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Title: ABPA and Asthma Fungal Sensitisation 2nd Advances Against Aspergillosis Thursday, February 23, 2006


1
ABPA and Asthma Fungal Sensitisation2nd Advances
Against AspergillosisThursday, February 23, 2006
  • Alan P. Knutsen, MD
  • Pediatric Allergy Immunology
  • Saint Louis University
  • St. Louis, MO

2
Diagnostic Criteria for ABPA
  • Major Criteria
  • Bronchial obstruction asthma, CF
  • Pulmonary infiltrates
  • Positive skin test to Aspergillus
  • Precipitating (IgG) antibodies to Aspergillus
  • Elevated serum IgG, IgA IgE anti-Aspergillus
  • Elevated IgE level gt1000 ng/ml
  • Blood eosinophilia
  • Proximal or central bronchiectasis
  • Minor Criteria
  • Sputum culture positive for A. fumigatus
  • Late-skin (Arthus) reactivity
  • History of expectoration of brown plugs

3
A. fumigatus in BALF and in Bronchial Tissue in
ABPA
4
Eosinophils in Bronchial Tissue
5
BALT IgE Lymphoid Follicles
  • IgE lymphoid follicles
  • BALT IgE-Af synthesis
  • IgG-Af exudate
  • (Greenberger et al)

6
Effect of A. fumigatus Proteases on Bronchilial
Epithelium H. Kauffmann
Il-4 IL-13 Asp f2/f3/f4
7
IgE Antibodies to Purified A. fumigatus allergens
in ABPA
Knutsen AP, Allergy 59198-203, 2004.
8
Asp f1 T-cell Lines Th2 CD4 T-cells in ABPA
Study TH PN SK NC KM KM CM
ABPA Atopic
Lymphoproliferation, SI Lymphoproliferation, SI Lymphoproliferation, SI Lymphoproliferation, SI Lymphoproliferation, SI Lymphoproliferation, SI Lymphoproliferation, SI Lymphoproliferation, SI
Asp f1 21.0 3.3 20.8 43 43 11.4
Tetanus toxoid 0.4 0.4 1.0 1.6 1.6 1.3
Cytokine Synthesis, pg/ml Cytokine Synthesis, pg/ml Cytokine Synthesis, pg/ml Cytokine Synthesis, pg/ml Cytokine Synthesis, pg/ml Cytokine Synthesis, pg/ml Cytokine Synthesis, pg/ml Cytokine Synthesis, pg/ml
IL-4 300 70,000 6,600 13,800 16,600 16,600
IFN-g lt100 1200 lt100 lt100 lt100 lt100
IL-2 nd nd lt300 nd lt300 lt300
Knutsen AP, J Allergy Clin Immunol 94215-221,
1994
9
Mast cell FceR1 IgE priming
Aspergillus Allergens Proteases Activation,
damage, leakage
Recruitment Activation
EOS
Lung Damage ECP, MBP, EDN, EPO
?IgE production
?IL4/IL-13 Activity IL-4Ra SNP IL-13 SNP
?IL-5
Allergic Inflammation ?IL-8, MCP-1, IL-6 ?Mucus
?TGF-b, ?EGFR ?Myofibroblast
activation Airway remodeling
B cell
?CD23, ?CD86
CD40 CD86/CD80 CD40L CD28
HLA-DR2/DR5
Th2
?IL-10 ?IL-12
Th0
APC
IL-4
10
HLA-DR Alleles in ABPA
HLA-DR ABPA, Non-ABPA, Control,
DR2/5 74.3 36.0 34.7
DR1 17 18 16
DR2 49 16 20
DR3 17 34 24
DR4 28 26 30
DR5 31 20 14
DR6 11 12 19
DR7 23 28 22
DR8 3 14 6
DR9 3 2 2
11
HLA-DRB1 Alleles in ABPA
DRB1 Alleles ABPA, Non-ABPA, Control,
DR2
DRB11501 25.7 10.0 7.14
DRB11502 0.0 4.0 0.36
DRB11503 20.0 0.0 0.66
DRB11601 2.8 2.0 2.4
DR5
DRB11101 11.4 10.0 5.7
DRB11103 0.0 2.0 0.39
DRB11104 17.1 8.0 2.2
DRB11202 2.8 0.0 0.12
12
HLA-DQ in ABPA
Subjects Value DQ2 DQ4 DQ5 DQ6 DQ7
ABPA 20.5 8.8 26.4 55.8 52.9
Non-ABPA 67.4 8.6 23.9 21.7 41.3
X2 19.1 0.00 0.00 8.44 .65
Pc lt.005 NS NS lt.005 NS
Controls 37.7 7.1 24.4 26.5 51.0
X2 4.16 0.00 0.00 8.42 0.0
Pc lt0.05 NS NS lt.005 NS
13
Spontaneous IgE Synthesis in ABPA
Subjects Serum IgE, IU/ml IgE, pg/ml Preformed Net IgE, pg/ml Preformed Net
ABPA (5) 4870836 1754595 1980617 1980617
ST/PPT (16) 29156 566205 220112 220112
ST/PPT- (14) 5822 16766 1310 1310
Control (23) --- 35558 7634 7634
P lt0.01 lt0.01 lt0.01 lt0.01
Knutsen AP, Clin Immunol Immunopath 55129-138,
1990.
14
Mast cell FceR1 IgE priming
Aspergillus Allergens Proteases Activation,
damage, leakage
Recruitment Activation
EOS
Lung Damage ECP, MBP, EDN, EPO
?IgE production
?IL4/IL-13 Activity IL-4Ra SNP IL-13 SNP
?IL-5
Allergic Inflammation ?IL-8, MCP-1, IL-6 ?Mucus
?TGF-b, ?EGFR ?Myofibroblast
activation Airway remodeling
B cell
?CD23, ?CD86
CD40 CD86/CD80 CD40L CD28
HLA-DR2/DR5
Th2
?IL-10 ?IL-12
Th0
APC
IL-4
15
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16
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17
IL-4Ra SNPs in Asthma and CF ABPA
Study ABPA (40) Non-ABPA (56) P
Extracellular
ile75val 32 (80) 30 (54) 0.008
asn98thr 2 (5) 4 (8) ns
homozygous ile75val 17 (43) 6 (11) 0.0003
Cytoplasmic
glu400ala 5 (13) 3 (5) ns
cys431arg 3 (8) 4 (7) ns
ser503pro 9 (23 10 (18) ns
gln576arg 8 (20) 14 (25) ns
Total 38 (95) 34 (61) 0.0001
Extracellular Cytoplasmic 11 (28) 12 (21) ns
Knutsen AP, Clin Mol Allergy, in press
18
IL-13 and IL-4Ra SNPs in Asthma and CF ABPA
Study ABPA (19) Non-ABPA (32)
arg110gln IL-13 10 (53) 12 (38)
IL-4Ra IL-13 SNPs 9 (47) 10 (31)
ile75val/arg110gln 8 (42) 9 (28)
19
CD23 Molecules per B-cell in ABPA Flare vs
Remission
20
Inhibition of IL-4 Up-Regulation of CD23
Expression by anti-CD86 mAb
21
Influence of interleukin-10 on airways
colonization by Aspergillus fumigatus in cystic
fibrosis patients
  • -1082GG genotype of IL-10 promoter associated
    with increased IL-10 synthesis
  • 378 CF Patients
  • -1082GG 23-25
  • -1082AG 49-53
  • -1082AA 24-26
  • -1082GG genotype associated with increased risk
  • Become colonized with A. fumigatus and
  • Develop ABPA 7
  • Plasma IL-10 levels examined in 48 CF patients
  • -1082GG - 495 pg/ml (range 324-784)
  • -1082AA - 249 pg/ml (range 30-826)

J Brouard, J Infect Dis 1911988-1991, 2005
22
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23
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24
Mast cell FceR1 IgE priming
Aspergillus Allergens Proteases Activation,
damage, leakage
Recruitment Activation
EOS
Lung Damage ECP, MBP, EDN, EPO
?IgE production
?IL4/IL-13 Activity IL-4Ra SNP IL-13 SNP
?IL-5
Allergic Inflammation ?IL-8, MCP-1, IL-6 ?Mucus
?TGF-b, ?EGFR ?Myofibroblast
activation Airway remodeling
B cell
?CD23, ?CD86
CD40 CD86/CD80 CD40L CD28
HLA-DR2/DR5
?IL-10 ?IL-12
Th2
Th0
APC
IL-4
25
Th1/Th2 cytokine synthesis of Co-cultures of Asp
f3 stimulated Mf-DC and CD3 T cells
Cytokine Synthesis, pg/ml ABPA (2) Non-ABPA (2)

IFN-g 39601040 4110890
IL-5 979571 8141
IL-10 1262 232
26
Collaborators
  • St. Louis University
  • Raymond G. Slavin, MD
  • Bela Chauhan, PhD
  • Barbara Kariuki, BA
  • Janet Smick, BS
  • Patricia S. Hutcheson, BS
  • A/I Fellows
  • James S. McClellan, MD
  • Seema Khan, MD
  • Manoj R. Warrier, MD
  • Medical College of Wisconsin
  • Viswanath P. Kurup, PhD
  • Laura Castillo, BS
  • CF Center Directors

27
Stages of ABPA
Stage X-ray IgE PPN IgE-Af IgG-Af Eos Symptoms
Acute Infitrates Symptomatic
Remission Resolved - Asymptomatic
Exacerbation Infiltrates Acute symptoms
Corticosteroid-dependent Asthma Resolved Asthma present, recurrence of acute symptoms, steroid dependence
Fibrotic (Airway remodeling) Fibrosis - Dyspnea, PFTs irreversible Restrictive obstructive disease Pulmonary fibrosis
28
CFTR Gene Mutations in ABPAP.A. Miller, Am J Hum
Genet 5945-51, 1996
  • Evaluated for mutations in cystic fibrosis
    transmembrane regulator conductance (CFTR) gene
  • 11 asthmatic ABPA patients
  • normal sweat chloride tests
  • Mutations in 6/11 patients
  • 1 - ?F508/R347H
  • 4 - ?F508
  • 1 - R117H

29
Summary - HLA-DR Restriction in ABPA
  • HLA-DR2 (DR15, DR16)
  • HLA-DR2 DRB11501, 1502, 1503, 1601
  • HLA-DR5 restriction
  • HLA-DR5 DRB11101, 1103, 1104, 1202
  • Low affinity binding
  • HLA-DQ2 is protective (DQB10201)

Chauhan B, J Immunol 1594072-4076, 1997
30
Summary - Immunopathogenesis of ABPA
  • HLA-DR2/DR5 restriction
  • DRB11501, 1502, 1503, 1601
  • HLA-DR5 DRB11101, 1103, 1104, 1202
  • HLA-DQ2 is protective (DQB10201)
  • IL-4Ra polymorphism
  • IL-13 polymorphism
  • IL-10 polymorphism
  • SP-A2 polymorphism
  • CFTR gene mutation
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