Maligayang Pagdating! Triggers and Mechanisms in the Idiopathic Inflammatory Myopathies Syed Atiqul Haq Professor of Rheumatology BSM Medical University, Dhaka Sections Some basic concepts Immune mechanisms in IIMs Genetic mechanisms Triggers IIMs are heterogeneous Upcoming therapeutic targets Conclusions Granzyme B ER Response to Malfolded Protein Stress Evidences of Role of Immunity • Cellular infiltrates in muscle biopsy • Autoantibodies in blood • MHC class II major genetic RF: – Presents antigens to CD4+ T cells Autoantibodies • Myositis-associated autoantibodies (MAAs): – Anti-SSA, anti-Ro52, anti-PMScl • Myositis-specific autoantobodies (MSAs): – Anti-aminoacyl-tRNA synthetases – Anti-Mi2 – Anti-TIF-1gamma – Anti-HMGCR – Anti-MDA5 tRNA Amino-acyl-tRNA synthetase Role of B Cells • Presence of autoantibodies in blood • B cells and plasma cells in muscle tissue • Large number of B cells in peripheral blood • High serum B cell activating factor (BAFF) • In situ differentiation of B cells: somatic mutation, isotype switching, clonal expansion, intraclonal variation Role of T cells • Homing or local proliferation of T cells with certain TCRs suggesting antigen in local tissue • Cytotoxic CD8+ T cells in endomyseal infiltrates in PM • Expression of MHC class I by muscle fibers Regained Properties of Muscle Cells • Expression of HLA class I antigens • Over-expression of TLR3, TLR7, CLR – RNA-associated autoantigen recognition • Production of IL-6 and CCL20: – ? Induced by TLR3 activation + Il17 stimulation • Production of IFN-beta (a local source) Initial Event in Autoimmune Cascade? • Muscle auto-antigens: – Granzyme B generated fragments of auto-antigenic aminoacyl-tRNA synthetases contain epitopes better recognized by autoantibodies • Innate: as PAMPs, binds to TLRs (in DCs and muscle cells) to activate cytokine production, and HLA class I overexpression • Adaptive: taken up by mDCs and presented to CD4+T → TH2 → B cells for production of specific antibodies Proposed Model of Pathogenesis ATF6-p50 Gene Associations of IIMs • Signal transducer & activator of transcription 4 (STAT4): – activated by cytokines incl type I IFN – Induces gene transcription s driving Th1 & Th17 – Rs7574865 SNP associated with DM & PM • MHC complex has strongest genetic association with IIMs – HLA-DRB1: risk locus for anti-MDA-5 associated DM: • Caucasians: anti-aminoacyl-tRNA synthetase • Asian: CADM – HLA-DRB1*03:01/01:01: associated with IBM Inference • “IIMs may be complex genetic diseases initiated by immune activation following specific environmental events in genetically predisposed individuals” Rothwell S et al. Curr Opin Rheumatol 2013; 25: 735-41 Triggers • Environmental • Endogenous Environmental Triggers  Viruses  Smoking  Statins, d-penicillamine  UV light  Vitamin D deficiency Viruses as a Trigger • Circulating CD28null T cells were significantly more common in human CMV seropositive myositis patients compared with HCMV-negative patients • CD28null T cells (NK/cytotoxic), not conventional CD28+ cells responded to antigenic stimulation Fasth AE et al, J Immunol 2009; 183: 4792-9 Smoking • The frequency of smoking was higher in antiJo-1 positive patients (OR 1.83, 95% CI 1.182.83) • In these smokers, the frequency of HLADRB1*03 was increased Chinoy H et al, Ann Rheum Dis 2012; 71: 961-5 Statins • Autoimmune necrotizing myopathy has been described in statin users. These patients have antibodies recognizing HMG CoA reductase • HLA-DRB1*11:01 allele confers risk for antiHMGCR myopathy Mammen AL et al, Arthritis Care Res 2012; 64: 1233-7 Endogenous Triggers • Muscle auto-antigen fragments: autoantigens are expressed in immature muscle precursors, cleaved by granzyme B: – Histidyl and asparaginyl tRNA synthetases • Alarmins: High mobility group box 1(HMGB1). Released from cells undergoing necrosis. Activates TLRs→upregulates MHC class I • Cancer cell products: presence of 2 autoantobodies: – Anti-transcription intermediary factor 1 gamma – Anti-nuclear matrix protein NXP2 Inferences • Multiple triggers, environmental and endogenous, have been proposed • Environmental triggers may lead to disease through interaction with predisposing gene alleles • Endogenous triggers may act as auto-antigens • Known triggers account for small proportion of cases Common Types • Dermatomyositis • Polymyositis • Overlap syndromes (with another systemic rheumatic disease) • Inclusion body myositis • Immune-mediated necrotizing myopathy (IMNM) DM vs. PM: Evidences of Pathogenesis Dermatomyositis Polymyositis T: B cell distribution Equal 8:1 Cells around vessels Equal Mostly B cells CD4 cells predominate CD8+ T cell driven disease Complements Membrane attack complex in capillary walls None Type I interferon signature In muscle & blood In blood, not muscle Characteristics CD type of T cells Inference • Clinical and histopathological distinctions between these conditions suggest that different pathogenic processes may underlie each of the inflammatory myopathies Observations With Pathogenetic Pertinence • Myofiber abnormalities: rimmed vacuoles, inclusion bodies, tubulofilaments, and congophilic material • Beta-amyloid (A-beta) mediated myofiber injury • Nuclear degeneration and TDP-43 sarcoplasmic redistribution • Evidences of adaptive immune responses Role of Adaptive Immunity • Infiltrates of CD4+ T cells, cytotoxic CD8+ T cells, myeloid dendritic cells, and plasma cells deep within fascicles, surrounding, displacing, invading myofibers • Clonally restricted maturation of intramuscular T and B cells • Most abundant transcripts are derived from Ig genes • Presence of myeloid dendritic cells • An autoantibody directed against cytosolic 5’-nucleotidase 1A (cN1A): specific for IBM Findings With Pathogenetic Pertinence • Endomysial T cells surrounding and invading myofibers, macrophages, myeloid dendritic cells and plasma cells • Circulating autoantibodies • Expression of type 1 interferon-inducible transcripts in blood • Myofiber injury by CD8+ cytotoxic T lymphocytes that surround and invade myofibers • Enhanced expression of class I major histocompatibility complex antigens by the muscle fibers Characteristics • Capillary injury • Perimysial perifascicular myofiber injury • Specific auto-antibodies: anti-aminoacyl tRNA synthetase Ab • Type I interferon signature Type I Interferon • CD4+ Plasmacytoid dendritic cells (pDCs) – natural interferon-producing cells • Immature muscle precursors expressing HLA class I local source of IFN-beta • Tubuloreticular inclusions, biomarker of type I interferon exposure, in muscle capillaries: specific • Type 1 IFN-inducible proteins: Jo-1, STAT-1, MHC-class I • Gene expression profile Gene Expression Profile • 90% of differentially upregulated transcripts in muscles belong to Type 1 IFN-inducible transcripts • IFN-stimulated gene 15 transcript 570-fold higher • MxA was 280-fold higher Targeted Therapies Target Author Year Molecule Efficacy Dalakas et al 2009 Anti-CD52 Alemtuzumab IBM B cells Oddis et al 2013 Rituximab JDM, PM Type I IFN Higgs et al 2013 Sifalimumab DM, PM IL-6 Narazaki et al 2011 Tocilizumab PM IL-18 Hong et al 2012 R-Fc-IL 18 BPc isoform IFN production Kokkola et al 2003 CD28null T cells HMGB1 Mouse & rat models Conclusions • IIMs are immunogenetically heterogenous group of disorders • Pathogenesis is orchestrated by triggers and genes • A better understanding of the immunogenetic pathway is ushering advent of a new paradigm of treatment that is likely to be more successful Salamat!