Molecular Mechanisms in ILD in Adult Connective Tissue Disease

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. 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. 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. ILD as “Formes Frustes” of
CTD
4

5. Disparate Forms of ILD
5

6. Multiple Histopathologies in
CTD-ILD
6

7. Mortality: Appearances do
matter in ILD
Flaherty et al., Thorax 2003;58:143-148
NSIP
NSIP
UIP

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. 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. 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. MDA5: A spectrum of ILD
• Initially described in Japanese
population as associated with CADM
with rapidly progressive ILD
11

12. Clinically amyopathic DM
(CADM)
12
Associated with a rapidly progressive, often fatal ILD

13. Fiorentino et al., Journal of the American Academy of Dermatology, 2011
Distinctive Cutaneous Phenotype
in MDA5 Dermatomyositis

14. MDA5–Associated Dermatomyositis:
Expanding the Clinical Spectrum
Hall et al., Arthritis Care & Research, 2013

15. Clearly auto-antibody is not the
whole story
• Environmental exposures: smoking
• Infectious exposures: viruses
• Medication exposures: biologics
15

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. 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. “Autoantigen” expression in tumors
Casciola-Rosen L et al. J Exp Med, 2005

19. Cellular components in CTD-ILD
19
Wells & Denton, Nat Rev Rheum, 2014

20. Molecular mechanisms of
CTD-ILD
20Castelino &Varga Arthritis Research & Therapy 2010

21. With Gratitude to the Lisa Sandler Spaeth &
Fisher Foundation Funds for Pulmonary Fibrosis at JH
And The Huayi and Siuling Zhang Discovery Fund