Pigeon breeders disease (PBD) is caused by the exposure of a susceptible host to avian antigens. However, genetic factors determining individual predisposition are unknown. In this work, polymorphisms of the major histocompatibility complex (MHC) class II alleles and tumor necrosis factor alpha (TNF-alpha) promoter were evaluated in 44 patients with PBD, 99 healthy unrelated controls (HC), and 50 exposed but asymptomatic subjects (EAS). MHC typing was performed by PCR-specific sequence oligonucleotide analysis, and TNF-alpha polymorphism at -238 and -308 positions by amplification refractory mutation system-PCR. PBD patients showed a significant increase of the alleles HLA-DRB1*1305 (p < 0.001, OR = 15.4, 95% CI = 3.18-102.6 [HC], and OR = 17.05, 95% CI = 2.25-357.8 [EAS]) and HLA-DQB1*0501 (p < 0.05, OR = 2.93, 95% CI = 1.21-7.15 [HC], and OR = 2.96, 95% CI = 1.0-9.14 [EAS]). A decrease of HLA-DRB1*0802 was also noticed in patients when compared with both control groups (p < 0.05). Haplotype analysis revealed an increase of DRB1*1305-DQB1*0301 and a decrease of DRB1*0802-DQB1*0402. PBD patients had an increased frequency of TNF-2(-)(308) compared with both control groups (p < 0.05). Patients exhibiting the TNF-2(-)(308) allele were younger (33.9 +/- 14.6 versus 44.2 +/- 10.4 yr; p < 0.05), and displayed more lymphocytes in their bronchoalveolar lavages (88.0 +/- 12.1 versus 68.9 +/- 17.2; p < 0.05). These results suggest that genetic factors located within the MHC region contribute to the development of PBD.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblast expansion, and tissue remodeling. It is considered a multifactorial disease but the possible involved genes are largely unknown. Interestingly, studies regarding the possible role of major histocompatibility complex (MHC) are scanty and show contradictory results. In this study, we evaluated the polymorphisms of the MHC, locus HLA-B, -DRB1, and -DQB1 in a cohort of 75 IPF patients and 95 controls by using PCR and hybridization with sequence-specific oligonucleotide probes. In addition, we examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes on alveolar epithelial growth rate by WST-1 cell viability assay and on epithelial apoptosis by flow cytometry and by cleaved caspase-3 in cell homogenates. Three haplotypes were significantly increased in IPF: (1) HLA-B*15-DRB1*0101-DQB1*0501 (OR=10.72, CI=1.43-459.6; pC=0.011); (2) HLA-B*52-DRB1*1402-DQB1*0301 (OR=4.42, CI=1.21-24.1; pC=0.024); and (3) HLA-B*35-DRB1*0407-DQB1*0302 (OR=4.73, CI=1.53-19.5; pC=0.005). BAL from patients with the later haplotype significantly reduced epithelial growth rate ( approximately 30%) and caused epithelial cell apoptosis assayed by cleaved caspase-3 (351.7+/-16.5 pg/10(6) cells versus 264+/-24 from controls, and 274+/-36.8 and 256.5+/-10.7 from the other haplotypes; P<0.05), and DNA breaks labeling by flow cytometry (23.7+/-6.9% versus 3.1+/-0.7% from controls, and 6.5+/-0.6% and 7.6+/-1.2% from the other two haplotypes; P<0.01). These findings suggest that some MHC polymorphisms confer susceptibility to IPF, which might be related with the induction of epithelial cell apoptosis, a critical process in the development of the disease.

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Hypersensitivity Pneumonitis (HP) is a lung inflammatory disorder caused by inhalation of organic particles by a susceptible host. Since only a small proportion of individuals exposed to HP-related antigens develop the disease, a genetic predisposition is largely suspected. However, studies regarding genetic susceptibility in this disease are scanty. We have previously found evidence supporting increased risk associated to the major histocompatibility complex (MHC) in sporadic HP. In the present study, we conducted a family-based research that includes nine multicase families with at least two related HP patients (RHP). We evaluated 19 RHP individuals, 25 additional healthy first-degree relatives (REA) and 246 healthy unrelated individuals (HUI). HLA class II typing (DRB1/3/4/5, DQA1, DQB1, DPA1, DPB1, DMA and DMB), and -863, -308 and -238 polymorphisms in the promoter region of TNF-α were performed by PCR based methods. We identified an increased frequency of HLA-DRB1*04:07, DRB1*04:05, DRB1*11:01 and DRB1*13:01 alleles in RHP individuals compared to healthy controls (p < 0.05). A significant higher frequency of DRB1*04:07-DQB1*03:02, DRB1*04:05-DQB1*03:02, and DRB1*04:03-DQB1*03:02 haplotypes was also detected in the group of patients. Likewise, TNF-238 GG genotype was more frequent in the RHP group as compared to REA (p = 0.01, OR = 7.2). Finally, the combination of HLA-DRB1*04 alleles and TNF-238 GG was significantly increased in the RHP group (p = 0.01, OR = 6.93). These findings indicate that genes located within the MHC region confer susceptibility to familial HP in Mexicans.