Immunolocalization of tumor necrosis factor-alpha and its receptors in inflammatory myopathies1
Introduction
Upregulation or induction of certain cell adhesion molecules has been implicated in the immunopathogenesis of inflammatory myopathies 1, 2, 3. In polymyositis (PM) and sporadic inclusion body myositis (IBM), cytotoxic CD8 T cells focally surround and invade non-necrotic muscle fibers 4, 5, 6, 7. The muscle fiber surfaces, facing the autoaggressive infiltrate, express intercellular adhesion molecule-1 (ICAM-1) that serves as a ligand for lymphocyte function associated antigen-1 (LFA-1) expressed on the invading T cells [1]. In dermatomyositis (DM), the main immune effector mechanism is humoral and directed against endothelial cells of the intramuscular microvasculature [8]. ICAM-1, but no other endothelial cell-associated adhesion molecules, is selectively upregulated on endothelial cells in affected parts of the muscle biopsies, suggesting that this ligand is differentially upregulated in this disease [1]. In all inflammatory myopathies, CD45RO+ memory cells represent the main T cell subset [9]. CD45RO+ cells adhere to and extravasate from blood vessels more readily than their CD45RA+ naive counterparts [10].
The cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) strongly upregulate ICAM-1 on cultured human myoblasts [11]. Previous studies failed to document an important role for IFN-γ in inflammatory myopathies [12]or yielded equivocal results [13]. In a recent study, signal transducer and activator of transcription 1 (STAT1) was increased in perifascicular muscle fibers in DM, indirectly indicating a possible role for IFN-γ in this myopathy [14]. The role of TNF-α in inflammatory myopathies is unknown.
TNF-α is a pleiotropic cytokine involved in diverse biologic functions including immune and inflammatory reactions. Besides induction of cell adhesion molecules, this monokine activates T and B cells and macrophages, triggers endothelia to secrete a number of cytokines, increases major histocompatibility class-I (MHC-I) expression on target structures of CD8 cytotoxic T cells, and induces apoptotic cell death in cultured cells 15, 16, 17. TNF-α exerts these effects via two receptors of 55 (TNF-R55) and 75 kD (TNF-R75), respectively. Based on their amino acid sequence, the two receptors are only 29% identical to each other, and there is ample evidence that they are differentially regulated [18]. Most TNF-α functions, including induction of adhesion molecule expression, antiviral activity, and cytotoxicity are predominantly mediated through TNF-R55, but others require the expression of both receptors on the target structure 19, 20, 21, 22, 23, 24, 25, 26. TNF-R75 then functions as a `ligand passer' concentrating TNF-α at the cell surface and transferring the ligand to TNF-R55 that mediates signaling [27]. Recently, it has been shown that TNF-R75, by itself, is able to mediate thymocyte proliferation and cytotoxic signaling in specific cell lines 20, 28.
The present study investigates the expression of TNF-α and its receptors on muscle fibers, endothelial cells and inflammatory cells in muscle from PM, IBM and DM patients and in normal controls.
Section snippets
Patients
Limb muscle biopsies from patients with IBM (six), PM (six), or DM (six) were studied. The diagnoses were based on conventional criteria. None of the patients had received immunosuppressive drugs within 3 months preceding the biopsy. All patients had had progressive disease in the weeks or months preceding the biopsy. Muscle specimens from six subjects who were ultimately deemed free of neuromuscular disease by clinical, electromyographic and histologic criteria served as controls.
Immunoreagents and immunocytochemical procedures
Consecutive 4-
Results
Table 2 summarizes TNF-α protein and TNF-R55 and TNF-R75 receptor immunolocalization at different sites in control specimens and in each disease. The findings in IBM and PM were similar and they are therefore described together.
Discussion
We demonstrate immunoreactivity for TNF-α and describe in detail the expression of the two known TNF receptors in each main type of inflammatory myopathy. Our observations strongly suggest the involvement of TNF-α in the pathogenesis of these myopathies. TNF-α was mainly detected in endothelial cells and macrophages and freely dispersed in endomysial or perimysial connective tissue. The strong TNF-R55 expression on myonuclei of regenerating muscle fibers suggests implication of TNF-α and
Acknowledgements
This study was supported by grants from the Flemish Fund for Scientific Research and the Gent University Research Fund. The authors thank W. Fiers and A.G. Engel, for their support and advice. S. Pappens and W. Drijvers provided expert technical assistance.
References (48)
- et al.
Expression of cell adhesion molecules in inflammatory myopathies
J Neuroimmunol
(1995) - et al.
Peripheral lymphoid tissue-like adhesion molecule expression in nodular infiltrates in inflammatory myopathies
Neuromusc Disord
(1996) - et al.
Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies
Hum Pathol
(1989) Tumor necrosis factor. Characterization at the molecular, cellular and in vivo level
FEBS Lett
(1991)- et al.
Ligand passing: the 75-kDA tumor necrosis factor (TNF) receptor recruits TNF for signaling by the 55-kDA TNF receptor
J Biol Chem
(1993) - et al.
Analysis of cytokine expression in muscle in inflammatory myopathies, Duchenne dystrophy, and non-weak controls
J Neuroimmunol
(1995) - et al.
Tumor necrosis factor induces a selective shedding of its p75 receptor from human neutrophils
J Biol Chem
(1994) - et al.
Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies
Hum Pathol
(1989) - et al.
Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization
J Biol Chem
(1996) - et al.
Major histocompatibility complex class II molecule expression on muscle cells is regulated by differentiation: implications for the immunopathogenesis of muscle autoimmune diseases
J Neuroimmunol
(1996)
Self-association of the `death domains' of the p55 tumor necrosis factor (TNF) receptor and Fas/APO1 prompts signaling for TNF and Fas/APO1 effects
J Biol Chem
Expression of cell adhesion molecules in inflammatory myopathies and Duchenne dystrophy
J Neuropathol Exp Neurol
Monoclonal antibody analysis of mononuclear cells in myopathies. I. Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells
Ann Neurol
Monoclonal antibody analysis of mononuclear cells in myopathies. V. Identification and quantitation of T8+ cytotoxic and T8+ suppressor cells
Ann Neurol
Polymyositis, dermatomyositis, and inclusion body myositis
N Engl J Med
Inclusion body myositis and myopathies
Ann Neurol
Microvascular changes in early and advanced dermatomyositis: a quantitative study
Ann Neurol
Immunocytochemical study of CD45 T cell isoforms in inflammatory myopathies
Am J Pathol
CD45RA-RO+ (memory) but not CD45RA+RO−(naive) T cells roll efficiently on E- and P-selectin and vascular cell adhesion molecule-1 under flow
J Immunol
Constitutive and cytokine-induced expression of human leukocyte antigens and cell adhesion molecules by human myotubes
Am J Pathol
Localization of interferon and interleukin-2 in polymyositis and muscular dystrophy
Clin Exp Immunol
Signal transducer and activator of transcription 1 in human muscle. Implications in inflammatory myopathies
Am J Pathol
Functional characterization of the human tumor necrosis factor receptor p75 in a transfected rat/mouse T cell hybridoma
J Exp Med
Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies
Proc Natl Acad Sci USA
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This paper was presented at the 50th Annual Meeting of the American Academy of Neurology, Minneapolis, MN, USA, April 1998.