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

Abstract

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.

Predictors of survival in coexistent hypersensitivity pneumonitis with autoimmune features

“…In multivariable analysis, we found that Caucasian subjects were 9.33 times more likely to die or undergo a lung transplant during follow-up than non-Caucasian patients. These findings may support a genetic role as has been suggested in prior studies by others, in the pathogenesis or disease course of HP but require validation (21, 22) .…”

Antibody and T cell responses against avian and microbial antigens associate with hypersensitivity pneumonitis disease parameters in pigeon breeders

“…[1][2][3] Pigeon-antigen-specific proliferative T cell responses are not associated with disease status 4 despite genetic association of HLA-DR with PFL suggesting CD4 + T cell involvement. 5 Detailed analysis of reactive T cell phenotypes in PFL is limited, whilst T reg appear reduced in PFL. 6 A role of lung microbial infections in exacerbating PFL and other lung conditions is suggested.…”

“…Gut microbial dysbiosis in the first year of life was associated with asthma in multiple birth cohort studies. [1][2][3][4][5] Microbial metabolites might play a crucial role in maintaining an adequate immune balance and preventing asthma through its influence on regulatory T-cells (Tregs) and the Foxp3 gene. 1,6 However, most data are derived from animal studies, whereas most human studies have focused on the association between infant gut microbiota and asthma-like symptoms at an age when a reliable diagnosis of asthma cannot yet be made.…”

Using Genome-Wide Association Study to Identify Genes and Pathways associated with Hypersensitivity Pneumonitis

“…Hypersensitivity pneumonitis (HP) is an interstitial lung disease resulting from complex interactions between antigen exposures and alleles of many genes 1–4 . HP development depends on the type, intensity, and duration of exposure to the inciting agent, host susceptibility, the site of interaction within the respiratory system, and the resulting level of dysregulation of the cellular and humoral immune response over time 5 . In the United States there is a significant increasing trend in overall age-adjusted mortality for HP 6 , with HP mortality in farm workers 10-50% more than expected 7 .…”

“…Only a small proportion of exposed individuals develop HP indicating there are likely to be genetic factors involved in the development of the disease. It has been found by previous researchers that genes of the major histocompatibility complex (MHC) and the tumor necrosis factor alpha (TNF-α) were associated with HP 4,5,8 . The expression of MHC class II molecules is required for activation of T lymphocytes cells during immune response triggering.…”