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COPA mutations impair Golgi-ER transport
causing hereditary autoimmune-mediated
lung disease and arthritis
Tony Shum, MD
A...
A patient with autoimmune-associated lung
and joint disease
• ID: 30 yo female with JIA, advanced ILD
• CC: coughing up bl...
More Data:
• Representative CT • ANA neg
• CCP/RF neg
• MPO Ab – highly elevated
• Hand films – no erosions
A family with a rare disorder of autoimmune -
associated lung lung and joint disease
• Clinical Features:
• High-titer aut...
Genetic Linkage IDs a Single Region of
Significance on Chr 1
Noah Zaitlen
LOD=3.5
LOD score > 3.0 = 1000 to 1 odds that li...
WES IDs a single rare, non-synonymous variant under
Chr 1 linkage peak
• Missense mutation in COPA c.G721A:p.E241K
• Minor...
Baylor-Hopkins Center for Mendelian Genomics
independently IDs COPA mutations in 2 families
with exact same clinical pheno...
Patient autoantibodies
Immunoglobulin levels, absolute lymphocyte
counts and CD4 to CD8 cell ratios were normal
Lungs of unrelated patients reveals
germinal center formation &
infiltrating CD4 T cells
Immune-mediated kidney disease
4 COPA mutations are discovered in 5 families
all located in highly conserved WD40 domain
Coatomer Subunit Alpha (COPA)
• Ubiquitously expressed
• Subunit of Coat Protein Complex I
(COPI)
• Enables protein transp...
COPA expression & localization
appear normal in patients
c
CO – control
PA – patient
COPI is important for retrograde
transport of proteins
K K
X X
Adapted from Brandizzi F and Barlow C Nat Rev Mol Cell Biol...
The COPA WD40 domain is critical for
retrograde transport of KKXX proteins
Eugster A EMBO J 2000
Mutant COPA has impaired binding to
KKXX proteins
K K X
X*
ER stress and the UPR have been implicated
in autoimmunity & lung disease
• Lung disease
– Misfolded surfactant proteins l...
Patient lungs demonstrate increase in
ER stress protein BiP
Patient BLCLs demonstrate
elevated levels of ER stress
CO – control
HC – healthy carrier
PA – patient
TG – thapsigargin
Expression of mutant COPA
causes an increase in ER stress
How might ER stress be linked to the
clinical phenotype in patients?
ER stress results in generation of Th17
priming cytokines in APCs
• KDEL-retained antigen in B lymphocytes induces a proin...
BLCLs with mutant COPA express Th17
priming cytokines
Th17 primingTh2 primingTh1 priming
CO – control
HC – healthy carrier...
CD4 T cells from patients are polarized to
Th17 phenotype
B
A
Summar y
• WD40 COPA mutations cause autoimmune-
associated lung & joint disease
• 1st description of a vesicular traffick...
Acknowledgements
SHUM LAB
• B i r t h e J e s s e n
• C h r i s L a w
• M a x J a n
• W i n t Lw i n
• O s c a r E s t ra ...
COPA mutations impair Golgi-ER transport causing hereditary autoimmune-mediated lung disease and arthritis
COPA mutations impair Golgi-ER transport causing hereditary autoimmune-mediated lung disease and arthritis
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COPA mutations impair Golgi-ER transport causing hereditary autoimmune-mediated lung disease and arthritis

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COPA mutations impair Golgi-ER transport causing hereditary autoimmune-mediated lung disease and arthritis

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COPA mutations impair Golgi-ER transport causing hereditary autoimmune-mediated lung disease and arthritis

  1. 1. COPA mutations impair Golgi-ER transport causing hereditary autoimmune-mediated lung disease and arthritis Tony Shum, MD Assistant Professor Pulmonary & Critical Care Cardiovascular Research Institute University of California San Francisco shumlab.ucsf.edu
  2. 2. A patient with autoimmune-associated lung and joint disease • ID: 30 yo female with JIA, advanced ILD • CC: coughing up blood • PMH: – JIA: Presented joint pain 2 yrs (knees, ankles, hands/fingers) – ILD: soon developed shortness of breath, diagnosed ILD (follicular bronchiolitis, lymphoid aggregates) • FH: sister and deceased aunt with similar medical history • SH: non-smoker • ROS: achy joints, no URI symptoms but slight fever • Exam: – Hypoxemic, tachypneic – Lungs with diffuse crackles – Coughing up scant bright red blood
  3. 3. More Data: • Representative CT • ANA neg • CCP/RF neg • MPO Ab – highly elevated • Hand films – no erosions
  4. 4. A family with a rare disorder of autoimmune - associated lung lung and joint disease • Clinical Features: • High-titer autoantibodies: ANCA, ANA • Inflammatory arthritis and ILD • Immunosuppression required (e.g. mycophenolate)
  5. 5. Genetic Linkage IDs a Single Region of Significance on Chr 1 Noah Zaitlen LOD=3.5 LOD score > 3.0 = 1000 to 1 odds that linkage did not occur by chance
  6. 6. WES IDs a single rare, non-synonymous variant under Chr 1 linkage peak • Missense mutation in COPA c.G721A:p.E241K • Minor allele frequency: not reported (i.e. very rare) • Predicted crippling (AVSIFT, Polyphen) • Sanger validated in > 15 subjects
  7. 7. Baylor-Hopkins Center for Mendelian Genomics independently IDs COPA mutations in 2 families with exact same clinical phenotype A B U C S F L . F a n C B a y l o r B a y l o r U C S F M . W a t e r f i e l d D E T o r o n t o ( S . D e l l )
  8. 8. Patient autoantibodies
  9. 9. Immunoglobulin levels, absolute lymphocyte counts and CD4 to CD8 cell ratios were normal
  10. 10. Lungs of unrelated patients reveals germinal center formation & infiltrating CD4 T cells
  11. 11. Immune-mediated kidney disease
  12. 12. 4 COPA mutations are discovered in 5 families all located in highly conserved WD40 domain
  13. 13. Coatomer Subunit Alpha (COPA) • Ubiquitously expressed • Subunit of Coat Protein Complex I (COPI) • Enables protein transport between the Golgi and ER • No disease associations reported in COPA or COPI Brandizzi F and Barlow C Nat Rev Mol Cell Biol 2013
  14. 14. COPA expression & localization appear normal in patients c CO – control PA – patient
  15. 15. COPI is important for retrograde transport of proteins K K X X Adapted from Brandizzi F and Barlow C Nat Rev Mol Cell Biol 2013
  16. 16. The COPA WD40 domain is critical for retrograde transport of KKXX proteins Eugster A EMBO J 2000
  17. 17. Mutant COPA has impaired binding to KKXX proteins K K X X*
  18. 18. ER stress and the UPR have been implicated in autoimmunity & lung disease • Lung disease – Misfolded surfactant proteins leads to ER stress and propensity to lung inflammation and scarring • Autoimmune disease – ER stress results in: • N F K B - m e d i a te d i m m u n e a c t i va t i o n • A b e r ra nt a nt i ge n p re s e nta t i o n i n c e l l s u n d e rgo i n g a u to p h a g y o r a p o p to s i s • G e n e ra t i o n o f a u to a n t i ge n s • S h a p i n g o f C D 4 T h e l p e r c e l l s u b s e t s Nogee NEJM 2001, Lawson PNAS 2011, Todd Nat Rev Imm 2008, Hasnain Immunol Cell Biol 2012
  19. 19. Patient lungs demonstrate increase in ER stress protein BiP
  20. 20. Patient BLCLs demonstrate elevated levels of ER stress CO – control HC – healthy carrier PA – patient TG – thapsigargin
  21. 21. Expression of mutant COPA causes an increase in ER stress
  22. 22. How might ER stress be linked to the clinical phenotype in patients?
  23. 23. ER stress results in generation of Th17 priming cytokines in APCs • KDEL-retained antigen in B lymphocytes induces a proinflammatory response: a possible role for endoplasmic reticulum stress in adaptive T cell immunity. J Immunol 2008 • HLA-B27 misfolding and the unfolded protein response augment interleukin-23 production and are associated with Th17 activation in transgenic rats. Arthritis Rheum 2009 • Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci 2010 • Proinflammatory Th17 cells are expanded and induced by dendritic cells in spondylarthritis-prone HLA-B27-transgenic rats. Arthritis Rheum 2012
  24. 24. BLCLs with mutant COPA express Th17 priming cytokines Th17 primingTh2 primingTh1 priming CO – control HC – healthy carrier PA – patient TG – thapsigargin
  25. 25. CD4 T cells from patients are polarized to Th17 phenotype B A
  26. 26. Summar y • WD40 COPA mutations cause autoimmune- associated lung & joint disease • 1st description of a vesicular trafficking defect as cause of autoimmunity • Identification of a novel molecular link between ER Stress and autoimmunity • Identification of a putative immunological mechanisms by which: mutant COPA ⟶ ER Stress ⟶ Th17 cells
  27. 27. Acknowledgements SHUM LAB • B i r t h e J e s s e n • C h r i s L a w • M a x J a n • W i n t Lw i n • O s c a r E s t ra d a T h e p a t i e n t s & t h e i r fa m i l i e s F u n d i n g a g e n c i e s : B AY L O R C O L L E G E O F M E D I C I N E • L e v i Wa t k i n s & J o rd a n O ra n g e • W. W i s z n i e w s k i & J i m L u p s k i U C S F • N o a h Z a i t l e n • P u i Kw o k & Pa u l Ta n g • K i r k J o n e s • F e ro z Pa p a & M a i ke T h a m s e n • M i ke Ro s e n b l u m • M i ke Wa te r f i e l d , M i c k i e C h e n g & M a r k A n d e rs o n • R a n d y S c h e k m a n ( U C B e r ke l e y ) To r o n t o S i c k K i d s • S h a ro n D e l l R 0 1 H L 1 2 2 5 3 3 P l e a s e v i s i t u s @ : s h u m l a b . u c s f. e d u

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