Immunopathogenic mechanisms in inflammatory myopathies

The idiopathic inflammatory myopathies (IIMs) are characterized by symmetrical, proximal muscle weakness and by inflammatory infiltrates in muscle tissue. Based on different clinical as well as histopathological features the IlMs can be separated into polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). Although differing clinically, the most prominent clinical symptom is shared by the three subsets of IIMs, namely muscle weakness. Histopathologically, careful studies have identified different proportions of CD4+ and CD8+ T cells and macrophages with various localizations in the different subsets of IIMs. However, it is unknown what mechanisms underly the clinical symptoms of muscle weakness. One would assume that the presence of inflammatory cells in muscle tissue is sufficient for causing the clinical manifestations, but there is no correlation between the degree of muscle weakness and the degree of inflammation as assessed by inflammatory infiltrates in muscle biopsies.

Our hypothesis is that molecules of the immune system that are expressed in muscle tissue of myositis patients might be involved in the mechanisms that cause the clinical symptom of decreased muscle function.

We have used immunohistochemistry to study expression of important immunological molecules such as cytokines and adhesion molecules in muscle tissue from myositis patients. Most investigators have previously used only muscle tissue from patients in an active phase of disease to study immunopathogenic mechanisms in inflammatory myopathies. We have chosen a broader strategy, in addition to investigating muscle tissue from patients in a clinically active phase of disease with presence of inflammatory cell clusters in muscle tissue we also included patients with clinical symptoms of muscle weakness but without presence of inflammatory cell clusters in muscle tissue and they were further divided according to disease duration.

The most prominent findings in muscle tissue were the phenotypic changes of endothelial cells and muscle fibers, implicating a role for these cells in the immunopathogenesis of myositis. Endothelial cells of capillaries expressed the cytokine interleukin (IL)-1 alpha and were in many cases morphologically changed, resembling endothelial cells of high endothelial venules. Muscle fibers expressed HLA-ABC and HLA-DR on the fiber membranes. These findings were similar in all studied subtypes of myositis and furthermore, these molecular markers on endothelial cells and muscle cells were present not only in muscles with inflammatory infiltrates, but also in muscle tissue from patients in an early phase of disease as well as in muscle tissue from patients in a late phase of disease, when inflammatory cell clusters were absent.

In summary, we have identified possible key immunological molecules in endothelial cells and muscle cells in myositis and described the association between expression of these molecules and the clinical symptom of decreased muscle function. We hope that these findings will be of help in the overall research goal of defining better and targeted therapies for patients with myositis.

List of scientific papers

I. Lundberg I, Ulfgren AK, Nyberg P, Andersson U, Klareskog L (1997). Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum. 40(5): 865-74.
https://pubmed.ncbi.nlm.nih.gov/9153548

II. Nyberg P, Wikman AL, Nennesmo I, Lundberg I (2000). Increased expression of interleukin 1alpha and MHC class I in muscle tissue of patients with chronic, inactive polymyositis and dermatomyositis. J Rheumatol. 27(4): 940-8.
https://pubmed.ncbi.nlm.nih.gov/10782820

III. Englund P, Nennesmo I, Klareskog L, Lundberg IE (2002). Interleukin-1alpha expression in capillaries and major histocompatibility complex class I expression in type II muscle fibers from polymyositis and dermatomyositis patients: important pathogenic features independent of inflammatory cell clusters in muscle tissue. Arthritis Rheum. 46(4): 1044-55.
https://pubmed.ncbi.nlm.nih.gov/11953983

IV. Englund P, Lindroos E, Nennesmo I, Klareskog L, Lundberg IE (2001). Skeletal muscle fibers express major histocompatibility complex class II antigens independently of inflammatory infiltrates in inflammatory myopathies. Am J Pathol. 159(4): 1263-73.
https://pubmed.ncbi.nlm.nih.gov/11583954