Diffuse Panbronchiolitis - Cause

Cause

DPB is idiopathic, which means an exact physiological, environmental, or pathogenic cause of the disease is unknown. However, several factors are suspected to be involved with its pathogenesis (the way in which the disease works).

The major histocompatibility complex (MHC) is a large genomic region found in most vertebrates that is associated with the immune system. It is located on chromosome 6 in humans. A subset of MHC in humans is human leukocyte antigen (HLA), which controls the antigen-presenting system, as part of adaptive immunity against pathogens such as bacteria and viruses. When human cells are infected by a pathogen, some of them can present parts of the pathogen's proteins on their surfaces; this is called "antigen presentation". The infected cells then become targets for types of cytotoxic T-cells, which kill the infected cells so they can be removed from the body.

Genetic predisposition for DPB susceptibility has been localized to two HLA haplotypes (a nucleotide or gene sequence difference between paired chromosomes, that is more likely to occur among a common ethnicity or trait) common to people of East Asian descent. HLA-B54 is associated with DPB in the Japanese, while HLA-A11 is associated with the disease in Koreans. Several genes within this region of class I HLA are believed to be responsible for DPB, by allowing increased susceptibility to the disease. The common genetic background and similarities in the HLA profile of affected Japanese and Korean individuals were considered in the search for a DPB gene. It was suggested that a mutation of a suspected disease-susceptibility gene located somewhere between HLA-B and HLA-A had occurred on an ancestral chromosome carrying both HLA-B54 and HLA-A11. Further, it is possible that a number of genetic recombination events around the disease locus (location on a chromosome) could have resulted in the disease being associated with HLA-B54 in the Japanese and HLA-A11 in Koreans. After further study, it was concluded that a DPB susceptibility gene is located near the HLA-B locus at chromosome 6p21.3. Within this area, the search for a genetic cause of the disease has continued.

Because many genes belonging to HLA remain unidentified, positional cloning (a method used to identify a specific gene, when only its location on a chromosome is known) has been used to determine that a mucin-like gene is associated with DPB. In addition, diseases caused by identified HLA genes in the DPB-susceptibility region have been investigated. One of these, bare lymphocyte syndrome I (BLS I), exhibits a number of similarities with DPB in those affected, including chronic sinusitis, bronchiolar inflammation and nodules, and the presence of H. influenzae. Also like DPB, BLS I responds favorably to erythromycin therapy by showing a resolution of symptoms. The similarities between these two diseases, the corresponding success with the same mode of treatment, and the fact that the gene responsible for BLS I is located within the DPB-causing area of HLA narrows the establishment of a gene responsible for DPB. Environmental factors such as inhaling toxic fumes and cigarette smoking are not believed to play a role in DPB, and unknown environmental and other non-genetic causes—such as unidentified bacteria or viruses—have not been ruled out.

Cystic fibrosis (CF), a progressive multi-system lung disease, has been considered in the search for a genetic cause of DPB. This is for a number of reasons. CF, like DPB, causes severe lung inflammation, abundant mucus production, infection, and shows a genetic predominance among Caucasians of one geographic group to the rarity of others; whereas DPB dominates among East Asians, CF mainly affects individuals of European descent. While no gene has been implicated as the cause of DPB, mutation in a specific gene—much more likely to occur in Europeans—causes CF. This mutation in the CF-causing gene is not a factor in DPB, but a unique polymorphism (variation) in this gene is known to occur in many Asians not necessarily affected by either disease. It is being investigated whether this gene in any state of mutation could contribute to DPB.