Editor’s note: The 17th IASP World Congress on Pain took place September 12-16, 2018, in Boston, US. At the Congress, 12 early-career pain researchers took part in the PRF Correspondents program, a science communications training experience that provides participants with knowledge and skills needed to communicate science effectively to a wide range of pain researchers and to patients and the wider public. As part of this program, the participants conducted interviews with plenary speakers at the meeting.
Here, plenary speaker Camilla Svensson, PhD, chats with PRF Correspondent Alexander Davies, PhD, a postdoctoral researcher in the Nuffield Department of Clinical Neurosciences at the University of Oxford, UK. Svensson is a professor of cellular and molecular pain physiology at the Karolinska Institute in Sweden. She spoke with Davies about the mechanisms of rheumatoid arthritis pain, what it’s like to work at the Karolinska Institute, and much more. Below is an edited transcript of their conversation.
Can you remember the moment in your career when you realized the key to chronic pain could lie in the immune system?
It really started when I was a PhD student focusing on inflammatory mechanisms of pain. I realized that even though pain is a big problem for individuals with arthritis, we were not really communicating closely with the rheumatologists. I had this feeling that the pain field and the rheumatology field were operating almost in silos.
Ever since I did a postdoc with a rheumatology lab, I have been trying to bridge between the two fields, and that has really given me new perspectives on pain in disease and how important it is to understand the underlying pathology. Soon after joining the rheumatology lab I started to suspect that there were aspects of the immunopathology of rheumatoid arthritis [RA] that could contribute to the pain characteristic of the disease but that had not yet reached the radars of pain researchers; the immunological aspect of RA is fascinating, and quite complex. One of our “big” moments showing that was when we found that antibodies isolated from RA patients induced mechanical hypersensitivity in mice, even though we could not see any signs of inflammation.
Is it a challenge working in a cross-disciplinary field like neuroimmunology? Do you have a strategy when communicating immunology to neuroscientists, and vice versa?
It is a challenge. For example, right now I’m applying for ERC [European Research Council] funding. I’m sending my grant to the neuroscience panel, but the grant is very “immunological,” and it is challenging to communicate the approach in a way that makes sense and is appealing to “hardcore” neuroscientists. You may struggle a bit more to make the funding agencies understand that what you are proposing is important.
It really takes some time to get to know the scientific language of the discipline that is not your home discipline. Personal interactions are critical for that, and you need to define an overlapping interest, even if you are coming at things from completely different angles. The key is to make enough time to be visible in both fields—to make the connections with researchers in both fields—and find ways to make both sides understand the advantage of working across the disciplines.
One benefit is that I rarely have a feeling of competition with rheumatology/immunology researchers; it’s more that we are complementing each other. I am often struck with the insight that we can accomplish so much when we work together across disciplinary borders; the synergy is obvious. In that regard, it is even easier to define new goals and feel innovative. You just take one ingredient from each side, you mix it together, and it becomes something new.
Some of your work has focused on what drives pain in RA in the absence of inflammation. You are also careful to phrase this with the caveat, no observable inflammation. Is it possible that subclinical inflammation persists in chronic arthritis?
You are addressing one of our key questions. Based on what we have found so far focusing on the innate immune response in early or late phases of our animal models of arthritis pain, we don’t see any signs of inflammation. But, of course, that doesn’t mean that it’s not there.
There are two perspectives that we have to consider. First, there is a risk that our approach may be too crude. In most of our experiments we have assessed the inflammatory factors in whole joint homogenates. But could there be very local changes in specific compartments in the joints, where the initial inflammatory pro-nociceptive drive is taking place? We have to use other techniques to address this possibility, and we are doing such studies now.
Second, there could be production of factors that we don’t traditionally think of as having a strong inflammatory drive that could still act on immune cells and be pro-nociceptive when they act on neurons. But if they do not activate the process that leads to the cardinal signs of inflammation, or if it takes a very long time, is it subclinical inflammation or not? That is a question of definition.
We have done experiments where we inject antibodies that I think of as being key components of the inflammatory process in autoimmune disease. When we inject these antibodies into mice that have immune cells lacking the ability to respond to antibodies, we see absolutely zero inflammation, not even a hint. However, these mice still develop pain-like behavior. This tells me that there must be inflammatory-associated factors that can drive pain without the inflammatory component in our model system.
Do we therefore need a new vocabulary to describe pain that’s caused by disease-related immune factors, falling somewhere in between classical “inflammatory pain” and “neuropathic pain”?
That’s a very good point. Just to give an example of how we have been trying to work around this issue, my rheumatology colleagues have identified “pre-RA” individuals who have antibodies against cyclic citrullinated protein [CCP]. They came to the clinic because they had joint pain, but on examination they do not fulfill the criteria for a diagnosis of RA; they have no or very few swollen joints and do not possess elevated levels of factors indicative of systemic inflammation. Thus, they are not patients who have RA because they don’t fulfill all the other criteria.
My colleagues are planning a clinical study where we will test the response of these patients to a set of bisphosphonates; these are agents that reduce osteoclast activity [to prevent bone resorption]. But getting ethical permission to do that, and getting the funding agencies to sponsor this study, are potential challenges because we don’t have a patient population; they don’t have a diagnosis. One way to facilitate things could be to identify a vocabulary for this population, like “anti-citrullinated protein antibody [ACPA] syndrome.” We would then have a group of individuals with a pain problem lacking an approved diagnosis but who could be put under a vocabulary. So from that perspective, it could be very helpful.
From a basic research perspective, we really have to think carefully about it. One situation that makes me reflect on this issue is when we talk about neuroinflammation. This term refers to inflammatory responses within the brain and spinal cord that are mediated by factors that, by definition, are inflammatory, like cytokines and chemokines. But when released in the CNS they are not causing classical signs of inflammation. Yet we call it neuroinflammation, which to me suggests that there is ongoing inflammation in the CNS. Is that a misleading term or not? Are these factors inflammatory in the CNS, or are they just acting as situation-specific transmitters between two different cell populations? And how much does it really have to do with what we define as an inflammatory process?
Maybe we should not introduce new vocabulary just because we can. But when we see that it can serve a purpose of helping us to identify patients or, as you are suggesting, of helping to move a concept forward, then it would be a good place to do it.
When you consult with your immunology colleagues regarding some of these processes, do they have an opinion on the relevance to classical inflammation?
Sometimes our fields are still so far apart. An immunologist may ask, “But why would a neuron have a TNF [tumor necrosis factor] receptor? Why would a neuron have an Fc gamma receptor [which directly responds to antibodies]?”
If I look at a textbook illustration depicting pathology in bone, I’ll see blood cells, immune cells, and bone cells, but I don’t see the neuron—it’s not even in the picture! So I actually have to start one step behind that and say, “Where is my neuron?”
In your plenary lecture at the World Congress, you presented some recent findings showing that Fc receptors on sensory neurons interact with autoantibodies, which you think may drive some of the pain hypersensitivity in RA. What are the potential implications of this mechanism, and how will it affect the way we look at inflammatory diseases like RA?
We and the immunologists have for a long time looked at autoantibodies as drivers of inflammatory cascades, where the body is activating immune cells, stimulating phagocytosis, complementing fixation, and so forth, and this gives rise to secondary symptoms. But we haven’t really thought about that process as being responsible forjust pain. I call this the potential for “inflammatory silent” autoantibodies, which is provocative for immunologists, especially T cell biologists and B cell biologists.
If it’s true, then we are now talking about critical concentrations of autoantibodies that are not enough to trigger a full-blown immune response, but just enough to facilitate activation of sensory neurons. Now you potentially have a completely new arena where autoantibodies could be an important driver of nervous system sensitization. And of course in an autoimmune disease like RA, we know that the antibodies are there for a very long time before joint disease becomes apparent. Actually, there’s only one drug that I know of, out of the six or seven classes of new anti-rheumatic drugs, which actually reduces levels of autoantibodies. So these autoantibodies could continue to sensitize nerves even when inflammation is controlled. You could consider that this is an issue also in lupus, in multiple sclerosis, and in a number of other autoimmune diseases where pain is also a problem.
What if you can have the generation of transient autoantibodies, due to injury? Or if you have a non-inflammatory disease that has a silent autoimmunity component that we haven’t even considered as being part of the pathology? Then you could have this pain trigger that could explain chronic pain in some conditions. A very good example of this is the work of David Bennett [at the University of Oxford], who found that an autoantibody binding to a potassium channel-complex protein caused pain [see PRF related news]. There’s also work by Andreas Goebel, David Clark, and colleagues suggesting that chronic regional pain syndrome has an autoimmune pain component.
When it comes to Fc gamma receptors, work from Chao Ma’s group has really paved the way for suspecting that even if the antigen is important, it is the location and concentration of immune complex that is critical for pain induction. We have work under revision that certainly supports this hypothesis. It really opens up a whole new way of looking at an undiscovered driver of chronic pain conditions, and it can be tested quite easily.
Presumably, there is a whole remit of treatments that already exists for other autoimmune conditions that could also potentially be used for pain?
Plasmapheresis [plasma exchange], for example, could be used to remove antibodies in general, or perhaps this could be modified to specifically remove those coupled to pain. However, it would be costly and a quite invasive approach to remove IgG [immunoglobulin antibodies] from patients.
IVIG [intravenous immunoglobulin]would also be one way to go because here you are flooding the system with monomeric antibodies that are not activating Fc gamma receptor 1 [the type found in sensory neurons]. However, it may not be as straightforward as one may think. When I looked into the literature on IVIG given to patients with antibody deficiency, one of the more frequent side effects is pain, including headache, abdominal pain, and muscle aches. It seems that you should not give too much IVIG at the same time; you have to give it slowly in order to not evoke pain. This of course raises the question of whether it was the IgG or something else in the treatment procedure that evoked pain in these patients.
In our work that I hope will be accepted for publication soon, we demonstrate that mice express both activating and inhibitory Fc gamma receptors on sensory neurons. The definition of “activating” and “inhibitory” comes from the immunology field, but does it mean that the inhibitory receptor is blocking signal transduction? We don’t know yet what the inhibitory receptor does on neurons, and that’s what we’re exploring. So it’s a bit more difficult to know how you would target the Fc gamma receptors for treatment. And, of course, you don’t want to prevent your ability to activate immune cells.
The trick may be in what is activated downstream of these receptors in neurons; if we are lucky, there could be engagement of factors that are specific to neurons and are not downstream of these receptors in immune cells, and this could be a point of potential intervention. So there may be opportunities, but we really need to define how this system of antibody receptors works in neurons.
You are based at the Karolinska Institute, the location of several key milestones in immunology research. What makes the Karolinska Institute such a great place to do immunology research?
It’s Sweden's only university that focuses solely on medicine, and that is a natural attraction for people who want to be in a place where you can really advance that area.
My lab is now located at the Center for Molecular Medicine [CMM], which is an interdisciplinary research center with advanced laboratories closely linked to the clinics and patients of the Karolinska University Hospital. Many of the diseases that are the focus of CMM have an autoinflammatory or autoimmune component. So, as a pain group in this environment, we have many opportunities for interesting conversations with new colleagues at the coffee machines—and we drink a lot of coffee in Sweden!
The pioneering work here in inflammation and immunology carries with it a certain prestige, and the Institute has taken good care of the historical aspects of being at the forefront of the immunology field. My department was located on Nanna Svartz Väg [Way]. Nanna Svartz was the first female professor at the Karolinska Institute, and she discovered the effect of sulfasalazine as an anti-rheumatic drug.
Before I moved my lab to the CMM, it was on Von Euler Street. Ulf Von Euler, together with John Gaddum, discovered substance P and prostaglandin. And two researchers at the Karolinska Institute, Sune Bergström and Bengt Samuelsson, along with John Vane, received the Nobel Prize in Physiology or Medicine for their research on prostaglandins and related factors. So the history goes way back.
Few medical prizes attract the same attention worldwide as the Nobel Prizes do. It is inspiring to work at the same place as the professors who make up the Nobel Assembly that is responsible for selecting the researchers who will receive the Nobel Prize in Physiology or Medicine each year. We get to listen to incredibly exciting research when the laureates present their work at the Karolinska Institute.
What were your highlights from the World Congress?
To be honest, between preparation for presentations and submission of a grant, I had too many things going on this year, and so I missed several talks and posters that I had planned to attend. But it was very interesting to hear about the advancement in understanding the role of mitochondria in pain conditions and how far we have come with respect to the role of microRNA. I’m curious to see what the next “flavor” of RNA regulation of pain will be. I did make sure to catch up with collaborators and friends, though, and that is always one of the highlights of IASP, and maybe the most important one—to connect with close and distant members of my “science family.”
Do you have a method or activity that you like to use to inspire your scientific creativity?
It’s to leave my head alone, in particular to go running, which I have come to appreciate over the years. It’s so important sometimes to let the body be busy and leave the mind free to go off on its own, and for me that happens when I’m running. I have to pass the one-hour time mark and then ideas come spontaneously to me; that’s my way of being creative.