Substances in the blood of people with the autoimmune muscle disease dermatomyositis (DM) can weaken healthy muscles without the involvement of infiltrating immune cells. In a new study, researchers markedly reduced this weakening by switching off a specific immune signal in the muscle. This changes the understanding of what drives the muscle weakness – and points to a new avenue for treatment.
When an autoimmune disease causes muscle weakness, it is natural to look for the explanation in the muscle itself. But in DM, part of the problem appears to come through the blood.
In a new study from Karolinska Institutet in Sweden, substances in patients’ blood were able to weaken healthy muscles in an experimental model – without the involvement of the immune cells that have otherwise been suspected of contributing to the muscle weakness. This shifts part of the explanation from inflammation in the muscle itself to the signals that reach it through the bloodstream.
DM is a rare autoimmune disease in which the immune system attacks the body’s skeletal muscles. People become weak and tire easily, and the disease is associated with reduced quality of life and increased mortality.
But why the muscles lose strength has so far remained unclear, and several mechanisms may be involved.
“The symptoms are in the muscle. That is where the weakness and fatigue are. But it is not certain that the immune cells in the muscle are themselves causing the problem. We suspected that there are systemic factors in the blood that weaken the muscle, and those are what we have been trying to understand better,” explains a researcher behind the study, Daniel C. Andersson, Associate Professor and Senior Consultant from the Department of Physiology and Pharmacology at Karolinska Institutet and the Department of Cardiology at Karolinska University Hospital in Stockholm.
The research has been published in Annals of the Rheumatic Diseases.
Something in the blood was enough to weaken the muscle
In the study, the researchers took small muscles from the hind legs of healthy mice and placed them in a bath containing human serum for 24 hours. The muscles remained viable, and because the tendons were still attached, the researchers were able to stimulate them electrically and measure their strength both before and after exposure to the serum.
Some muscles were bathed in serum from nine patients with active DM, whilst others were bathed in commercial serum from healthy donors. The patient sample was small, and the age and sex of the donors providing the control serum were unknown.
Serum is the liquid component of blood that does not contain blood cells; it contains proteins, antibodies and signalling molecules but no immune cells. Nevertheless, the muscles exposed to patient serum clearly lost strength, whereas the control muscles did not. The researchers had previously observed the same effect in inflammatory muscle diseases. This suggests that circulating substances can cause the muscle tissue itself to enter a kind of immune state of alarm – and weaken it without any immune cells being present.
“No immune cells are present in this medium. So it cannot be them that are triggering anything. It must be factors in the serum that provoke the muscle tissue to behave like an immunologically active organ and start producing signalling substances locally,” explains Daniel C. Andersson.
An immune signal turned out to be part of the explanation
The researchers then began looking for what might be triggering the weakening.
One obvious line of enquiry was type I interferons. These normally help the body’s cells respond to viral infections but can also keep the immune system unnecessarily activated. Clear signs of increased interferon activity have previously been found in the blood, skin and muscles of people with DM.
Interferons work by binding to a receptor on the surface of cells, including muscle cells. When the researchers blocked this receptor, the muscles were largely protected from the effects of the patients’ serum.
They then disrupted the connection further inside the cell. Here, the signal is relayed through the Janus kinase−signal transducer and activator of transcription (JAK/STAT) signalling pathway, and when the researchers inhibited this step using the drug ruxolitinib, the muscles were once again protected.
Finally, the researchers examined gene activity in the muscle. When the interferon receptor was blocked, 10 known targets of type I interferons became less active. Muscle strength, the two blockade experiments and the changes in the muscle cells thus all pointed to the same mechanism: in the experimental model, the type I interferon system is a key element of the chain leading from patient serum to muscle weakness.
Cocktail time
The researchers then attempted to replicate the effect of the patient serum using the two main type I interferons, interferon-alpha and interferon-beta. Here, a surprise awaited them.
On their own, they had no effect. Only when combined did they cause muscle strength to decline. The concentrations were relatively high, so the result shows that the combination can induce weakness – not that patients’ muscles are necessarily exposed to equivalent levels.
“We were a bit puzzled at first, because one substance on its own had no effect. But we have always suspected that DM is the result not of a single factor in the blood but rather a cocktail effect. And sure enough, when you combine the two interferons, you can see that the muscle loses strength,” says Daniel C. Andersson.
Another experiment began one step earlier in the process. Healthy muscles were exposed to a synthetic strand of double-stranded RNA that mimics a danger signal from a virus and causes the tissue to activate the interferon system itself. Here too, muscle strength declined, and blocking the interferon receptor attenuated the effect.
The researchers still do not know what triggers the process in patients’ blood. Interferon-alpha and interferon-beta may be part of the explanation, but other substances may also cause the muscle to produce interferon itself. And because blocking the receptor did not completely eliminate the reduction in strength, other mechanisms must also be at play.
Paving the way for treatment targeting the muscle itself
Treatment of DM currently relies on high doses of corticosteroids, which broadly suppress inflammation but can also have many undesirable effects on the rest of the body.
Targeting the interferon system has already been tested among humans. In a randomised Phase 2 clinical trial, people with DM were treated with dazukibart, an antibody that binds to interferon-beta before it reaches its receptor. The treatment improved both muscle and skin symptoms.
The clinical trial cannot prove that the mechanism observed in isolated mouse muscles is the same for humans or how much of the muscle weakness it explains. However, the laboratory experiments and the patient study independently suggest that the interferon system plays a role in the disease. A Phase 3 trial is now underway.
For Daniel C. Andersson, this opens up the possibility of targeting more directly what actually causes the muscle weakness.
“We need more treatments, and in particular treatments that target the muscle itself and the interaction between metabolism and immune signals. Because that is where the symptoms are. At the moment, we are suppressing the entire immune system, but the body needs that too. I hope that we can help to test approaches that instead target what is happening in the muscle itself, because I believe that this could be an important key to helping these patients,” concludes Daniel C. Andersson.
