Tumor necrosis factor-alpha-308 promoter gene polymorphism and increased tumor necrosis factor sevum bioactivity in farmer's lung patients

Hypersensitivity pneumonitis (HP) represents an immunologic reaction of the pulmonary parenchyma to an inhaled agent. Since tumor necrosis factor (TNF )-alpha is thought to be involved in the pathogenesis of HP, and polymorphi sms in the TNF genes have been associated with variations in the production of TNF-alpha, we investigated the serum bioactivity and genotype of TNF in HP. TNF bioactivity was measured after hay dust challenge in eight patient s with farmer's lung (Group A) and in 12 healthy, sensitized (antibody-posi tive) controls (Group B). Genotyping for the -308 TNF-alpha promoter polymo rphism and the TNF-beta intron 1 gene polymorphism was performed in 20 pati ents with farmer's lung, 25 patients with pigeon breeder's lung, and 216 co ntrols. TNF bioactivity increased in Group A at 4 to 10 h after hay dust ch allenge, but not in Group B (p < 0.05). The frequency for the TNFA2 allele, a genotype associated with high TNF- <alpha>: production in vitro, was sig nificantly higher in farmer's lung patients (frequency [f] = 0.43, p = 0.00 12) than in controls (f = 0.19) or patients with pigeon breeder's lung (f = 0.16). Genotyping for TNF-beta revealed no significant abnormalities. Thus , increased production of TNF-alpha after hay contact, and a genetic predis position to TNF-alpha production, are implicated in the pathogenesis of alv eolitis in farmer's lung.