Pathogenesis of Idiopathic Inflammatory Myopathy
Dr Rachel Shupak St. Michael’s Hospital
Idiopathic Inflammatory Myopathy
• Heterogenous muscle disorders
• Progressive, symmetrical, proximal weakness
• Inflammatory infiltrate • Autoantibodies in 60-90%
– Myositis specific antibodies (MSA’s) – Myositis associated antibodies (MAA’s)
• Criteria for diagnosis
Idiopathic inflammatory Myopathy Peter & Bohan Classification
• Polymyositis • Dermatomyositis • IIM and Malignancy • JDM & Vasculitis • IIM & CTD • Inclusion Body Myositis
Idiopathic Inflammatory Myopathy
Understanding pathogenetic mechanisms
Rationale for specific targeted therapies
Histology and Immunochemistry
• Dermatomyositis
– B cells, macrophages – CD4 T cells
– Decrease capillaries – Perifascicular atrophy – Perivascular infiltrate
• Polymyositis
– Mononuclear cells – CD8 T cells
– Endomysial infiltrate – Myonecrosis – Patchy, focal
Pathogenesis of Idiopathic inflammatory Myopathy Explanations Needed
• Poor correlation muscle cell damage, CPK elevation, MRI and degree of clinical weakness • Focal patchy infiltrate causes weakness whole muscle group • Slow clinical response to high dose steroids with lag in clinical response after normalization of muscle enzymes
Pathogenesis of Idiopathic inflammatory Myopathy Explanations Needed
• Clinical phenotypes: differences and similarities
• Extra-muscle involvement
– Skin, vasculitis, lung, GI, cardiac, raynaud’s
• Association with malignancy • Association with CTD
Etiology of IIM
• Genotype
– HLA DRB1.0301 & DQ.0501 – Strong association with white caucasion sporadic & familial forms of IIm – Strongest correlation with antisynthetase syndrome
• Microchimerism
– GVH disease
– JDM
Etiology of IIM
• Infectious agents
– Parasites
• Trichinosis, toxoplasma gondi, Borrelia burgdorferi
– Viral
• Influenza, coxsackie and echovirus (self-limited)
• Picornaviruses interact with aminoacyl tRNA synthetase antibodies chronic myositis 2° to autoimmunity
• Animal models of myositis • Retroviruses (HIV, HTLV-1)
• No current histological evidence to date
Etiology of IIM
• Drugs and Toxins
– Vacuolar myopathy
• Hydroxy-chloroquine, colchicine, amiodarone
– Mitochondral myopathy
• AZT
– Corticosteroid myopathy – Statin Myopathy
• Inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase decreasing conversion of HMG-CoA to mevalonic acid.
• Muscle pain, CK increase, weakness, rhabdomyolysis
• Pathogenesis unknown
Pathogenesis
• Cellular immunity
– In vitro studies – Role of MHC
– Cell damage – Cytokines and chemokines
• Microvascular • Humoral immunity
– MSA’s – MAA’s
• Metabolic Disturbance
Pathogenesis
• Cellular immunity
Histologic evidence in PM & IBM • Activated CD8+ T-cytotoxic cells surround and invade muscle cells • MNC express co-stimulatory receptors • NK cells are absent • Restricted Tcell receptors cells to unspecified Ag expansion of T
• MHC Class I Ag expression in normal, necrotic and all regenerating muscle cells suggests early event in pathogenesis
• ??? Primary immune response or secondary to muscle injury/damage
Pathogenesis
• Muscle cell damage
– Not Apoptosis
– Not NK T cell mediated cytotoxicity
– ? Lysosomal / extra-lysosomal proteases & Matrix metalloproteinases tissue damage – ? Soluble factor (inflammatory cells, endothelial cells or muscle itself)
Pathogenesis
• Cytokines and chemokines
– Upregulation of IL-1 expression muscle Bx in MNC – Upregulation TNFα, IFN-у, IL6, IL-10 in macrophages, regenerating muscle, endomysial/perimysial tissue, endothelial cells. – TNFα CD8 + Lymphocytes & Macrophages invading muscle in PM only
– Up regulation chemokines MIP-1α, M1P-1β, RANTES – Effects on muscle cells:
• negative effect on regeneration • Inhibits protein synthesis, glucose transport • Disrupts myogenesis
– Reflects ongoing immune response, inflammation and attempts at repair
Pathogenesis
• Microvascular
– Obliteration capillaries DM
– Membrane attack complex of complement in vessel wall
– Increased B cells, CD4 cells in muscle biopsy
– Endothelial cells increase IL-1α, adhesion molecules ICAM
– Correlates with muscle function >> cellular infiltrate
Pathogenesis
• Humoral Evidence
– Membrane attack complex of C3 in vessel wall – Immunoglobulin IgG deposit in endothelial wall – MSA’s – MAA’s
Pathogenesis
• Myositis specific Antibodies
– ? Pathogenetic/ ?Epiphenomenon (injury) – Ab against cytoplasmic Ags involved in protein synthesis
– Ubiquitous to all cells
– Aminoacyl t-RNA Synthetase (ARS) catalyzes formation of aminoacyl t-RNA
– Histidyl, threonine, alanine, glycine, asparagine, isoleucine – Immunization with enzyme or innoculation with genes encoding for enzyme antibody production but not disease
MSA and associated Disease features
Ab
Anti Jo1 antiPL7 antiPL12 antiPL12 antiOJ AntiEJ AntiSRP
Anti Mi-2 Anti KJ
Ag
HisRS ThrRS AlaRS tRNA-Ala IleRS GLyRS SRP protein
Prevalence
15-40 5 5 5 5 5 5
10 1
Disease
antisynthetase antisynthetase antisynthetase antisynthetase antisynthetase antisynthetase severe acute PM
classic DM ILD
nuclear helicase ?protein
Pathogenesis
• Metabolic disturbance
Hypoxia TNFα mitochondrial dysfunction contractile dysfunction accelerates catabolism proteolysis and insulin resistance blocks IGF inhibits protein synthesis decreases muscle regeneratiom
IL-1
Pathogenesis
ARS (Aminoacyl t-RNA Synthetase) molecules and proteolytic fragments 2° to inflammation & apoptosis have chemo-attractant properties influx MNC, lymphocytes & APC to site of muscle injury. Processing and presentation of these autoantigens on MHC class I & II molecules generates immune response resulting in muscle injury.