Molecular pain research – Camilla Svensson's research group

Pain is one of the most problematic symptoms of rheumatic diseases, such as rheumatoid arthritis (RA) osteoarthritis (OA) and fibromyalgia (FM). RA is an autoimmune disease characterized by joint inflammation along with bone and cartilage destruction that affects around 1% of the population. In RA, current anti-inflammatory treatments effectively control joint-inflammation (and inflammatory pain) in many patients. Unfortunately, well-controlled joint inflammation does not mean pain relief. RA patients frequently present with debilitating pain prior to joint-inflammation, which often persists even when the disease is medically controlled or in remission. Effective analgesic therapies for the “non-inflammatory” pain are lacking. We identified that several RA-associated antibodies, isolated from RA patients, induce pain-like behavior without classical signs of inflammation when transferred to mice.

FM is a highly prevalent disease affecting 2-4% of the population, which predominantly affects women (7/10).  Hallmarks of FM include widespread musculoskeletal pain, stiffness, and physical/cognitive fatigue. There is growing evidence of central nervous system (CNS) disturbances in FM, however, our lack of understanding the underlying pathophysiology has prevented development of effective therapies. Further, available treatments are often ineffective and frequently associated with adverse effects. FM is currently not considered an autoimmune disease, but we have discovered that transfer of antibodies (immunoglobulin G, IgG) purified from FM patients’ blood to mice gives rise to an increased sensitivity to deep pressure and cold and a reduced activity without causing an overt tissue inflammation.

The insight that autoantibodies may generate pain in the absence of visible inflammation led us to the hypothesis that not only in RA, but also in FM, there are undiscovered links between antibodies and chronic pain. Several projects in the lab are centered on investigating mechanisms by which antibodies contribute to long-lasting pain, with a focus on the molecular and cellular processes responsible for pronociceptive properties of antibodies, and the consequences of their actions. 

Commentaries about our work

https://www.jci.org/articles/view/150382

https://news.ki.se/autoantibodies-a-possible-contributor-to-fibromyalgia

https://www.theguardian.com/society/2021/jul/01/fibromyalgia-may-be-a-condition-of-the-immune-system-not-the-brain-study

https://www.verywellhealth.com/autoimmunity-neuroinflammation-in-fibromyalgia-5197944

https://www.versusarthritis.org/news/2021/june/research-shows-that-fibromyalgia-is-likely-a-condition-of-the-immune-system/

https://www.painresearchforum.org/news/180579-antibodies-patients-cause-fibromyalgia-symptoms-mice

https://www.sciencealert.com/mouse-study-suggests-fibromyalgia-really-is-an-autoimmune-disorder

https://www.expressen.se/premium/halsa/nya-studien-ger-hopp-for-personer-med-fibromyalgi/

https://www.aftonbladet.se/halsa/a/Ryzmer/nya-ron-ger-hopp-at-drabbade-av-fibromyalgi

https://www.nature.com/articles/s41584-019-0269-8

https://news.ki.se/rheumatoid-arthritic-pain-could-be-caused-by-antibodies

Previous group members

• Sara Sadek - Bachelor student
• Merna Bitar - Master student
• Nicole Nova - Master student
• Max Larsson - Researcher
• Kristina Ängeby-Möller - Doctoral student
• Teresa Fernandez-Zafra - Doctoral student
• Payam Emami - Postdoc
• Shibu Krishnan - Postdoc
• Tianle Gao - Postdoc
• Anahita Morbagha - Bachelor student
• Fatima Rhordo - Master student
• Christina Christianson - Visiting PhD student
• Johanna Pettersson - Master student
• Joshua Gregory - Postdoc
• Pia Sandberg - Bachelor Student
• Hanna Steurer - Bachelor Student
• Ebba Gregory - Doctoral student
• William Nyberg - Master student
• Simone Codeluppi - Asisstant professor
• Magdalena Kegel - Master student
• Kim Kultima - Associated
• Ada Delaney - Postdoc
• Tianle Gao - Postdoc
• Camilla Ultenius - Postdoc
• Anya Finn - Doctoral student
• Jungo kato - Postdoc
• Jie Su - Doctoral student
• Katarzyna Rogoz - Postdoc
• Duygu Belkis Baş - Postdoc
• Gustaf Wigerblad - Doctoral student
• Sally AbdelMoaty - Postdoc
• Ahmad Shareef - Research assistant
• Jaira Villarreal Salcido - Master student
• Diana Nascimento - Postdoc
• Nilesh Agalave - Postdoc (previously PhD student)
• Azar Baharpoor - Biomedical scientist
• Yuki Nomura - Asisstant professor
• Vinko Palada - Postdoc
• Tinna Ängeby Möller - PhD Student
• Freija ter Heegde - Postdoc
• Louisa Brieskorn - Master student
• Francisca Castillo - Research assistant
• Resti Rudjito - PhD student
• Femke de Krom - Master student
• Chrisitan Martin Gil - Visiting pPhD student
• Ivan Voloshyn - Research assistant
• Zhenggang Wang - Visiting PhD student
• Emerson Krok - Postdoc
• Freja Holländer - Masterstudent
• Paul Benjamin - Masterstudent
• Juan Antonio Vazquez Mora - Masterstudent
• Julia Döring - Masterstudent
• Sigita Venckute - Master student and Laboratory assistant
• Federico Picciau - Intern
• Carlos Eduardo Morado Urbina - PhD student
• Annelie Lifvergren - Bachelor student
• Elena PDurán González - Visiting PhD student
• Linda Kaupp - Master Student
• Lydia Moll - PhD Student

Selected awards and funding

2020             UCSD Pharmacology Department Annual Outstanding Alumnus Award

2019             ERC Consolidator grant ANTIBODYPAIN

2019             Wallenberg Academy Scholar, Knut and Alice Wallenberg Foundation

2018             Wallenberg Academy Fellow prolongation, Knut and Alice Wallenberg Foundation

2012             Wallenberg Academy Fellow, Knut and Alice Wallenberg Foundation                     

2012             Söderberg Fellow in Medicine, Ragnar Söderberg Foundation                              

2010             Future Research Leader 4, Swedish Foundation for Strategic Research                    

2009             Early Career Award, International Association for Studies of Pain                         

2006             McDuffie Honor Award, American Arthritis Foundation                   

2021             FOREUM “Pain and Fatigue”

2020             FOREUM “Sex and gender issues”

2020             EIC-FETPROACT: BoneFix (lead by Michael Malkoch, KTH)

2019             EU-ITN: TOBeATPAIN (lead by Marcia Malcangio, KCL)

2019             SSF E-NeuroPharma (lead by Magnus Berggren, Linköping University)

2018             EU-ITN: BONEPAIN.II (lead by Anne-Marie Heegaard, Copenhagen University)

2014             EU-ITN: BONEPAIN (lead by Anne-Marie Heegaard, Copenhagen University)

2013             Vetenskapsrådet Bidrag till framstående yngre forskare

Group activities

Research retreats and conferences

Autoantibody-mediated pain mechanism

Anti–modified protein antibodies (AMPAs)

Antibodies binding citrullinated epitopes of e.g. vimentin, alpha-enolase and fibrinogen (so called anti-citrullinated protein antibodies, ACPA) are the most disease specific RA autoantibodies, present in 70% of the patients. In the past, autoantibodies in RA have predominantly been coupled to pain as an intermediary factor during inflammation, which enhance activation of immune cells that  subsequently release pain-inducing factors such as cytokines and prostaglandins. In sharp contrast, data from our laboratory demon­strated for the first time that injection of total IgG purified from RA patients, or isolated ACPA IgG, mediate long-lasting pain-like behavior in mice without causing classical signs of inflammation.

Prior to their clinical diagnosis many RA patients experience pain prior to signs of joint inflammation. Similarly, ACPA and additional members of the anti-modified protein antibodies (AMPAs, which show reactivity towards e.g. carbamylation, acetylation or malondialdehyde) family can be present in the blood for many years before clinical manifestation and diagnosis. We aim to better understand how AMPAs and other RA-associated antibodies drive pain in the absence of overt joint inflammation. We have found that osteoclasts play an important role; blocking their activation in mice injected with ACPA and other RA-associated antibodies prevents the development of pain-related behaviors. This reveals a fascinating interplay between the immune system, the nervous system and bone homeostasis. We are also currently exploring how different cell types such as osteoblasts, fibroblasts, macrophages, satellite glia cells, CNS microglia and astrocytes contribute to AMPA-mediated pain.

For more information:

Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism.
Wigerblad G, Bas DB, Fernades-Cerqueira C, Krishnamurthy A, Nandakumar KS, Rogoz K, Kato J, Sandor K, Su J, Jimenez-Andrade JM, Finn A, Bersellini Farinotti A, Amara K, Lundberg K, Holmdahl R, Jakobsson PJ, Malmström V, Catrina AI, Klareskog L, Svensson CI
Ann Rheum Dis 2016 Apr;75(4):730-8

Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, osteoclast activity, and acid-sensing ion channel 3-dependent sensitization.
Jurczak A, Delay L, Barbier J, Simon N, Krock E, Sandor K, Agalave NM, Rudjito R, Wigerblad G, Rogóż K, Briat A, Miot-Noirault E, Martinez-Martinez A, Brömme D, Grönwall C, Malmström V, Klareskog L, Khoury S, Ferreira T, Labrum B, Deval E, Jiménez-Andrade JM, Marchand F, Svensson CI
Pain 2021 Nov;():

Pathogenic Citrulline-Multispecific B Cell Receptor Clades in Rheumatoid Arthritis.
Titcombe PJ, Wigerblad G, Sippl N, Zhang N, Shmagel AK, Sahlström P, Zhang Y, Barsness LO, Ghodke-Puranik Y, Baharpoor A, Hansson M, Israelsson L, Skriner K, Niewold TB, Klareskog L, Svensson CI, Amara K, Malmström V, Mueller DL
Arthritis Rheumatol 2018 12;70(12):1933-1945

Chronic hypersensitivity (inflammatory and late phases of CAIA model)

We have previously identified several potential factors that could drive persistent pain-like behavior in the CAIA model, such as high mobility group box 1 (HMGB1) and lysophosphatidic acid (LPA).  

HMGB1 is an important molecule in the pathogenesis of RA. We have reported the involvement of both peripheral and spinal HMGB1 in CAIA-induced pain-like behavior in both inflammatory and late phases. Interestingly, the pronociceptive role of HMGB1 is redox- and sex-dependent, thus highlighting the importance of these two parameters when developing novel therapeutics.

LPA is a bioactive phospholipid that had been linked to neuropathic pain in animal models and to joint inflammation in RA patients and RA models. We found that blocking LPA signaling reverses CAIA-induced pain-like behavior during both the inflammatory and late phases, independent of joint inflammation. We determined that LPA signaling between satellite glia cells (SGCs), the resident DRG glia, and neurons  can regulate pain-like behavior. These findings highlight the importance of local signaling events within the DRG itself and that LPA and SGCs are potential antinociceptive targets in persistent RA-associated pain.

Currently, we are investigating if changes in bone metabolism contribute to long-lasting pain-like behavior in the CAIA model. Even following the resolution of joint inflammation, the “post-inflammatory” phase, there are residual signs of bone destruction present. Our current work suggests that osteoclasts display an interesting pronociceptive role in the CAIA model that is not only linked to their resorptive actions, but also coupled to their modulation of bone vascularization and innervation via release of factors such as netrin-1. In collaborations with Netris Pharma (France), we are examining the potential of anti-netrin-1 antibody, currently in Phase II clinical trials for cancer, as a possible therapeutic for the treatment of chronic pain.

In addition, we are exploring the antinociceptive mechanism of baricitinib, a disease modifying anti-rheumatic drug used for the treatment of RA, in collaboration with Eli Lilly (USA). Baricitinib is known to reduce joint inflammation and disease activity by targeting the JAK/STAT signaling pathway. Interestingly, it has been shown that baricitinib also targets molecules involved in the clathrin-mediated endocytosis, such as AAK1. We are exploring whether clathrin-mediated endocytosis is an integral aspect of chronic pain signaling in the CAIA model and if this pathway represents an additional pain-reducing mechanism of baricitinib.

Role of NGF in RA-induced pain

NGF has been implicated in joint pain and interestingly a missense mutation in the Ngf gene, identified in a Norrbottnian Swedish family, results in a loss of deep pain sensation in bones and joints. We are examining the role of NGF in joint health using genetically modified mice where  NGF is replaced with the human mutated NGF. While a role of NGF in pain signaling has been confirmed in patients with bone cancer and osteoarthritis, as well as animal models, the role of NGF in RA pain and bone erosion is unknown. The overall aim of this project is to explore and understand the link between NGF, bone homeostasis and pain using both evoked pain and non-evoked pain tests to assess deep pain sensation, as well as molecular and imaging techniques.

Mechanisms of chronic pain in osteoarthritis

Pain experienced by patients with osteoarthritis (OA) is highly variable and  linked to sex . Identification of molecular mechanisms that underlie sex-dependent differences could provide personalised approaches to patient care. In collaboration with Eva Kosek (Department of Clinical Neuronscience, KI), we are involved in studies addressing this and the neuroimmune components of pain in OA. Joint instability and repeated mechanical joint loading in mice provide clinically relevant models of painful OA. Using such models, we have projects in the lab that are exploring molecular and cellular mechanisms behind chronic pain in OA. One of them has a sex-focus, the project is led by our collaborator Tonia Vincent (Oxford University, UK). Epidemiological studies of OA indicate that pain in  females often coincides with lower levels of structural damage and is more often complicated by evidence of central sensitization. Few studies to date have examined molecular mechanisms that may explain this apparent sexual dimorphism in OA. Identifying such pathways could provide a number of clinically useful outcomes: (i) new treatments tailored according to the sex of the patient, (ii) biomarkers (potentially sex-dependent) of painful disease that could be used in clinical evaluation and for personalised approaches to pain management (iii) opportunities to combine treatments to reduce side effects of existing pain therapies.

Macrophage heterogeneity and function in the DRG

Macrophages are resident immune cells that inhabit every organ of the body including the central and peripheral nervous systems. Macrophages can have diverse functions that are tailored to their tissue microenvironment and multiple macrophage subsets have been found in individual organs, including lungs, brain and liver. In this project we are characterizing the distinct subsets of macrophages residing in the DRG from a molecular and functional perspective during homeostasis and in conditions of chronic pain, primarily in models of RA and FM. In addition, just like the blood-brain barrier, there is a blood-nerve barrier, which can prevent the entry of pathogens and neurotoxic compounds into the peripheral nerves. This barrier is significantly more permeable in the DRG, as demonstrated in rodents by the high accumulation of intravenously injected dyes in the DRG parenchyma. One aspect of this project is focused on delineating the interaction between macrophages and the vasculature system in the regulation of tissue homeostasis and development of chronic pain.

Application of new technologies for pain relief and nerve regeneration

In collaboration with Magnus Berggren, Daniel Simon and colleagues (Department of Science and Technology, Linköping University), we are part of two projects that are focused on the development of new technologies for precise spatial and temporal delivery of drugs or other compounds to neurons in vitro and in vivo. In the Ionotronix project we are developing an ionic pump that, after being positioned for example around the sciatic nerve, can be used to deliver local anesthetic drugs in situ, to obtain their potent pain-relief action while avoiding systemic side effects. Moreover, we are exploring the biocompatibility and tolerance of conductive biopolymers, with the ultimate goal of utilizing these substances for in vivo nerve modulation and regeneration.