback or make a tax deductible donation at www.standinguptopots.org. You can also engage with us on social media at the handle @standinguptopots. If you like what you heard today, please consider subscribing to our podcast and sharing it with your friends and family. You can find us wherever you get your podcasts or at www.thepotscastcom. Thanks for listening. © 2022 Standing Up to POTS. All rights reserved. [Transcriber’s note: If you would like a copy of this transcript or the transcript for any other episode of the POTScast, please send an email to volunteer@standinguptopots.org]