TNF

Tumour necrosis factor alpha (TNF-alpha) is one of the most frequently studied pro-inflammatory cytokines. It drives the activation and recruitment of inflammatory cells, amplifies the production of other pro-inflammatory cytokines, and activates nuclear transcription factors, thereby promoting and maintaining the inflammatory response. The importance of TNF-alpha in arthritis is well documented. It may be that TNF-alpha is also markedly involved in muscle inflammation (myositis).

From studies in tissue other than muscle, it is known that macrophages and other immunoactive cells such as monocytes, mast cells, and neutrophils are responsible for TNF-alpha production. Data addressing a possible TNF-alpha production by inflammatory cells in myositis comes almost entirely from studies of patients affected by a group of diseases known as “idiopathic inflammatory myopathies” (inflammatory myopathies). These autoimmune diseases include mainly the subgroups inflammatory myopathic polymyositis, dermatomyositis, and inclusion body myositis. In these conditions, inflammatory cell-related TNF-alpha expression is localized predominantly to macrophages.

Relevance

Blockade of TNF-alpha in the dystrophic (mdx) mouse, which is the most frequently used model of Duchenne’s muscular dystrophy, reduces TNF-mediated adverse responses to exercise-induced muscle damage (1). However, without further information, it is difficult to reach conclusions on the importance of TNF-alpha and the possible usefulness of TNF-blocking in muscle disorders, including in myositis.

An animal model in which the importance of TNF-alpha for myositis development can be followed has previously been lacking. Using a newly established rabbit model of myositis development, a marked TNF-alpha expression has here been shown for the cells of the inflammatory infiltrates within damaged muscle. There was thus a clear evidence of local TNF-alpha production via infiltrated inflammatory cells, presumably leading to secondary inflammation-modifying effects. (2). Inhibiting VEGF and TNF-α may be a useful therapeutic option to treat inflammatory myopathy. (3)

Fas/ Fas ligand

The Fas ligand is predominantly expressed in activated T lymphocytes and is one of the major effector molecules of cytotoxic T lymphocytes and natural killer cells. Fas/Fas ligand (FasL) interaction can induce apoptosis, have a costimulatory role or act as a mechanism by which cytotoxic T cells produce target cell lysis. A strong Fas signal occurred on the sarcolemma, and to a lesser extent in the sarcoplasm of neural cell adhesion molecule (NCAM)-positive or developmental myosin heavy chain-positive regenerating muscle fibers and of injured fibers with presumed abortive regenerative activity, including some nonnecrotic invaded fibers in PM and IBM and some of the atrophic perifascicular fibers in DM.

Several studies identifies regenerating muscle fibers as the main site of Fas immunoreactivity in inflammatory myopathies, and Fas expression may be part of an activated or reactivated developmental program of new gene expression in regenerating or denervated muscle fibers.

The mechanism by which T cells damage muscle fibers in inflammatory myopathies is not known. Immunohistochemical investigation showed expression of Fas ligand in many of the muscle infiltrating mononuclear cells. Fas was expressed both in mononuclear cells and on the surface of muscle fibers in inclusion body myositis patients and in patients with polymyositis but not in patients with Duchenne muscular dystrophy or denervation. The results indicate that the Fas/Fas ligand system may be of importance for the inflammatory reaction and T-cell–mediated muscle cell injury. (5)

Article contributed by Dr. JOSE PEREIRA, MD

Footnotes:

1. Radley H. G., “Reduced muscle necrosis and long-term benefits in dystrophic mdx mice after cV1q (blockade of TNF) treatment,” Neuromuscular Disorders, vol. 18, no. 3, pp. 227–238, 2008. View at Publisher 

2. Sture, F. TNF-Alpha in the Locomotor System beyond Joints: High Degree of Involvement in Myositis in a Rabbit Model.International Journal of Rheumatology
   Volume 2012 (2012), Article ID 637452, 11 pages
   http://dx.doi.org/10.1155/2012/637452

3. Yoshida K. Angiogenesis in Fasciitis Associated with Dermatomyositis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). http://acrabstracts.org/abstract/angiogenesis-in-fasciitis-associated-with-dermatomyositis/. Accessed January 10, 201

4. Bleeckera, J.Immunolocalization of FAS and FAS ligand in inflammatory myopathies. Acta NeuropathologicaJune 2001, Volume 101, Issue 6, pp 572-578. http://link.springer.com/article/10.1007/s004010000324#

5. Anders ,O. Upregulation of Fas/Fas ligand in inclusion body myositis. Annals of Neurology.Volume 43, Issue 1, pages 127–130, January 1998. http://onlinelibrary.wiley.com/doi/10.1002/ana.410430123/abstract