Genetic susceptibility to multicase hypersensitivity pneumonitis is associated with the TNF-238 GG genotype of the promoter region and HLA-DRB1*04 bearing HLA haplotypes.

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.

PSMB8 (LMP7) but not PSMB9 (LMP2) gene polymorphisms are associated to pigeon breeder's hypersensitivity pneumonitis.

Hypersensitivity Pneumonitis (HP) is a lung inflammatory disorder caused by inhalation of organic particles by a susceptible host. However, only a small proportion of individuals exposed to HP-associated antigens develop the disease, suggesting that additional host/environmental factors may play a role. We have previously found that genetic susceptibility associated to the major histocompatibility complex (MHC) plays an important role in this disease. The low molecular weight proteosome (LMP, currently named PSMB) genes code for subunits of the proteosome, a multimeric enzymatic complex that degrades proteins into peptides in order to be presented in the MHC class I pathway. We hypothesized that polymorphisms in PSMB8 or PSMB9 genes could be involved in the susceptibility to HP. Thus, in this study we analyzed the polymorphic site at amino acid position 60 (Arg/His) of the fourth exon in the PSMB9 gene and the amino acid position 49 (Gln/Lys) in the second exon of PSMB8 gene in 50 Mexican patients with HP and 50 healthy ethnically matched controls. PSMB typing was performed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Our results demonstrated that HP patients had a significant increase of the PSMB8 KQ genotype frequency (OR = 7.25, CI = 2.61-21.3; p = 0.000034). No differences were found in the distribution of PSMB9 alleles/genotypes. However, PSMB9-RH/PSMB8 KQ haplotype was significantly increased in HP patients (OR = 6.77, CI = 1.34-65.31, p < 0.02). These findings suggest that PSMB8 KQ genotype could increase the risk to develop hypersensitivity pneumonitis.

Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is a lung inflammatory disease caused by the inhalation of a variety of antigens. Previous studies support the role of the major histocompatibility complex (MHC) class II genes in the susceptibility to develop HP. However, the putative role of other MHC loci has not been elucidated. Transporters associated with antigen processing (TAP) genes are located within the MHC class II region and play an important role transporting peptides across the endoplasmic reticulum membrane for MHC class I molecules assembly. The distribution of single nucleotide polymorphisms (SNPs) in TAP1 genes was analyzed in 73 hypersensitivity pneumonitis (HP) patients and 58 normal subjects. We found a significant association of the allele Gly-637 (GGC) (p=0.00004, OR=27.30, CI=3.87-548.04) and the genotypes Asp-637/Gly-637 (p=0.01, OR=16.0, CI=2.19-631.21), Pro-661/Pro-661 (p=0.006, OR=11.30, CI=2.28-75.77) with HP. A significant decrease in the frequency of the allele Pro-661 (CCA) (p=0.008, OR=0.06, CI=0-0.45), the genotype Asp-637/Asp-637 (p=0.01, OR=0.17, 95% CI=0.05-0.58) and the haplotype [Val-333 (GTC), Val-458 (GTG), Gly-637 (GGC), Pro-661 (CCA)] was detected in HP patients compared with controls (p=0.002, OR=0.07, CI=0.0-0.57). These findings suggest that TAP1 gene polymorphisms are related to HP risk, and highlight the importance of the MHC in the development of this disease.

Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis.

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.

Symposium Trasplante de órganos en México: Inmunología de trasplantes / Trasplantation Immunology

En el presente artículo se revisan brevemente los antecedentes históricos trascendentales de la inmunología de los trasplantes de órganos. Se describen los aspectos fundamentales de la tipificación del sistema HLA y la clasificación de sus antígenos en clase, I, II y III. También se discuten los hechos más relevantes en relación con el cultivo de mezcla de linfocitos y la importancia de la pre-sensibilización a antígenos de histocompatibilidad

Inmunogenética en tuberculosis pulmonar / Immunogenetics in pulmonar tuberculosis

La predisposición genética a la tuberculosis y enfermeades infecciosas crónicas similares, ha sido tema de numerosos estudios y controversias, debido a la diversidad de resultados obtenidos. En un estudio previo realizado en una población abierta de enfermos, determinando los antígenos de histocompatibilidad se describió una disminución importante en expresión de estos marcadores. También se describió un incremento en la beta 2 microglobulina, péptido asociado estructuralmente a estos antígenos. En este trabajo, se estudiaron 19 familias de tuberculosos (23 enfermos y 58 sanos) los antígenos HLA (incluyendo el locus DQ) y la beta 2 microglobulina, así como, las subpoblaciones de linfocitos T. Encontrando que la coincidencia en enfermos del alelo DQ1 e incremento de la beta 2 microglobulina sérica es altamente significativa (p<0.00001). Estos datos apoyan la existencia de una predisposición genética en la mayoría de los enfermos con tuberculosis.