Nav: Home

Rheumatoid arthritic pain could be caused by antibodies

June 13, 2019

Antibodies that exist in the joints before the onset of rheumatoid arthritis can cause pain even in the absence of arthritis, researchers from Karolinska Institutet in Sweden report. The researchers believe that the finding, which is published in the Journal of Experimental Medicine, can represent a general mechanism in autoimmunity and that the results can facilitate the development of new ways of reducing non-inflammatory pain caused by rheumatoid arthritis and other autoimmune diseases.

"We all know that inflammation is painful," says Camilla Svensson, professor at the Department of Physiology and Pharmacology, Karolinska Institutet. "But pain can appear before any sign of inflammation in the joints and can remain a problem after it has healed. Our aim was to find possible mechanisms to explain that."

Rheumatoid arthritis is an autoimmune disease that occurs when immune cells attack the cartilage and bone of the joints. The disease affects roughly one per cent of the Swedish population.

A common early symptom is joint pain, but even before that, the body has started to produce immune antibodies against proteins in the joint. Researchers at Karolinska Institutet have now studied how these autoantibodies can generate pain.

After injecting cartilage-binding autoantibodies into mice, which served as a model for human rheumatoid arthritis, the researchers found that the mice became more sensitive to pain even before they could observe any signs of inflammation in the joints. Antibodies that had been designed not to activate immune cells and trigger inflammation also induced pain-like behaviour in the mice, suggesting increased pain sensitivity in the joints.

The researchers found that the antibodies that caused the behavioural change form so called immune complexes, comprising clusters of antibodies and cartilage proteins in the joints. These complexes activate pain cells via so-called Fc-gamma receptors, which the researchers discovered were present on pain neurons in the tissue.

When they cultivated pain neurons from the mice, the researchers found that the cells were activated when coming into contact with the antibody complexes. The process was dependent upon the Fc-gamma receptors on the neurons but not on the presence of immune cells. Antibodies in complex can thus act as pain-generating molecules in themselves, independently of the activity of the immune cells, as Camilla Svensson, one of the study's two corresponding authors explains:

"Antibodies in these immune complexes can activate the pain neurons directly, and not, as previously thought, as a result of the destructive joint inflammation," she says. "The antibodies can affect the pain neurons also in conditions without any distinct tissue damage or inflammation."

Although the study was conducted in mice, the researchers show that human pain neurons also have antibody receptors that are functionally similar to those they found on the mouse pain neurons, which leads them to believe that their findings are also relevant to humans.

The results can explain the early pain symptoms in rheumatoid arthritis patients. However, joint and muscle pain are also common symptoms of other autoimmune diseases, and since this newly discovered mechanism operates through the constant part - "the shaft" - of the autoantibody, the researchers believe that it can explain non-inflammatory pain caused by other autoimmune diseases too.

"We think that this can be a general pain mechanism in effectively all autoimmune diseases in which these kinds of immune complex form locally in tissue," says Professor Svensson.

More detailed study of what happens in the nerve cell when the antibody complex binds to the receptor could also lead to new targets for reducing the neuronal activity.

"By learning more about the molecular mechanisms of antibody-mediated pain we hope to lay the groundwork for a new way of reducing pain caused by rheumatoid arthritis and other autoimmune diseases," says Rikard Holmdahl, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, and the study's other corresponding author.
-end-
The study was financed with grants from the Swedish Research Council, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the Ragnar Söderberg Foundation, the Torsten Söderberg Foundation, the Åke Wiberg Foundation, the Alfred Österlund Foundation, the Krapperup Foundation, the King Gustaf V 80-year Foundation, the Swedish Rheumatism Association, Hansa Medical AB, the Royal Physiographic Society, Karolinska Institutet's funds, the Canadian Institutes of Health Research and the Guangdong province of China. The financiers have had no influence on the paper or the decision to publish it.

One of the researchers holds a patent on the use of a type of antibody used in the study and a royalty agreement with Hansa Medical, which also holds a patent on a particular application of the antibodies. See the article for further details.

Publication: "Cartilage binding antibodies induce pain through immune complex mediated activation of neurons". Alex Bersellini Farinotti, Gustaf Wigerblad, Diana Nascimento, Duygu B Bas, Carlos Morado Urbina, Kutty Selva Nandakumar, Katalin Sandor, Bingze Xu, Sally Abdelmoaty, Matthew A Hunt, Kristina Ängeby Möller, Azar Baharpoor, Jon Sinclair, Kent Jardemark, Johanna T Lanner, Ia Khmaladze, Lars E. Borm, Lu Zhang, Fredrik Wermeling, Mark S Cragg, Johan Lengqvist, Anne-Julie Chabot-Doré, Luda Diatchenko, Inna Belfer, Mattias Collin, Kim Kultima, Birgitta Heyman, Juan M. Jimenez-Andrade, Simone Codeluppi, Rikard Holmdahl, Camilla I Svensson. Journal of Experimental Medicine, online 13 June 2019, doi: 10.1084/jem.20181657.

Karolinska Institutet

Related Neurons Articles:

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.
Shaping the social networks of neurons
Identification of a protein complex that attracts or repels nerve cells during development.
With these neurons, extinguishing fear is its own reward
The same neurons responsible for encoding reward also form new memories to suppress fearful ones, according to new research by scientists at The Picower Institute for Learning and Memory at MIT.
How do we get so many different types of neurons in our brain?
SMU (Southern Methodist University) researchers have discovered another layer of complexity in gene expression, which could help explain how we're able to have so many billions of neurons in our brain.
These neurons affect how much you do, or don't, want to eat
University of Arizona researchers have identified a network of neurons that coordinate with other brain regions to influence eating behaviors.
Mood neurons mature during adolescence
Researchers have discovered a mysterious group of neurons in the amygdala -- a key center for emotional processing in the brain -- that stay in an immature, prenatal developmental state throughout childhood.
Connecting neurons in the brain
Leuven researchers uncover new mechanisms of brain development that determine when, where and how strongly distinct brain cells interconnect.
The salt-craving neurons
Pass the potato chips, please! New research discovers neural circuits that regulate craving and satiation for salty tastes.
When neurons are out of shape, antidepressants may not work
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed medication for major depressive disorder (MDD), yet scientists still do not understand why the treatment does not work in nearly thirty percent of patients with MDD.
Losing neurons can sometimes not be that bad
Current thinking about Alzheimer's disease is that neuronal cell death in the brain is to blame for the cognitive havoc caused by the disease.
More Neurons News and Neurons Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Speedy Beet
There are few musical moments more well-worn than the first four notes of Beethoven's Fifth Symphony. But in this short, we find out that Beethoven might have made a last-ditch effort to keep his music from ever feeling familiar, to keep pushing his listeners to a kind of psychological limit. Big thanks to our Brooklyn Philharmonic musicians: Deborah Buck and Suzy Perelman on violin, Arash Amini on cello, and Ah Ling Neu on viola. And check out The First Four Notes, Matthew Guerrieri's book on Beethoven's Fifth. Support Radiolab today at Radiolab.org/donate.