Chemicals and Immunologic Lung Disease:Gene and Environment
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Transcript of Chemicals and Immunologic Lung Disease:Gene and Environment
Chemicals and Immunologic Lung Disease:Gene and
EnvironmentMeinir G Jones PhD
NHLI @ ICSMLondon
• Only a minority of subjects exposed develop disease
• Cases tend to develop within the first two years of exposure
• Exposure response - disease develops at low exposures
• Suggestive of immune response gene effects
Sensitisation to acid anhydrides and association with HLA-DR3
Cases Refs P value OR
TMA 8/11 2/14 0.004 16
PA 2/12 2/14 NS 1.2
TCPA 5/7 0/0
Total 15/30 4/28
Young et al 1995
Isocyanate asthma and HLA-DQB1
DQB1 Isocyanateasthman=56
Refs
n=32
OR
*0501 1 (2%) 5 (16%) 0.14
*0503 7 (13%) 0 (0%) 9.85
Bignon et al 1994
DQB1 Isocyanateasthmatic
n=30
referentsn=12
*0503 30% 0%
*0501 0% 25%
Balboni et al 1996
• DQB1*0503 and *0501 differ by one amino acid at position 57
• DQB1*0503 has aspartic acid at position 57
• DQB1*0501 has valine at position 57
Possible role for Aspartic acid at position 57 - HLA-DQB1
DQB1* TDI asthman=30
Referentsn=138
Asp57++ 17 (57%) 44 (32%)
Asp57+ 12 (40%) 73 (53%)
Asp57- 1(3%) 21 (15%)
Balboni et al 1996
Chronic beryllium diseaseHLA-DPB1
DPB1 CBDn=33
Controlsn=44
Gen pop
*0201 30% 10% 10%
*0401 14% 48% 52%
Richeldi et al 1993
• HLA-DPB1*0201 and *0401 differ at three positions
• position 36
• position 55 and 56 - aspartic acid, glutamic acid /alanine, alanine
• position 69 - glutamic acid /valine
HLA-DPB1 Glutamate 69
• DPB1*0201 - glutamate at position 69• DPB1*0401 - valine at position 69
• Glu69 variant - 97% CBD cases 27% referents
Richeldi et al 1993
• Position 57 DQB1 associated with insulin dependent diabetes mellitus and isocyanate induced asthma
• Position 71 DRB1 associated with rheumatoid arthritis
• The side chains of DP Glu69 and Asp55 are projected towards the peptide binding cleft
• 95% of CBD Glu69
• 30-45% referents Glu69
• ~10% develop CBD
HLA-DPB1 Glu69
• Glu69/Glu69 - 6/20 (30%) CBD -1/75 (1%)
control
Wang et al 1999
Phenotypic frequency of Glu69 carriers in CBD and referents
HLA-DPB1 CBDn=19
Refsn=34
02010202
Glu69+
9(42%)
23(67%)
non0201
Glu69+
16(84%)
12(35%)
Wang et al 1999
• CBD carried predominantly non-*0201 allele (84%)
• Controls carried predominantly *0201 allele (68%)
• Specific Glu69 alleles and copy numbers may confer greatest susceptibility on CBD
Association of cobalt withHLA-DPB1Glu69
DPB1* Cobalt casesn=20
Referentsn=35
Glu69 + 19/20 (95%) 17/35 (48%)
Potolcchio et al 1997
T cell responses to beryllium
• 25 T cell clones raised from 3 CBD patients
• All proliferated to Be, but not Co or Ni
Lombardi et al 2001
Panel of homozygous cell lines
• EBV-transformed B lymphoblastoid cell lines (Xth IHW)
• 02012• 0402• 1001
• All were restricted by HLA-DP alleles with Glu69
• T cell response to Be completely inhibited by anti-DP mAb
Is Glu69 critically important in T cell recognition of Be?
• Murine DAP.3-DP2 transfectants
• only 3/12 T cell clones able to respond to DAP.3DP2 transfectants
• DPB1*0201 recognised, but not *0402
T cell response to beryllium
• T cell lines raised from lungs of CBD patients
• T cell response inhibited by anti-DP • DP alleles which presented beryllium
matched those implicated in disease association studies
Fontenot et al 2000
Beryllium binding to HLA-DP
• Soluble HLA-DP2 molecule
• Glu69 variant
• mutated lysine at position 69
Amicosante et al 2001
• Beryllium could compete out from DP Glu69 molecule the biotinylated-CLIP at low concentration
• Be bound at pH 5 and 7.5 - suggesting Be bound in absence of antigen processing
• Be altered the binding of a mAb, thought to recognise epitopes within the binding groove
Cobalt binding to DP
• HLA-DP but not -DR bound cobalt• DP*0201 bound cobalt at least three times
more efficiently than *0401 (Asp55/Glu69)• DP*0201 binds more cobalt than *0402
(Glu69)• DP*0402 binds more cobalt than *0401
(Asp55)
Potolicchio et al 1999
• Strong evidence from disease association and binding studies of genetic susceptibility
• Is there a gene environment interaction?
Association of HLA-DR3 with exposure to anhydrides in the development of specific IgE
Exposure Cases Refs OR
Low 1/1(100%)
2/34(6%)
39(1.2,1277)
Med 3/5(60%)
3/15(20%)
6(0.7,54)
High 1/1(100%)
1/3(33%)
5(0.1,220)
Platinum study - subject characteristics
Casesn=44
Referentsn=57
Age 30 (24-55) 29 (23-50)Duration ofemployment
64 (6-256) 69 (19-176)
Currentsmoking
29 (66%) 19 (33%)
Race, blackExposure
(high)
21 (48%)33 (75%)
31 (54%)39 (68%)
HLA-DR3 and Platinum sensitivity
Cases Refs Case +Ref -
Case –Ref +
OR
All 18(41%)
15(26%)
14 6 2.3(1.0,5.6)
Low 6(55%)
4(22%)
4 0 Infinite
High 12(36%)
11(28%)
10 6 1.6(0.6,4.1)
HLA-DR6 and platinum sensitivity
Cases Refs Case +Ref -
Case –Ref +
OR
All 16(36%)
34(60%)
8 19 0.4(0.2,0.8)
Low 2(18%)
12(67%)
8 19 0.1(0.02,1.1)
High 14(42%)
22(56%)
7 11 0.5(0.2, 1.3)
• Strength of HLA-DR3 and DR6 association with sensitisation to platinum varies with intensity of exposure
CBD, HLA-DPB1 Glu69 and Be exposure
Nonmachinist
Machinist Total
Glu69 –ve 0/55(0%)
1/31(3.2%)
1/86(1.2%)
Glu69 +ve 1/25(4%)
4/16(25%)
5/41(12%)
Total 1/80(1%)
5/47(10%)
6/127(5%)
Richeldi et al 1997
• Genetic susceptibility increased risk at high exposure of beryllium
Conclusions
• Identified genetic susceptibility
• Gene-environment interaction