Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP beta chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (-308) PM. The most significant results were found for the TGF-beta(1) (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-beta(1) (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-alpha and TGF-beta(1), with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.

Gaede, K., Amicosante, M., Schürmann, M., Fireman, E., Saltini, C., Müller Quernheim, J. (2005). Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease. JOURNAL OF MOLECULAR MEDICINE, 83(5), 397-405 [10.1007/s00109-004-0626-0].

Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease

AMICOSANTE, MASSIMO;SALTINI, CESARE;
2005-05-01

Abstract

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP beta chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (-308) PM. The most significant results were found for the TGF-beta(1) (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-beta(1) (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-alpha and TGF-beta(1), with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.
mag-2005
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/04 - PATOLOGIA GENERALE
Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO
Settore MED/44 - MEDICINA DEL LAVORO
English
Con Impact Factor ISI
United States; HLA-DQ beta-Chains; Berylliosis; Codon; Genetic Variation; Tumor Necrosis Factor-alpha; Gene Frequency; Polymorphism, Genetic; Humans; Israel; HLA-DQ Antigens; Alleles; HLA-DP beta-Chains; HLA-DP Antigens; Adult; Case-Control Studies; Transforming Growth Factor beta; Middle Aged; Chronic Disease; Genetic Predisposition to Disease; Germany; Male; Female
Gaede, K., Amicosante, M., Schürmann, M., Fireman, E., Saltini, C., Müller Quernheim, J. (2005). Function associated transforming growth factor-beta gene polymorphism in chronic beryllium disease. JOURNAL OF MOLECULAR MEDICINE, 83(5), 397-405 [10.1007/s00109-004-0626-0].
Gaede, K; Amicosante, M; Schürmann, M; Fireman, E; Saltini, C; Müller Quernheim, J
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/107077
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