Etiology and Pathogenesis of Myopathies

Plotz, P H.

Abstract

Idiopathic inflammatory myopathy (polymyositis, dermatomyositis, and related disorders) is a family of inflammatory diseases in which disease-specific autoantibodies occur and for which there is considerable indirect evidence pointing to a viral etiology. We have over the past several years, seen and studied and collected serum, blood, and muscle specimens from well over 500 patients suspected of having myositis and we have collected epidemiologic information on many patients. Our recent attention has been focussed on the mechanism of autoimmunity and on the details of tissue within the affected muscles. We have completed studies on the primary sequence of two more of the target autoantigens, isoleucyl- and (in collaboration with Paul Schimmel at MIT) alanyl-tRNA synthetase and have identified the chromosomal location of four of the target aminoacyl-tRNA synthetases. We have produced pure recombinant histidyl-tRNA synthetase (HRS) and, with Craig Hyde, made large crystals, but the x-ray diffraction studies have so far been of only low resolution. Dr. Terry O'Hanlon and Dr. Fred Miller of CBER/FDA with Dr. Raben, have identified a transcript of what appears to be the mitochondrial HRS. We have studied the cytokines and chemokines produced by circulating leukocytes (with Dr. Dennis Klinman of CBER/FDA) and by cells within affected muscle biopsies, and we have continued preparations to study the peptides found in Class I HLA antigens on the surface of myoblasts.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Type: Intramural Research (Z01)
• Project #: 1Z01AR041074-08
• Application #: 5200628
• Support Year: 8
• Fiscal Year: 1995

Institution

• Name: National Institute of Arthritis and Musculoskeletal and Skin Diseases
• Country: United States

Publications

Plotz, Paul H (2014) Autoimmunity: the history of an idea. Arthritis Rheumatol 66:2915-20

Harris-Love, M O; Shrader, J A; Koziol, D et al. (2009) Distribution and severity of weakness among patients with polymyositis, dermatomyositis and juvenile dermatomyositis. Rheumatology (Oxford) 48:134-9

Levine, Stuart M; Raben, Nina; Xie, Dan et al. (2007) Novel conformation of histidyl-transfer RNA synthetase in the lung: the target tissue in Jo-1 autoantibody-associated myositis. Arthritis Rheum 56:2729-39

Nagaraju, Kanneboyina; Rider, Lisa G; Fan, Chenguang et al. (2006) Endothelial cell activation and neovascularization are prominent in dermatomyositis. J Autoimmune Dis 3:2

Oppenheim, Joost J; Dong, Hui Fang; Plotz, Paul et al. (2005) Autoantigens act as tissue-specific chemoattractants. J Leukoc Biol 77:854-61

Nagaraju, Kanneboyina; Casciola-Rosen, Livia; Lundberg, Ingrid et al. (2005) Activation of the endoplasmic reticulum stress response in autoimmune myositis: potential role in muscle fiber damage and dysfunction. Arthritis Rheum 52:1824-35

Casciola-Rosen, Livia; Nagaraju, Kanneboyina; Plotz, Paul et al. (2005) Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy. J Exp Med 201:591-601

Howard, O M Zack; Dong, Hui Fang; Su, Shao Bo et al. (2005) Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate. Blood 105:4207-14

Plotz, Paul H (2003) The autoantibody repertoire: searching for order. Nat Rev Immunol 3:73-8

Howard, O M Zack; Dong, Hui Fang; Yang, De et al. (2002) Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. J Exp Med 196:781-91