Myositis research

Myositis research

All conditions associated with muscle inflammation are called inflammatory myopathies or myositis. This usually includes the following disorders; infectious, toxic, and idiopathic inflammatory myopathies (probably autoimmune). Symptonatology does not differ between the groups and is characterized by fatigue, fever, muscle weakness, and muscle pain. In our research we mainly work with idiopathic inflammatory myopathy.

 

IDIOPATHIC INFLAMMATORY MYOPATHY

Idiopathic inflammatory myopathy can be sub-classified in mainly three different diagnoses; polymyositis, dermatomyositis, and inclusion body myositis. The disease is rare and the incidence rate is around 10-cases/million inhabitants/year. In Sweden there are approximately 1,000 people with idiopathic inflammatory myopathy. The disease may occur singly but also with other rheumatic diseases. It may develop acute, sub-acute or slow and lead to pronounced proximal muscle weakness. Muscles that are usually affected are thighs, shoulders, and neck. This often occurs in the inability to get up from sitting, climbing up a ladder, combing the hair, or dressing, as mention a few examples. In the most severe forms problems with swallowing may occur. Muscle involvement is usually symmetrical. In many cases, an involvement of other organs than skeletal muscle is often seen. The most common is skin, joints, malignancy, pulmonary, cardiac, and gastrointestinal symptoms. Fever and fatigue are also very common. Pathogenesis is currently unknown, but many argue that cellular mediated immunity plays an important role in the appearance of these diseases.

 

The treatment traditionally consists of cortisone at high doses in combination with an immunosuppressant drug. With this treatment, muscle strength is often improved, however, many patients do not regain their full capacity. Common side effects are osteoporosis, high blood pressure, diabetes, and cardiovascular disease, and the need for new treatments is therefore high. Our research group was the first in the world to simultaneously demonstrate the positive effect of physical exercise on muscle strength and on molecularly beneficial changes in muscle tissue. These findings have now led to a changed international understanding of the treatment of idiopathic inflammatory myopathies, from not having recommended exercise to now advocate physiotherapy from the very beginning.

 

Hypothetical figure of the pathogenic mechanisms in idiopathic inflammatory myopathies. (1) An unknown trigger (for example viral infection or ultraviolet radiation) in the respiratory tract or through the skin leads to the cleavage of histidyl-tRNA synthetase by granzyme B through antiviral CD8+ T lymphocytes in the lungs. (2) Immature dendritic cells (DCs) carry receptors on its surface that recognize common features of many pathogens. When a DC takes up a pathogen in infected tissue it becomes activated and migrates to the lymph node. (3) Upon activation, the DC matures into a highly effective antigen-presenting cell (APC) and undergoes changes that enable it to activate pathogen-specific lymphocytes in the lymph node. T lymphocytes become activated and B lymphocytes, with active help from CD4+ T lymphocytes, proliferate and differentiate into plasma cells. (4) Activated DCs, T lymphocytes, and B lymphocytes could release cytokines into the bloodstream. (5) The activated T lymphocyte, on which the DC-MHC–antigen complex is bound, itself binds to specialized endothelial cells called high endothelial venules (HEV). For this purpose it uses the VLA-4 (very late activation antigen-4) and LFA-1 (lymphocyte function associated antigen-1) molecules on its surface to interact with adhesion molecules (vascular cell-adhesion molecule-1 (VCAM-1) and intercellular cell-adhesion molecule-1 (ICAM-1)) on HEVs, where they can penetrate into peripheral lymphoid tissues. (6,7) Naïve T lymphocytes and B lymphocytes that have not yet encountered their specific antigen circulate continuously from the blood into the peripheral lymphoid tissues. (8,9) Various cytokines from the bloodstream or produced locally could affect the muscle tissue or cell in many different ways. However, it is not clear whether the muscle cell itself could produce and release cytokines. (10-12) DCs, macrophages (Mø), and B lymphocytes can interact with T lymphocytes in various ways. T lymphocytes could possibly also bind to muscle cells through inducible co-stimulators (ICOS), CD40 ligand (CD40-L), CD28, and CTLA-4 (CD152) on T lymphocytes to ICOS ligand (ICOS-L), CD40, and BB-1 antigen on the muscle cell. In that fashion, the muscle cell would function as an APC. (13) Plasma cells (CD138+) can be found in the muscle tissue of certain subgroups of patients with idiopathic inflammatory myopathy, but whether these cells could produce autoantibodies locally is not yet known. (14) T lymphocytes have been shown to bind in close contact with muscle cells and to release perforin, granzyme A, and granulysin, which may cause necrosis of muscle tissue or cells. This figure is modified from the original figure in Arthritis Res Ther 2007:)9(2):208.

 

OUR MAIN RESEARCH GOAL

The aim of our research is to gain increased knowledge of the causes of idiopathic inflammatory myopathies and the mechanisms that lead to muscle weakness and the high incidence of skeletal muscle and lung inflammation in order to provide patients with the best treatment possible. The basis for our research projects is longitudinal studies of patients with idiopathic inflammatory myopathies. By combining clinical outcome measures with investigations of molecular expression in repeated muscle biopsies and in peripheral blood after different interventions, pharmacological therapies, and physical exercise we hope to increase the understanding of these diseases. Another aim is to understand why both the muscle and the lung becomes a target of the immune system for certain patients.

 

To accomplish our goals we combine clinical epidemiological research with molecular research on patient samples and using experimental systems with muscle cell cultures at the Center for Molecular Medicine (CMM), Karolinska Institutet. We follow patients at Karolinska University Hospital in a systematic way. In addition we are part of a Swedish Myositis Network (SweMyoNet) and of an international myositis network (MyoNet), www.myonet.eu, where Professor Ingrid E. Lundberg is PI and we contribute to the international myositis registry EuroMyositis, www.euromyositis.eu, in which more than 3,500 patients with idiopathic inflammatory myopathies have been enrolled. We are also part of several international collaborations.

 

RESEARCH AREAS

-Physical exercise studies

-Longitudinal studies of clinical material

-Epidemiological studies

-New treatments

-Pathogenetic studies of new target molecules

- Malignancy

-Specific autoantibodies and its importance

_Cardiac studies

-Genetics

GruppChefPortlet

Group leader

Ingrid Lundberg

E-mail

ingrid.lundberg@ki.se

Job title

Professor, senior physician

House

D2:01

GroupInformationPortlet

Research

Autoimmunity, Immunology, Inflammation

Disease

Myositis, Rheumatic diseases

Competence/titles

Autoimmunity, Immunohistochemistry, Microscopy