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DOI: 10.1055/s-2004-830251
Modifizierende Gene bei der zystischen Fibrose
Cystic Fibrosis Modifying GenesPublication History
Eingang: 22. Dezember 2004
Nach Revision akzeptiert: 3. März 2005
Publication Date:
01 July 2005 (online)
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Zusammenfassung
Die zystische Fibrose (CF) ist eine häufige autosomal rezessive Erbkrankheit, die durch Mutationen im Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gen hervorgerufen wird. Das CFTR-Gen kodiert einen Membran-gebundenen Chlorid Ionenkanal; Mutationen im CFTR-Gen führen zu einer gestörten Salz- und Flüssigkeitssekretion in verschiedenen Geweben. Die Symptome der CF können, selbst bei Geschwistern oder Zwillingen mit den gleichen CFTR-Mutationen, in ihrer Ausprägung sehr variabel sein. Neben Umwelteinflüssen wird der Verlauf der pulmonalen Erkrankung auch durch weitere genetische Faktoren, so genannte modifizierende Gene, beeinflusst. Das Verständnis der molekularen und zellulären Grundlagen der gefundenen Genotyp-Phänotyp-Assoziationen wird zum besseren Verständnis der Erkrankung beitragen und wird helfen neue Ziele für pharmakologische Interventionen bei der CF zu identifizieren.
Abstract
Cystic fibrosis is a common autosomal recessive disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a membrane-bound chloride ion channel. CFTR gene mutations cause alterations in fluid and salt secretion of various tissues. The CF phenotype is highly variable even in siblings and twins carrying the same CFTR mutations. The course of CF pulmonary disease is modulated by both environmental and genetic factors independent of CFTR. This review summarises association studies that focused on disease modifier genes in CF. Understanding the molecular and cellular basis of the genotype-phenotype associations will help to better understand the disease and to identify new targets for therapeutic interventions in CF.
Literatur
- 1 Population variation of common cystic fibrosis mutations . The Cystic Fibrosis Genetic Analysis Consortium. Hum Mutat. 1994; 4 167-177
- 2 Kerem B, Rommens J M, Buchanan J A. et al . Identification of the cystic fibrosis gene: genetic analysis. Science. 1989; 245 1073-1080
- 3 Cystic Fibrosis Foundation, Patient Registry 2000 Annual Report. Bethesda, MD 2001
- 4 Kristidis P, Bozon D, Corey M. et al . Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet. 1992; 50 1178-1184
- 5 Kerem E, Corey M, Kerem B S. et al . The relation between genotype and phenotype in cystic fibrosis - analysis of the most common mutation (δF508). N Engl J Med. 1990; 323 1517-1522
- 6 Kerem B, Kerem E. The molecular basis for disease variability in cystic fibrosis. Eur J Hum Genet. 1996; 4 65-73
- 7 Mickle J E, Cutting G R. Genotyp-phenotyp relationships in cystic fibrosis. Med Clin North Am. 2000; 84 597-607
- 8 Lester L A, Kraut J, Lloyd-Still J. et al . δF508 genotype does not predict disease severity in an ethnically diverse cystic fibrosis population. Pediatrics. 1994; 93 114-118
- 9 Mekus F, Ballmann M, Bronsveld I. et al . Categories of δF508 homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics. Twin Res. 2000; 3 277-293
- 10 Bronsveld I, Mekus F, Bijman J. et al . Chloride conductance and genetic background modulate the cystic fibrosis phenotype of δF508 homozygous twins and siblings. J Clin Invest. 2001; 108 1705-1715
- 11 Salvatore F, Scudiero O, Castaldo G. Genotype-phenotype correlation in cystic fibrosis: the role of modifier genes. Am J Med Genet. 2002; 111 88-95
- 12 Rozmahel R, Wilschanski M, Matin A. et al . Modulation of disease severity in cystic fibrosis transmembrane conductance regulator deficient mice by a secondary genetic factor. Nat Genet. 1996; 12 280-287
- 13 Zielenski J, Corey M, Rozmahel R. et al . Detection of a cystic fibrosis modifier locus for meconium ileus on human chromosome 19q13. Nat Genet. 1999; 22 128-129
- 14 Kent G, Iles R, Bear C E. et al . Lung disease in mice with cystic fibrosis. J Clin Invest. 1997; 100 3060-3069
- 15 Haston C K, McKerlie C, Newbigging S. et al . Detection of modifier loci influencing the lung phenotype of cystic fibrosis knockout mice. Mamm Genome. 2002; 13 605-613
- 16 Insel P A. Seminars in medicine of the Beth Israel Hospital, Boston. Adrenergic receptors-evolving concepts and clinical implications. N Engl J Med. 1996; 334 580-585
- 17 Feldman R D, Fick R B, McArdle W, Lai C C. Are lymphocyte β-adrenoceptors altered in patients with cystic fibrosis?. Clin Sci (Lond). 1987; 73 407-410
- 18 Büscher R, Herrmann V, Insel P A. Human adrenoceptor polymorphisms: evolving recognition of clinical importance. Trends Pharmacol Sci. 1999; 20 94-99
- 19 Büscher R, Eilmes K J, Grasemann H. et al . β2-adrenoceptor gene polymorphisms in cystic fibrosis lung disease. Pharmacogenetics. 2002; 12 347-353
- 20 Bonfield T L, Panuska J R, Konstan M W. et al . Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med. 1995; 152 2111-2118
- 21 Greally P, Hussein M J, Cook A J. et al . Sputum tumour necrosis factor-α and leukotriene concentrations in cystic fibrosis. Arch Dis Child. 1993; 68 389-392
- 22 Kroeger K M, Carville K S, Abraham L J. The - 308 tumor necrosis factor-α promoter polymorphism effects transcription. Mol Immunol. 1997; 34 391-399
- 23 Abraham L J, Kroeger K M. Impact of the - 308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol. 1999; 66 562-566
- 24 Hull J, Thomson A H. Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis. Thorax. 1998; 53 1018-1021
- 25 Arkwright P D, Pravica V, Geraghty P J. et al . End-organ dysfunction in cystic fibrosis: association with angiotensin I converting enzyme and cytokine gene polymorphisms. Am J Respir Crit Care Med. 2003; 167 384-389
- 26 Witt H. Chronic pancreatitis and cystic fibrosis. Gut. 2003; 52 Suppl 2 ii31-41
- 27 Ignotz R, Massague J. Transforming growth factor-β stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986; 261 4337-4345
- 28 Nakamura Y, Tate L, Ertl R F. et al . Bronchial epithelial cells regulate fibroblast proliferation. Am J Physiol. 1995; 269 L377-387
- 29 Kawamoto M, Romberger D J, Nakamura Y. et al . Modulation of fibroblast type I collagen and fibronectin production by bovine bronchial epithelial cells. Am J Respir Cell Mol Biol. 1995; 12 425-433
- 30 Awad M R, El-Gamel A, Hasleton P. et al . Genotypic variation in the transforming growth factor-β1 gene: association with transforming growth factor-β1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation. 1998; 66 1014-1020
- 31 El-Gamel A, Awad M, Sim E. et al . Transforming growth factor-β1 and lung allograft fibrosis. Eur J Cardiothorac Surg. 1998; 13 424-430
- 32 Phan S H, Kunkel S L. Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res. 1992; 18 29-43
- 33 Arkwright P D, Laurie S, Super M. et al . TGF-β(1) genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax. 2000; 55 459-462
- 34 Hull J, Vervaart P, Grimwood K, Phelan P. Pulmonary oxidative stress response in young children with cystic fibrosis. Thorax. 1997; 52 557-560
- 35 Brown R K, Kelly F J. Role of free radicals in the pathogenesis of cystic fibrosis. Thorax. 1994; 49 738-742
- 36 Cantin A M, North S L, Hubbard R C. et al . Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol. 1987; 63 152-157
- 37 Wilkinson 4th J, Clapper M L. Detoxication enzymes and chemoprevention. Proc Soc Exp Biol Med. 1997; 216 192-200
- 38 Hayes J D, Strange R C. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000; 61 154-166
- 39 Strange R C, Matharoo B, Faulder G C. et al . The human glutathione S-transferases: a case-control study of the incidence of the GST1 0 phenotype in patients with adenocarcinoma. Carcinogenesis. 1991; 12 25-28
- 40 Harrison D J, Cantlay A M, Rae F. et al . Frequency of glutathione S-transferase M1 deletion in smokers with emphysema and lung cancer. Hum Exp Toxicol. 1997; 16 56-360
- 41 Baranova H, Perriot J, Albuisson E. et al . Peculiarities of the GSTM1 0/0 genotype in French heavy smokers with various types of chronic bronchitis. Hum Genet. 1997; 99 822-826
- 42 Mann C L, Davies M B, Boggild M D. et al . Glutathione S-transferase polymorphisms in MS: their relationship to disability. Neurology. 2000; 54 552-557
- 43 Mattey D L, Hassell A B, Plant M. et al . Association of polymorphism in glutathione S-transferase loci with susceptibility and outcome in rheumatoid arthritis: comparison with the shared epitope. Ann Rheum Dis. 1999; 58 164-168
- 44 Strange R C, Spiteri M A, Ramachandran S. et al . Glutathione-S-transferase family of enzymes. Mutat Res. 2001; 482 21-26
- 45 Fryer A A, Bianco A, Hepple M. et al . Polymorphism at the glutathione S-transferase GSTP1 locus. A new marker for bronchial hyperresponsiveness and asthma. Am J Respir Crit Care Med. 2000; 161 1437-1442
- 46 Baranov V S, Ivaschenko T, Bakay B. et al . Proportion of the GSTM1 0/0 genotype in some Slavic populations and its correlation with cystic fibrosis and some multifactorial diseases. Hum Genet. 1996; 97 516-520
- 47 Flamant C, Henrion-Caude A, Boelle P Y. et al . Glutathione-S-transferase M1, M3, P1 and T1 polymorphisms and severity of lung disease in children with cystic fibrosis. Pharmacogenetics. 2004; 14 295-301
- 48 Henrion-Caude A, Flamant C, Roussey M. et al . Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism. Hepatology. 2002; 36 913-917
- 49 Birrer P, McElvaney N G, Rudeberg A. et al . Protease-antiprotease imbalance in the lungs of children with cystic fibrosis. Am J Respir Crit Care Med. 1994; 150 207-213
- 50 Suter S, Schaad U B, Tegner H. et al . Levels of free granulocyte elastase in bronchial secretions from patients with cystic fibrosis: effect of antimicrobial treatment against Pseudomonas aeruginosa. J Infect Dis. 1986; 153 902-909
- 51 Colp C, Pappas J, Moran D. et al . Variants of α1-antitrypsin in Puerto Rican children with asthma. Chest. 1993; 103 812-815
- 52 King M A, Stone J A, Diaz P T. et al . α1-antitrypsin deficiency: evaluation of bronchiectasis with CT. Radiology. 1996; 199 137-141
- 53 Eriksson S. Studies in α1-antitrypsin deficiency. Acta Med Scand Suppl. 1965; 432 1-85
- 54 Cook P J. Genetic aspects of the Pi system. Postgrad Med J. 1974; 50 362-364
- 55 Döring G, Krogh-Johansen H, Weidinger S. et al . Allotypes of α1-antitrypsin in patients with cystic fibrosis, homozygous and heterozygous for δF508. Pediatr Pulmonol. 1994; 18 3-7
- 56 Mahadeva R, Westerbeek R C, Perry D J. et al . α1-antitrypsin deficiency alleles and the Taq-I G → A allele in cystic fibrosis lung disease. Eur Respir J. 1998; 11 873-879
- 57 Mahadeva R, Stewart S, Bilton D. et al . α1 antitrypsin deficiency alleles and severe cystic fibrosis lung disease. Thorax. 1998; 53 1022-1024
- 58 Morgan K, Scobie G, Marsters P. et al . Mutation in an α1-antitrypsin enhancer results in an interleukin-6 deficient acute-phase response due to loss of cooperativity between transcription factors. Biochim Biophys Acta. 1997; 1362 67-76
- 59 Henry M T, Cave S, Rendall J. et al . An α1-antitrypsin enhancer polymorphism is a genetic modifier of pulmonary outcome in cystic fibrosis. Eur J Hum Genet. 2001; 9 273-278
- 60 Frangolias D D, Ruan J, Wilcox P J. et al . α1-antitrypsin deficiency alleles in cystic fibrosis lung disease. Am J Respir Cell Mol Biol. 2003; 29 390-396
- 61 Burnett D, McGillivray D H, Stockley R A. Evidence that alveolar macrophages can synthesize and secrete α1-antichymotrypsin. Am Rev Respir Dis. 1984; 129 473-476
- 62 Hudig D, Haverty T, Fulcher C. et al . Inhibition of human natural cytotoxicity by macromolecular antiproteases. J Immunol. 1981; 126 1569-1574
- 63 Kalsheker N, Morley S, Morgan K. Gene regulation of the serine proteinase inhibitors α1-antitrypsin and α1-antichymotrypsin. Biochem Soc Trans. 2002; 30 93-98
- 64 Poller W, Faber J P, Weidinger S. et al . A leucine-to-proline substitution causes a defective α1-antichymotrypsin allele associated with familial obstructive lung disease. Genomics. 1993; 17 740-743
- 65 Mahadeva R, Sharples L, Ross-Russell R I. et al . Association of α(1)-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis. Thorax. 2001; 56 53-58
- 66 Rigat B, Hubert C, Alhenc-Gelas F. et al . An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest. 1990; 86 1343-1346
- 67 Montgomery H, Clarkson P, Barnard M. et al . Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training. Lancet. 1999; 353 541-545
- 68 Uhal B D, Gidea C, Bargout R. et al . Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am J Physiol. 1998; 275 L1013-1017
- 69 Molteni A, Moulder J E, Cohen E F. et al . Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker. Int J Radiat Biol. 2000; 76 523-532
- 70 Matsushita M, Fujita T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med. 1992; 176 1497-1502
- 71 Madsen H O, Garred P, Kurtzhals J A. et al . A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein. Immunogenetics. 1994; 40 37-44
- 72 Garred P, Madsen H O, Svejgaard A. Genetics of human mannose-binding protein. In: Ezekowitz RA, Sastry K, Reid KBM (eds). Collectins and innate immunity Auscin, TX:RG Landes 1996: 139-164
- 73 Madsen H O, Garred P, Thiel S. et al . Interplay between promoter and structural gene variants control basal serum level of mannan-binding protein. J Immunol. 1995; 155 3013-3020
- 74 Summerfield J A, Sumiya M, Levin M. et al . Association of mutations in mannose binding protein gene with childhood infection in consecutive hospital series. BMJ. 1997; 314 1229-1232
- 75 Summerfield J A, Ryder S, Sumiya M. et al . Mannose binding protein gene mutations associated with unusual and severe infections in adults. Lancet. 1995; 345 886-889
- 76 Garred P, Pressler T, Madsen H O. et al . Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest. 1999; 104 431-437
- 77 Gabolde M, Guilloud-Bataille M, Feingold J. et al . Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study. BMJ. 1999; 319 1166-1167
- 78 Gabolde M, Hubert D, Guilloud-Bataille M. et al . The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis. J Med Genet. 2001; 38 310-311
- 79 Tobin M J, Maguire O, Reen D. et al . Atopy and bronchial reactivity in older patients with cystic fibrosis. Thorax. 1980; 35 807-813
- 80 Warner J O, Taylor B W, Norman A P. et al . Association of cystic fibrosis with allergy. Arch Dis Child. 1976; 51 507-511
- 81 Aron Y, Swierczewski E, Lockhart A. HLA class II haplotype in atopic asthmatic and non-atopic control subjects. Clin Exp Allergy. 1995; 25 Suppl 2 65-67
- 82 Aron Y, Desmazes-Dufeu N, Matran R. et al . Evidence of a strong, positive association between atopy and the HLA class II alleles DR4 and DR7. Clin Exp Allergy. 1996; 26 821-828
- 83 Aron Y, Polla B S, Bienvenu T. et al . HLA class II polymorphism in cystic fibrosis. A possible modifier of pulmonary phenotype. Am J Respir Crit Care Med. 1999; 159 1464-1468
- 84 Barnes P J, Belvisi M G. Nitric oxide and lung disease. Thorax. 1993; 48 1034-1043
- 85 Asano K, Chee C B, Gaston B. et al . Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells. Proc Natl Acad Sci USA. 1994; 91 10 089-10 093
- 86 Belvisi M G, Stretton C D, Yacoub M. et al . Nitric oxide is the endogenous neurotransmitter of bronchodilator nerves in humans. Eur J Pharmacol. 1992; 210 221-222
- 87 Dupuy P M, Shore S A, Drazen J M. et al . Bronchodilator action of inhaled nitric oxide in guinea pigs. J Clin Invest. 1992; 90 421-428
- 88 Fang F C. Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest. 1997; 99 2818-2825
- 89 Balfour-Lynn I M, Laverty A, Dinwiddie R. Reduced upper airway nitric oxide in cystic fibrosis. Arch Dis Child. 1996; 75 319-322
- 90 Grasemann H, Michler E, Wallot M. et al . Decreased concentration of exhaled nitric oxide (NO) in patients with cystic fibrosis. Pediatr Pulmonol 1997. Sep; 24 (3) 173-177
- 91 Grasemann H, Ratjen F. Cystic fibrosis lung disease: the role of nitric oxide. Pediatr Pulmonol. 1999; 28 442-448
- 92 Wooldridge J L, Deutsch G H, Sontag M K. et al . NO pathway in CF and non-CF-children. Pediatr Pulmonol. 2004; 37 338-350
- 93 Grasemann H, Ioannidis I, Tomkiewicz R P. et al . Nitric oxide metabolites in cystic fibrosis lung disease. Arch Dis Child. 1998; 78 49-53
- 94 Ho L P, Innes J A, Greening A P. Exhaled nitric oxide is not elevated in the inflammatory airways diseases of cystic fibrosis and bronchiectasis. Eur Respir J. 1998; 12 1290-1294
- 95 Grasemann H, Lax H, Treseler J W. et al . Dornase α and exhaled NO in cystic fibrosis. Pediatr Pulmonol. 2004; 38 379-385
- 96 Wechsler M E, Grasemann H, Deykin A. et al . Exhaled nitric oxide in patients with asthma: association with NOS1 genotype. Am J Respir Crit Care Med. 2000; 162 2043-2047
- 97 Grasemann H, Knauer N, Büscher R. et al . Airway nitric oxide levels in cystic fibrosis patients are related to a polymorphism in the neuronal nitric oxide synthase gene. Am J Respir Crit Care Med. 2000; 162 2172-2176
- 98 Grasemann H, Storm van's Gravesande K, Gärtig S. et al . Nasal nitric oxide levels are associated with a polymorphism in the neuronal nitric oxide synthase (NOS1) genes in cystic fibrosis patients. Nitric Oxide. 2002; 6 236-241
- 99 Grasemann H, Ratjen F. Pulmonary metabolism of nitric oxide (NO) in patients with cystic fibrosis. Pneumologie. 2002; 56 376-381
- 100 Texereau J, Marullo S, Hubert D. et al . Nitric oxide synthase 1 as a potential modifier gene of decline in lung function in patients with cystic fibrosis. Thorax. 2004; 59 156-158
- 101 Marsden P A, Heng H H, Scherer S W. et al . Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem. 1993; 268 17 478-17 488
- 102 Tesauro M, Thompson W C, Rogliani P. et al . Intracellular processing of endothelial nitric oxide synthase isoforms associated with differences in severity of cardiopulmonary diseases: cleavage of proteins with aspartate vs. glutamate at position 298. Proc Natl Acad Sci USA. 2000; 97 2832-2835
- 103 Storm van's Gravesande K, Wechsler M E, Grasemann H. et al . Association of a missense mutation in the NOS3 gene with exhaled nitric oxide levels. Am J Respir Crit Care Med. 2003; 168 228-231
- 104 Grasemann H, Storm van's Gravesande K, Büscher R. et al . Endothelial nitric oxide synthase variants in cystic fibrosis lung disease. Am J Respir Crit Care Med. 2003; 167 390-394
- 105 Lantin-Hermoso R L, Rosenfeld C R, Yuhanna I S. et al . Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. Am J Physiol. 1997; 273 L119-126
- 106 Grasemann H, Storm van's Gravesande K, Büscher R. et al . Effects of sex and of gene variants in constitutive nitric oxide synthases on exhaled nitric oxide. Am J Respir Crit Care Med. 2003; 167 1113-1116
- 107 Sullivan K J, Kissoon N, Duckworth L J. et al . Low exhaled nitric oxide and a polymorphism in the NOS I gene is associated with acute chest syndrome. Am J Respir Crit Care Med. 2001; 164 2186-2190
- 108 Morris C R, Morris Jr S M, Hagar W. et al . Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease?. Am J Respir Crit Care Med. 2003; 168 63-69
- 109 Sharan K, Surrey S, Ballas S. et al . Association of T-786C eNOS gene polymorphism with increased susceptibility to acute chest syndrome in females with sickle cell disease. Br J Haematol. 2004; 124 240-243
- 110 Bonfield T L, Panuska J R, Konstan M W. et al . Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med. 1995; 152 2111-2118
- 111 Osika E, Cavaillon J M, Chadelat K. et al . Distinct sputum cytokine profiles in cystic fibrosis and other chronic inflammatory airway disease. Eur Respir J. 1999; 14 339-346
- 112 Moss R B, Bocian R C, Hsu Y P. et al . Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR). Clin Exp Immunol. 1996; 106 374-388
- 113 Chmiel J F, Kostan M W, Knesebeck J E. et al . IL-10 attenuates excessive inflammation in chronic Pseudomonas infection in mice. Am J Respir Crit Care Med. 1999; 160 2040-2047
- 114 Chmiel J F, Konstan M W, Saadane A. et al . Prolonged inflammatory response to acute Pseudomonas chalange in interleukin-10 knockout mice. Am J Respir Crit Care Med. 2002; 165 1176-1181
- 115 Cenci E, Mencacci A, Fe d'Ostiani C. et al . Cytokine- and T helper-dependent lung mucosal immunity in mice with invasive pulmonary aspergillosis. J Infect Dis. 1998; 178 1750-1760
- 116 Roilides E, Dimitriadou A, Kadiltsoglou I. et al . IL-10 exerts suppressive and enhancing effects on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus. J Immunol. 1997; 158 322-329
- 117 Kurup V P, Grunig G. Animal models of allergic bronchopulmonary aspergillosis. Mycopathologia. 2002; 153 165-177
- 118 Brouard J, Knauer N, Boelle P Y. et al . Influence of Interleukin-10 on airways colonization by Aspergillus fumigatus in cystic fibrosis patients. J Infect Dis. 2005; in press
- 119 Knowles M R, Konstan M, Schluchter M. et al . CF gene modifiers: comparing variation between unrelated individuals with different pulmonary phenotypes. Pediatric Pulmonol. 2004; Suppl 27 139-140
- 120 Dorfman R, Sandford A, Markiewicz D. et al . Analysis of candidate genes as modifiers of cystic fibrosis. Pediatric Pulmonol. 2004; Suppl 27 220-221
PD. Dr. Hartmut Grasemann
Zentrum für Kinder- und Jugendmedizin · Universitätsklinikum Essen
Hufelandstr. 55
45122 Essen, Germany ·
Email: hartmutg@hotmail.com