The 8.1 ancestral MHC haplotype is associated with delayed onset of colonization in cystic fibrosis

Abstract

Major cause of death in patients with cystic fibrosis (CF) is colonization with Staphylococcus aureus and Pseudomonas aeruginosa. The wide phenotypic variation in CF patients suggests that genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene modify the disease. The 8.1 ancestral haplotype (8.1AH) in main histocompatibility complex is associated with alterations of the immune response. To study the influence of carriage of 8.1AH on frequency and onset of colonization in CF patients, DNA samples of 72 CF patients (39 homozygous and 33 heterozygous for DeltaF508) were genotyped for member alleles of the 8.1AH: HLA-DQB1*0201, HLA-DRB1*0301, receptor for advanced glycation end products (AGER) -429C, HSP70-2 -1267G (HSP70-2G) and tumor necrosis factor-alpha (TNF-alpha) -308A (TNF2). Colonization was verified by regular clinical and bacteriological screening. Frequency of colonization was significantly (P = 0.012) lower in the 8.1AH carriers; age, gender and DeltaF508 genotype-adjusted odds ratio to be colonized of the carriers versus non-carriers was 0.112 (0.024-0.520). According to survival analysis, patients with 8.1AH had significantly (P < 0.0001) longer colonization-free period compared with non-carriers. Our novel observations demonstrate that the 8.1AH is associated with delayed onset of colonization in CF, presumably by influencing defense mechanisms against infections.

Autoimmune-associated HLA-B8-DR3 haplotypes in Asian Indians are unique in C4 complement gene copy numbers and HSP-2 1267A/G

“…A recent update on the MHC haplotype project [47] states that the haplotypes selected for the project are ancestral haplotypes, and their haplotypic tree space analyses indicates that these are well conserved and representative of MHC diversity in the European population. Our study and others [13,29,45] One recent report that supports this idea, for example, is the delayed colonization in cystic fibrosis in Caucasian individuals with AH8.1 [13]. It is plausible that natural selection favours survival of a population against prevalent infections [48,49] or environmental challenges so that individuals could survive at least up to a reproductive stage, even if it gradually leads to development of autoimmune disorders at later stages.…”

“…It is associated with several autoimmune diseases [3,[5][6][7], including type 1 diabetes [1,4,8], celiac disease [9], systemic lupus erythematosus [10], common variable immunodeficiency [11], myasthenia gravis [12], immunologic hyperreactivity [5], delayed colonization in cystic fibrosis [13], and accelerated progression to acquired immunodeficiency syndrome (AIDS) [14].…”

Decreased expression of HLA-DQ and HLA-DR on cells of the monocytic lineage in cystic fibrosis

“…This observation leads to the hypothesis that impaired MHC class II protein receptor expression may interfere with host defence mechanisms and may lead to elevated microbial colonization of the lungs of CF patients. This concept is supported by several other studies on the role of MHC class II molecules in CF, e.g., in Aron et al [12] where they found higher levels of IgE and more frequent Psuedomonas aeruginosa colonization in CF patients with DR7/DQA*0201 haplotype [12] or in Laki et al where they found lower frequency of bacterial colonization in CF with the 8.1 ancestral MHC haplotype [17].…”

Ancestral haplotype 8.1 and lung disease severity in European cystic fibrosis patients

“…8.1AH appeared to be a good candidate because it is carried by up to one quarter of Caucasians and comprises a cassette of linked alleles that play key roles in the inflammatory response: LTA +252A/G (Lymphotoxin A), TNF−308G/A (Tumor necrosis factor), HSP70-2 + 1267A/G (Heat shock protein) and RAGE−429T/C (Receptor for Avanced Glycation Endproducts). Moreover, 8.1AH has been associated with delayed onset of lung bacterial colonization in CF patients in a small cohort of Hungarian patients [10]. As airway inflammation is a key component inducing CF lung damage, we investigated whether the 8.1AH represents such modifier in European CF patients from France, UK and Germany.…”