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Molecular Mechanisms in ILD in Adult Connective Tissue Disease

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Molecular Mechanisms in ILD in Adult Connective Tissue Disease

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Molecular Mechanisms in ILD in Adult Connective Tissue Disease

  1. 1. February 7, 2015 1 Sonye K. Danoff, MD, PhD Co-Director, Johns Hopkins ILD/PF Program Associate Director, Johns Hopkins Myositis Center Molecular mechanisms in ILD in Adult Connective Tissue Disease ILD in sJIA Meeting, Stanford Center for Excellence in Pulmonary Biology
  2. 2. ILD as a manifestation of adult CTD • Occurs with many forms of CTD • May be first/only manifestation of CTD • Has variety of presentations • Outcomes vary with presentation • In contrast to chILD, less clearly linked to genetics, more highly linked to exposure • Likely differing driving mechanisms 2
  3. 3. Frequency of ILD varies by CTD and by ascertainment method CTD Prevalence PFT CT Lung biopsy Timing in disease Rheumatoid Arthritis 1-2% of US ~2.5 million 40-50% 19% 80% Late Lupus ~1.3 million 3-8% Late Sjogren’s ~1 million 10-24% Late SSc ~300,000 23-40% 70-80% Early DM/PM ~15,000 60-90% Early MCTD Unknown 20-60% Early 3
  4. 4. ILD as “Formes Frustes” of CTD 4
  5. 5. Disparate Forms of ILD 5
  6. 6. Multiple Histopathologies in CTD-ILD 6
  7. 7. Mortality: Appearances do matter in ILD Flaherty et al., Thorax 2003;58:143-148 NSIP NSIP UIP
  8. 8. Mechanisms of lung injury in CTD-ILD • Antibody driven injury • Virally triggered injury • Cellular injury (environmental factors) • Innocent bystander effect in malignancy 8
  9. 9. Antisynthetase: Unique phenotypes associated with specific antibodies Antibody Antigen (tRNA synthetase) Prevalence in IIM (%) Prevalence of ILD (%) Jo-1 histidyl 25-30 66 PL-7 threonyl 2-5 78 PL-12 alanyl 2-5 90 EJ glycyl 1 OJ isoleucyl 1 KS asparaginyl 1 Zo phenylalanyl 1 Tyr tyrosyl 1 Immbert-Masseau A. Joint Bone Spine, 2003
  10. 10. ASAs: Potentially Causative? • Murine Jo1 antibodies demonstrate an increase in targeted B- and T-cells – phenotype consistent with diffuse lung and muscle inflammation • Disease activity directly correlates with antisynthetase antibody titer • Serve directly as chemokines and cytokines – migration of mononuclear cells and immature dendritic cells Katsumata Y et al. J Immunology, 2007 Stone KB et al. Arth Rheum, 2007 Levine SM et al. Cur Opin Rheum, 2003
  11. 11. MDA5: A spectrum of ILD • Initially described in Japanese population as associated with CADM with rapidly progressive ILD 11
  12. 12. Clinically amyopathic DM (CADM) 12 Associated with a rapidly progressive, often fatal ILD
  13. 13. Fiorentino et al., Journal of the American Academy of Dermatology, 2011 Distinctive Cutaneous Phenotype in MDA5 Dermatomyositis
  14. 14. MDA5–Associated Dermatomyositis: Expanding the Clinical Spectrum Hall et al., Arthritis Care & Research, 2013
  15. 15. Clearly auto-antibody is not the whole story • Environmental exposures: smoking • Infectious exposures: viruses • Medication exposures: biologics 15
  16. 16. Age has a critical impact on CTD-ILD 16 "The Life & Age of Woman - Stages of Woman's Life from the Cradle to the Grave", ca. 1849
  17. 17. Association between autoimmunity and cancer • Increased risk of malignancy in DM, PM, SSc • Evidence of antigen expression in tumor that is recognized by autoantibody • Resolution of autoimmunity with treatment of tumor 17
  18. 18. “Autoantigen” expression in tumors Casciola-Rosen L et al. J Exp Med, 2005
  19. 19. Cellular components in CTD-ILD 19 Wells & Denton, Nat Rev Rheum, 2014
  20. 20. Molecular mechanisms of CTD-ILD 20Castelino &Varga Arthritis Research & Therapy 2010
  21. 21. With Gratitude to the Lisa Sandler Spaeth & Fisher Foundation Funds for Pulmonary Fibrosis at JH And The Huayi and Siuling Zhang Discovery Fund

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