The Science Behind Autoimmune Disease – with Meghan Free, PhD

This is Episode One of “Autoimmune Disease: Pieces of the Picture,” a new Chair’s Corner podcast series. Dr. Ron Falk and Dr. Meghan Free begin this series with a conversation about what goes wrong in the cells of the human body during an autoimmune disease process. Dr. Free is a basic science researcher whose work focuses on the autoimmune disease vasculitis; she is an Assistant Professor of Medicine in the UNC Division of Nephrology.

Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.

We begin today a series that will concentrate on autoimmune disease. What causes it, what is it, and how can patients find experts who can help them and figure out the best treatments that will make them feel better? We’ll be joined in this series by several experts to help us explore these and other topics, and take a close look at some specific types of autoimmune diseases and treatments.

Today, we’ll look at current research in autoimmunity and we welcome Dr. Meghan Free who is an Assistant Professor at the University of North Carolina in the Division of Nephrology, and she specializes in autoimmune disease and the basic science that underpins what causes how people react to themselves. Her studies focus on very important cells that are players in autoimmune disease – T cells, and B cells, and the role they play in various disorders.

Welcome, Meghan Free.

Meghan Free, PhD: Thank you.

Common Threads in Autoimmune Disease

Falk: Meghan, your research focuses really on translational science of a particular form of autoimmune disease, and that is inflammation of blood vessels called vasculitis. There are so many different autoimmune diseases. Help us understand some common threads that you and others have observed that link these autoimmune diseases together.

Free: I think that’s one question that often times comes to mind with patients with autoimmune diseases: What caused my disease? Was there anything that I could have done to prevent that? We know through research that there isn’t one gene that causes autoimmune disease, but through various research studies we know that there are certain genes that have come up in numerous autoimmune diseases. One of those genes is called HLA, or human leukocyte antigen. That is a gene that codes for a protein receptor that basically tells your immune system what’s in your immune system: is it bacteria, is it a virus, is it yourself? And there are certain HLA’s that predispose people to Type I diabetes or vasculitis or rheumatoid arthritis. But that gene alone doesn’t cause disease. We know that there are different environmental factors that can also predispose people and what we’re starting to understand is it’s the combination of all these events that often lead to autoimmune disease.

Falk: So it’s the combination of your genes and the environment that interact and result in a break in what’s called tolerance. We’ll talk about tolerance in a moment. It’s now a reaction to oneself. You’re not supposed to have your immune system react to you, you’re supposed to have your immune system react to bacteria, viruses, or foreign substances. Now you’ve broken through normal, regulatory pathways and you’re reacting to some protein in your body, yourself. What you’re saying is that’s a consequence of some alteration – a genetic background that now has come in contact with an environmental stimulus.

T cells, B cells, and self-antigens

Falk: What is a T cell and what is a B cell?

Free: Most people know that we all have white blood cells that float around in our blood. White blood cells is a heterogenous population of immune cells. There are two portions of the immune system that can be categorized. You have your innate immune system – which are your first responders, things like neutrophils and monocytes. There is also the adaptive immune system. Some people think that these cells are a little smarter, because they’ve been trained more, they have specific targets, and those are B cells and T cells. B cells are the ones that make our antibodies, which, in patients with autoimmune disease, they have antibodies to self, that’s what is tested for in the clinical labs. T cells are also specific for self in patients with autoimmune disease.

Falk: What is a self-antigen?

Free: A self-antigen is any protein that is supposed to be in our body. So, it can be a liver protein, it can be a bone protein, a kidney protein: anything that, basically is internal to our own person.

Falk: Some patients make antibodies-instead of to a bacteria or to a virus, make antibodies to that self. Antigen to that self-protein.

Free: Correct. If the self-antigen is known in the disease, that is known often times what is tested for in the clinical labs. Patients with vasculitis are tested to see if they have anti-neutrophil cytoplasmic autoantibody.

Falk: Or in rheumatoid arthritis, they’re tested for antibodies to citrullinated proteins. There are lots of tests in the clinical lab that are looking for antibodies to a self-antigen.

Tolerance, and how T cells & B cells learn their functions

Falk: So what is tolerance? What is a break in tolerance?

Free: The number one function of the immune system, in my view, is supposed to be able to discriminate self from non-self. What that means, like you’ve alluded to, is that your immune system is supposed to be very good at protecting your body from external antigens, be it bacteria, viruses, other foreign pathogens, while preserving the self. You don’t want to harm yourself. So tolerance is the mechanism by which your immune system discriminates bacteria from your lungs, from your kidneys, and so on.

That is often taught very early in life – the T cell is taught in the thymus, the B cell is taught in the bone marrow. We know in patients with autoimmune disease that there are breaks in tolerance, that there are certain genes or certain receptors or proteins, that are either misfolded, dysregulated – there’s something amiss within those pathways that causes your body to mistake yourself for an antigen. That can also happen through something called molecular mimicry, wherein your body is trained to respond to bacteria or virus and something has happened to yourself, that either the protein becomes misfolded or misexpressed, and it now looks like that bacterial protein or looks like a viral protein. That’s why a lot of times we see patients present initially with a respiratory illness or the flu that then can lead to autoimmune disease.

Falk: You used an interesting word choice. You said that T cells and B lymphocytes – you used the word that these cells were “taught.” What does that mean? Help us understand that.

Free: I think of it in a rudimentary way in that T cells and B cells essentially – they’re born, they go to school, and they learn what they’re supposed to learn. A more scientific way to think about it is that, in your thymus, for example, which is this organ right above your heart, your T cells go there and there are cells that are called medullary thymic epithelial cells. They know all the proteins in your body and they present little pieces of all these different proteins to your T cells. If your T cell reacts too strongly to your self-protein, that cell will become deleted.

Falk: This is during development, in utero.

Free: Yes. It’s educated by deletion, but also if those cells react too strongly to self, they can be taught to become a regulatory T cell, which provides an anti-inflammatory response during times of inflammation.

Falk: Your work and others have shown that there are, in humans with various forms of autoimmune disease – in your work, vasculitis – there are cells that are no longer listening to lessons that they may have learned and are proliferating and are not being able to be regulated by other forms of T cells.

Free: In vasculitis in particular, there are two anomalies that we have found with T cells. One of those, as we’ve alluded to, is the regulatory T cell type, or the anti-inflammatory T cell. These are cells that are supposed to keep your immune system under check and not allow too much inflammation to go on. We know in patients with vasculitis that those cells don’t function as they’re supposed to.

Falk: That’s true of other autoimmune disease.

Free: Right, they’ve seen it in lupus, they’ve seen it in a number of other autoimmune diseases. That goes back to the common threads of autoimmune disease. We don’t know exactly why those cells don’t function as they’re supposed to. We have hints and clues that the genetics of those cells may be amiss. The flip side of that coin is that there are effector T cells that are supposed to be inflammatory and do their job when appropriate. There is a population of those cells in patients with vasculitis that have expanded beyond their normal means and are exceedingly pro-inflammatory and can’t be kept in check by those nonfunctioning regulatory T cells. So it’s a perfectly bad storm of two different populations not functioning appropriately.

The difference between an autoimmune disease and an allergy

Falk: What’s the difference between an autoimmune disease and an allergy?

Free: Both instances can be seen as states of a hyper immune system. That the white blood cells are responding to something inappropriately, they are overly inflammatory towards something. The biggest difference is that allergy is a reaction to something external: a peanut protein, or a pollen – something that is external to your body. While autoimmune disease, you are having an inflammatory response to something that is an internal protein.

Falk: That’s a beautiful differentiation. Just in summary, then, there are genetic reasons for people to have an autoimmune disease, there are environmental triggers that may cause the disease, they can cause a flare. There are T cells and B lymphocytes that have been taught during development to be under control; there are T cells that are there to regulate other T cells, and B cells there to regulate other B cells. This is a beautiful balance between regulatory components that are supposed to keep the immune system in check, and somehow, in the process of an autoimmune disease, are no longer functioning like they’re supposed to. That’s really this concept of breaking tolerance to your own protein.

What is a prodrome?

Falk: Most patients with an autoimmune disease don’t come in with a sign on their forehead that says “I have rheumatoid arthritis.” They start with vague symptoms; they come in with not necessarily specific findings, and that is known as a “prodrome.” How would you explain a prodrome from a scientific perspective?

Free: The best way that I think about it is there are so many pieces to an autoimmune disease that go wrong, essentially. Something goes wrong with T cells, B cells, neutrophils in the case of vasculitis, and often times all those pieces don’t go wrong at the same time. It’s an additive effect. Maybe when you see a patient the first time, only the regulatory T cell component has gone bad. That then leads to dysregulation of B cells and dysregulation of neutrophils. It’s only over the course of time that more and more symptoms occur as these dysregulations in the immune system are also occurring.

Falk: The body actually can self-heal in some of those circumstances. So once that process has begun, there is the possibility for the immune system to gain control again and thwart an autoimmune disease from occurring. That process is happening on a regular basis in most of us as we are exposed to different factors in the environment. So a prodrome may be this possibility of the immune system becoming out of check and producing inflammatory signals.

Free: The other issue there, and I think you see a lot in vasculitis, is that the same function that our system is playing in autoimmune disease – those same immune cells are also responsible for a response to a respiratory infection, and sometimes it’s hard to decipher if a person’s respiratory symptoms are due to a mere infection, or is this early vasculitis?

Falk: Meghan, thank you so much for this introduction to the science behind autoimmune disease that begins this series for patients on autoimmune disease in general. Thanks so much.

Free: Thanks for having me.

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