SEARCH

SEARCH BY CITATION

Keywords:

  • disease susceptibility;
  • gene cluster;
  • HLA antigen;
  • mucin;
  • panbronchiolitis

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

Diffuse panbronchiolitis is characterized by chronic inflammation in respiratory bronchioles and sinobronchial infection. The pathophysiology accompanying the persistent bacterial infection is noteworthy for the accumulation of lymphocytes and foamy macrophages around the small airways, for mucus hypersecretion, and for the number of neutrophils in the large airways. Until the establishment of long-term macrolide therapy, the prognosis was generally poor. Case studies of diffuse panbronchiolitis in East Asians, including Japanese, Koreans and Chinese, have frequently been reported, and genetic predisposition to the disease has been assumed in Asians. Immunogenetic studies revealed a strong association with human leukocyte antigen (HLA)-B54 in Japanese, whereas an association with HLA-A11 was reported in Koreans. These findings imply that a major susceptibility gene may be located between the HLA-A and HLA-B loci on the short arm of human chromosome 6. We have recently cloned novel mucin-like genes in this candidate region. In addition to accumulated knowledge of classical HLA genes and mucin genes, further analysis of newly identified genes may provide insights into the pathogenesis of the disease.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

Diffuse panbronchiolitis is characterized by chronic inflammation in respiratory bronchioles and sinobronchial infection.1–3 Inflammatory nodular lesions around the bronchioles occur diffusely throughout the lung. This was proposed as a disease entity, distinct from COPD, by Homma and Yamanaka in the 1960s in Japan, but it was not accepted internationally until the 1980s,1 probably because the disease was rarely experienced, clinically and pathologically, in Western countries.

Outside Asia, only a limited number of cases have been reported. Of the patients reported in Western countries, about half are Asian immigrants.3 The age of Japanese patients at onset of the disease varies from young to elderly with a peak at 40–60 years. No significant gender difference has been demonstrated; the male to female ratio among clinically defined cases in a Japanese nationwide survey in 1980 was 1.4 to 1. Two-thirds of the patients were non-smokers. The prevalence was 11.1 per 100 000 among 70 000 employees of the Japanese national railway corporation in 1980, but according to a recent unofficial survey in Japan, it appears to have decreased to 3.4 per 100 000.

Patients with diffuse panbronchiolitis present with chronic cough, expectoration of large amounts of purulent sputum and exertional dyspnoea. Most patients have a current or past history of chronic sinusitis. On chest CT, many small centrilobular nodules are observed in the periphery of both lung fields. Histopathologically, the nodules consist of lymphocytes and foamy macrophages around respiratory bronchioles. Pulmonary function tests show an obstructive pattern and hyperinflation. Blood gas analyses reveal progressive hypoxaemia. When the disease advances further, secondary dilatation of bronchioles and bronchi is difficult to distinguish radiographically and histopathologically from diffuse bronchiectasis of unknown cause.

The diagnostic criteria proposed in 1998 by a working group of the Ministry of Health and Welfare of Japan are still useful for case definition:4 (i) persistent cough, sputum and exertional dyspnoea; (ii) a history of, or current chronic sinusitis; (iii) bilateral diffuse small nodular shadows on plain CXR or centrilobular micronodules on chest CT; (iv) coarse crackles; (v) FEV1/FVC <70% and PaO2 <80 mm Hg; and (vi) titre of cold haemagglutinin ≥64. Definite cases should fulfil criteria 1, 2 and 3, and at least two of criteria 4, 5 and 6.

Patients suffer from chronic bacterial infection due to Haemophilus influenzae and other species in the airways. Bacteria in the airway are gradually replaced by Pseudomonas aeruginosa and the disease is progressive in nature. In the past, without effective treatment, chronic respiratory failure followed, with a fatal outcome. In those days, the 5-year survival rate was 60%. In 1982, Kudoh et al.5 at the Tokyo Metropolitan Komagome Hospital had a chance to examine a patient who discontinued the previous treatment and received other medications for 2 years in his hometown. Interestingly, his condition improved remarkably after receiving this medication. From the detailed prescription records, it appeared that 600 mg of erythromycin every day for 2 years was potentially effective. Thus, the first open trial of low-dose, long-term erythromycin therapy was successfully performed.5 It was not long before this positive effect was confirmed by others.6–9 Since then, the prognosis of this disease has improved dramatically and we can now say that diffuse panbronchiolitis is curable.10 Nevertheless, the cause of this disease is still unknown and the reason for its particular occurrence in Asian patients remains unclear. In addition, we have not yet been able to propose a single definitive mechanism for the efficacy and specificity of macrolide antibiotics in the treatment of this disease. We do not know why some patients are unresponsive to therapy, and have intractable disease.

PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

Normal airways are protected by three networks: a physical barrier that includes mucociliary transport, innate immunity regulated by epithelial cells or phagocytes on the mucosal surface, and acquired immunity provided by Ig and T-cell receptors. Chronic airway infection is often triggered by a defect in one of these three networks.11–13 Once microorganisms are inhaled into airways carrying such a defect, they will attach firmly to the bronchial mucosal surface, replicate and injure the surrounding tissue by inducing an inflammatory response. Neutrophils are predominantly recruited to the site by substances derived from the organisms themselves or by neutrophil chemotactic factors produced by the mucosal cells. In turn, activated neutrophils in the airways release proteolytic enzymes and superoxide, promoting further fixation of microorganisms. Although epithelial cells have the potential to produce a variety of antimicrobial peptides, for reasons that are not clear, these may not effectively kill pathogens at sites of disease. In this setting, there is often excessive production of mucus and mucociliary clearance is seriously disturbed. A vicious cycle of chronic airway infection is thus established. When the upper and lower airways are both injured, patients are designated as having sinobronchial syndrome.

Researchers believe that this pathogenesis of sinobronchial syndrome is generally applicable to diffuse panbronchiolitis.1–3 On that basis, however, the unique characteristics of the disease, which is accompanied by persistent bacterial infection, should also be emphasized (Fig. 1): lymphocytes and foamy macrophages around the small airways, mucus hypersecretion, large numbers of neutrophils in the large airways and immunological aspects of the disease.

image

Figure 1. Schematic representation of the pathology and proposed pathogenesis of diffuse panbronchiolitis. Lymphocytes and foamy macrophages around the small airways, as well as mucus hypersecretion with large number of neutrophils in the large airways, are characteristic of the disease. An unknown defect in host defence mechanisms is assumed.

Download figure to PowerPoint

Hyperplasia of lymphoid tissue around the bronchioles may cause airflow limitation, but may also contribute to mucosal defence mechanisms through the local production of IgG and IgA.14 Increased numbers of dendritic cells in the bronchiolar tissues of patients with the disease may also support an enhanced mucosal immune response around the bronchioles, through promotion of antigen presentation,15 although these defence mechanisms do not appear to effectively clear bacteria from the airways. Analysis of T lymphocytes in BAL fluid showed that the absolute number of T lymphocytes, especially activated CD8+ cells, was increased, together with the number of neutrophils.16 The significance of the lymphocytes and foamy macrophages located in the airways remains largely unknown.

Copious sputum production with accumulation of neutrophils in the proximal airways is another important feature of the disease.17 Hyperplasia of goblet cells and submucosal glands packed with mucins is observed in histopathological sections.18 Although the definitive mechanism resulting in hypersecretion is not clear, the volume of purulent sputum is remarkably reduced and mucus rheology is normalized after therapy with macrolides and the facilitation of mucociliary clearance.19,20 Neutrophil numbers and elastase activity were significantly elevated in bronchial fluid from patients.21 Excessive production of neutrophil chemotactic factors such as IL-8 and leukotriene B4 at the site of inflammation, and upregulation of adhesion molecules such as CD11b in the circulation, are followed by the recruitment of neutrophils into the proximal airways.22

Laboratory findings suggest immunological abnormalities, presumably secondary to chronic infection.23 The titre of cold haemagglutinin autoantibodies against surface antigens of red blood cells is continuously raised in most patients, without evidence of Mycoplasma infection.24 Serum IgA is increased and rheumatoid factor positivity is often observed.

In many patients with chronic airway infection, genetic predisposition is additionally involved in the functional impairment of the upper and lower airways. Cystic fibrosis, primary ciliary dyskinesia and IgG subclass deficiency are typical examples of the role of genetic factors in the development and progression of such disease phenotypes.25,26 In these genetic disorders, it is likely that airway mucosal defence mechanisms are more or less damaged. Previous studies have suggested that diffuse panbronchiolitis is also strongly influenced by host genetic factors, although it is not a simple Mendelian genetic disease. In this review article, we summarize the genetic predisposition to diffuse panbronchiolitis, the mysterious Eastern disease, through an overview of the research history in this field.

GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

The cause of diffuse panbronchiolitis is still unknown, although it is reasonable to assume that interactions between environmental factors and genetic susceptibility contribute to the development of the disease. The evidence for genetic predisposition comes from the following observations. The disease is reported mainly in patients living in East Asian countries, including Japan, Korea27 and China.28,29 In Western countries, the disease is rare and reports from those countries often relate to immigrants from Asian countries.25,26 Therefore, researchers have hypothesized that genetic variations in Asian populations may be involved in the development of the disease. Familial cases have also been described in domestic records from Japan, although these have not been reported in international journals.

ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

Human leukocyte antigen (HLA) was identified in 1958. Humans recognize ‘self’ through HLA class I molecules on the surface of their cells. Initiation of adaptive immunity through presentation of foreign antigens is facilitated by HLA class II molecules on the antigen presenting cells.30,31 Because of these vital roles, HLA molecules have been investigated extensively in infection, inflammation, autoimmunity and transplantation medicine.32

The human MHC spans 3600 kb on the short arm of chromosome 6 (6p21.3) and contains the classical class I (HLA-A, B and C) and class II (HLA-DR, DQ and DP) genes, as well as many other genes that contribute to immune and inflammatory reactions. Entire nucleotide sequences of the MHC region were determined in 1999,33 and variations carrying different HLA haplotypes of European descent were also reported in 2008.34 These studies demonstrated that HLA genes are remarkably rich in genetic polymorphisms, and that a number of immune-related genes are densely packed in the MHC region, which appears to be relevant to many disease processes.35 The MHC region is also characterized by strong and wide linkage disequilibrium, in which a set of genetic variations is preserved in the region of interest, mostly unchanged through generations, without chromosomal recombination. This characteristic causes difficulties in statistically identifying a single responsible gene using conventional genetic association analysis.36

A relationship between diffuse panbronchiolitis and HLA was first reported by Sugiyama et al.37 They recruited 38 patients, and by analysing serological typing of HLA class I antigens, showed that HLA-B54 (formerly HLA-Bw54) antigens were more frequently observed in the disease group than in a control group. HLA-B54 antigens are known to distribute in East Asians, including Japanese, Koreans and Chinese.38 This provided the first clue as to why this disease is mostly seen in East Asians (http://pypop.org/popdata/2008/maps/B-5401.gif). Later, we confirmed this association in 76 patients; 36.8% of the Japanese patients carried HLA-B54 (HLA-B*5401 by DNA typing), whereas only 14.6% of the control subjects carried this antigen.39 Another rare allele, HLA-B*5504, was also identified during the HLA genotyping. Therefore, we can conclude that diffuse panbronchiolitis is a lung disease that is strongly associated with an HLA class I gene, and it is likely that both HLA-B*5401 and HLA-B*5504 confer susceptibility to diffuse panbronchiolitis in Japanese subjects.

This finding suggests two possibilities about the pathogenesis of the disease; the first is that the distinctive molecular structure of HLA class I alleles (HLA-B*5401 in Japanese) is crucial. In this case, CD8+ T cells that recognize pathogen-derived peptides through the particular HLA-B molecules may cross-react with tissue-specific peptides with a sequence motif similar to the exogenous peptides, and induce chronic inflammation at sites of disease, although we have no definitive evidence to support this hypothesis. The second possibility is that another gene closely linked to the HLA-B gene contributes to genetic predisposition to diffuse panbronchiolitis. Interestingly, clinical characteristics and treatment response were similar, irrespective of whether the patients carried HLA-B54.39,40 This may support the possible influence of another gene rather than a direct effect of HLA-B54. Furthermore, reports on other East Asian patients did not demonstrate a clear association between the disease and HLA-B54. Tsang et al. reported that none of seven patients in Hong Kong carried HLA-B54.29 Park et al. in Korea reported that HLA-B54 antigens were present in only 13.3% of 30 patients, which was not different to the control population (12.5%).41 She et al. investigated 24 patients in Shanghai and showed no association with HLA-B antigens.42 Because of the rarity of the disease, the sample size in each study was rather small, and it is difficult to draw a definitive conclusion from these reports. Nevertheless, it was notable that the association with HLA-B antigens has not been confirmed in non-Japanese Asian populations. Interestingly Park et al. reported a strong association with HLA-A11.41 The report from Shanghai was also consistent with an association with HLA-A11.42

These findings raised the attractive hypothesis that one of the disease susceptibility genes is located between the HLA-A locus and the HLA-B locus. The importance of an HLA-A11-B54 haplotype (a set of alleles on a single chromosome) in East Asians should be considered. A mutation that determines disease susceptibility may have occurred on a common ancestral chromosome carrying HLA-B54 and HLA-A11.39 In Japanese, after many generations, recombination occurred mainly between HLA-A and the disease loci in the class I region, and subsequently the mutation may have been retained with HLA-B54. In Koreans, however, recombination may have resulted in the separation of HLA-B from the disease loci in the class I region, and HLA-A11 has probably been retained with the mutation. A schematic diagram of this hypothesis is shown in Figure 2. The similar genetic background of Japanese and Koreans should be considered when investigating similarities and differences in the distribution of HLA types in these two populations.

image

Figure 2. A hypothesis that may explain the findings that diffuse panbronchiolitis is associated with different HLA types in Japanese and Koreans. A disease susceptibility gene may be located between HLA-A locus and the HLA-B locus (see text for details).

Download figure to PowerPoint

Narrowing down the candidate region for the disease susceptibility gene

Based on the above hypothesis, we attempted to narrow down the candidate region for the disease susceptibility gene in the HLA class I region.43 Fourteen genetic markers between the HLA-A and HLA-B loci, spanning around 1400 kb, were first characterized and genotyped. The haplotypes and association with the disease were then analysed. A common segment shared by disease haplotypes was identified in this study, and a marker showing the strongest association was identified within this segment. We therefore estimated that there is a 200-kb candidate region for the disease susceptibility gene, 300 kb distant from the HLA-B locus in the direction of the HLA-A locus on human chromosome 6.

A series of these studies on genetic predisposition to diffuse panbronchiolitis were summarized and registered as MIM604809 in the public database, Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/604809).

Mucin-like genes and polymorphisms in the candidate region

Fine mapping of the 200-kb region described previously was also attempted in our laboratory. There were originally very few known genes in this region. For this reason, exon-like structures were first predicted using a gene prediction computer program and more than 100 single nucleotide polymorphisms were then identified within the predicted exons and exon-intron boundaries. Using these genetic markers, the linkage disequilibrium structure was next analysed. As a result, strong linkage disequilibrium was demonstrated within 80 kb of the 200-kb region (Fig. 3). Markers showing a strong association with the disease were also located in the 80-kb region. Thus, new genes were cloned and designated panbronchiolitis-related mucin-like 1 and 2 (PBMUCL1 and PBMUCL2);44 these consisted of a mucin-like gene cluster together with two adjacent genes, MUC21 and DPCR1.45,46 Two mucin gene clusters have already been identified in the human genome.47 As far as we know, this is the third mucin or mucin-like gene cluster identified in humans (Fig. 4). Genetic polymorphisms that were associated with diffuse panbronchiolitis were identified in PBMUCL1. Despite the strong association with HLA-B in Japanese, it is conceivable that the mucin-like gene, PBMUCL1, is also one of the candidate genes for disease susceptibility.44 These mucin-like genes were not identified on the basis of pathogenesis, but from information on the possible location of the susceptibility genes. The significance of these genes is therefore still unclear and further investigation is necessary to link the disease with these genes.

image

Figure 3. Linkage disequilibrium pattern of the HLA class I candidate region for susceptibility to diffuse panbronchiolitis in the Japanese population. D prime, one of the linkage disequilibrium parameters, was calculated and visualized using the Haploview program (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview). Single nucleotide polymorphisms with minor allele frequencies >0.01 are shown. Strong linkage disequilibrium structure (black inverted triangle on the right side) is observed throughout 80 kb of the 200-kb region. Genetic markers showing a strong association with the disease were also located in this region.

Download figure to PowerPoint

image

Figure 4. A novel mucin or mucin-like gene cluster in the HLA class I region on the short arm of chromosome 6 (6p21.3), members of which showed associations with diffuse panbronchiolitis. DPCR1, MUC21, PBMUCL1 and PBMUCL2 are all mucin or mucin-like genes.

Download figure to PowerPoint

Classical mucin genes and diffuse panbronchiolitis

Cloning of mucin-like genes raised the possibility that classical mucin genes might also be involved in the pathogenesis of diffuse panbronchiolitis. Excessive airway mucus secretion in this disease is another reason why mucin or mucin-like genes have been investigated as disease-related target genes.

Mucins are high MW glycoproteins secreted from epithelial cells or glands. The core proteins of mucins consist of repetitive sequences rich in proline, threonine and serine residues that, characteristically, are bound to O-linked sugar chains.48 To date, more than 20 mucin genes have been identified. In the lung and bronchus, at least, expression of nine mucin genes (MUC1, 2, 3, 4, 5AC, 5B, 7, 8 and 13) has been confirmed.49 MUC1 and MUC4 are expressed in ciliated epithelial cells as membrane-associated mucins; MUC5AC in goblet cells, MUC5B in mucous cells and MUC7 in serous cells of the bronchial glands, are secreted as gel-forming mucins.

Optimal mucus secretion is necessary to protect the airways both mechanically and biochemically. For example, mucins are rich in sugar chains and trap some viruses inside the mucin gel before they reach and infect the surface epithelial cells.50 Despite this protective role, excessive mucus secretion may clog the airways and impair ventilation. Dysregulation of mucus production may also interrupt mucociliary transport, resulting in frequent infection of the mucosal surface of the airways. Overexpression of mucin genes is therefore likely to be associated with chronic airway inflammation.

Based on this background, regulatory polymorphisms in six airway mucin genes were analysed in patients with diffuse panbronchiolitis.18 A functional insertion/deletion polymorphism was identified in the regulatory region of the MUC5B gene; this deletion allele showed a negative association with the disease (Fig. 5). The segment that included the deletion allele showed lower transcriptional activity than other segments, by luciferase assay. These findings suggested that the deletion allele may protect the airways of patients with the disease from mucus hypersecretion, through downregulation of MUC5B expression. Expression of MUC5B is normally limited to submucosal glands. However, in the disease state of chronic airway inflammation, MUC5B may also be aberrantly expressed on the surface of the airway mucosa. MUC5AC was coexpressed in airway epithelial cells with goblet cell hyperplasia. This phenomenon has also been reported in the upper airways.51 In healthy individuals, MUC5AC is expressed on the surface of sinus epithelial cells and MUC5B is localized in submucosal glands. In contrast, in inflammatory tissues, MUC5B was expressed in the sinus epithelial cells, as well as in submucosal glandular cells.

image

Figure 5. Distribution of functional insertion/deletion polymorphism in the MUC5B gene was statistically different between control subjects (n = 128) and patients with diffuse panbronchiolitis (n = 92). The deletion allele was less frequently observed in the patients.18 Genotype: (inline image) II; (inline image) ID; (inline image) DD. DD, deletion and deletion; ID, insertion and deletion; II, insertion and insertion.

Download figure to PowerPoint

It is therefore likely that the mechanism regulating mucin expression is rather different under normal compared with chronic inflammatory conditions. Although MUC5AC is known to be an airway mucin and has been extensively investigated,52,53 MUC5B may also have a crucial role in the inflammatory state. Regulatory polymorphisms in the MUC5B gene may therefore modify the excessive mucus secretion that is characteristic of diffuse panbronchiolitis.

HLA class I deficiency

HLA class I deficiency is a very rare Mendelian genetic disease also known as bare lymphocyte syndrome type I. We treated a 51-year-old female patient with this rare autosomal recessive inherited disorder. In her case, the genetic defect was apparently caused by consanguineous marriage. Her clinical profile was previously reported by Maeda et al.54

Since childhood, she had presented with symptoms of sinobronchial syndrome. H. influenzae had been detected in her sputum. Chronic cough, purulent sputum, complication of chronic sinusitis, diffuse small nodular shadows on CXR, abnormal lung sounds, impaired lung function and an elevated titre of cold haemagglutinin were all typical signs and symptoms of diffuse panbronchiolitis. She was treated with 600 mg of erythromycin, according to a standard therapeutic regimen for diffuse panbronchiolitis, and within a few months, cough and sputum had decreased remarkably and alleviation of hypoxaemia and improvement in pulmonary function were also observed.55 In other words, the clinical profile and response to treatment in this patient were quite similar to those of patients with diffuse panbronchiolitis. For these reasons, HLA class I antigen types have been intensively studied by these researchers. Surprisingly, in this patient, all class I molecules were barely detectable on blood cells using conventional serological methods, and the diagnosis of bare lymphocyte syndrome type I was confirmed.

Bare lymphocyte syndrome type I is caused by a defect in the antigen presenting system through HLA class I molecules. The class I molecules themselves are synthesized normally, whereas their expression on the cell surface is markedly downregulated. Consequently HLA class I antigens cannot be detected by routine serological typing methods. In 1994, de la Salle et al. reported a homozygous defect in the TAP2 gene in patients with HLA class I deficiency.56,57 Interestingly these patients also had chronic sinusitis and bronchial inflammation, similar to the present case.

In general, during the course of antigen presentation, fragmented antigens enter the endoplasmic reticulum through antigenic peptide transporters, TAP1/TAP2, and encounter class I molecules and β-2 microglobulin therein. The molecular complex generated there is transported further and presented on the cell surface. If either TAP1 or TAP2 is defective, the heterodimer of TAP molecules does not function and antigenic peptides are not correctly transported to the endoplasmic reticulum. As a result, most class I molecules do not bind to antigenic peptides, are unstably located on the cell surface and are barely detected by routine serological methods.

The present patient was found to be homozygous for a single nucleotide substitution in the splice acceptor site of the first intron of the TAP1 gene. A frame shift due to this mutation was found to be the cause of a functionally deficient TAP1 molecule.58 Although a causative mutation for this disease was thus clearly demonstrated, it remains unknown why the disease resembles diffuse panbronchiolitis in phenotype and why macrolide treatment was so effective. Further investigation is necessary to identify the common mechanism by which the phenotype of sinobronchial syndrome occurs in diffuse panbronchiolitis and HLA class I deficiency.

CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

Cystic fibrosis is mainly observed in European descendants and shows a marked contrast in geographical distribution compared with diffuse panbronchiolitis.25 Cystic fibrosis is caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, located on the long arm of chromosome 7 (7q31). CFTR ΔF508 is the predominant mutation observed in patients of European descent. Historically, this mutation presumably occurred after Europeans had separated from Asians.59,60 This founder effect explains the high prevalence of cystic fibrosis among Europeans and its rarity in Asians. A similar effect has been proposed for Asians, in the case of diffuse panbronchiolitis, although it does not follow a Mendelian mode of inheritance, but is multifactorial genetic disease, suggesting that the contribution of each responsible gene to diffuse panbronchiolitis is not large. The CFTR ΔF508 mutation has not been reported in patients with diffuse panbronchiolitis.61

The CFTR deletion impairs mucociliary clearance, compromising the airway microenvironment, and leading to a progressive cycle of infection and inflammation, and possibly, chronic respiratory disease.62,63 The poly-T and TG repeats in intron 8 (IVS8) are the CFTR polymorphisms commonly found even in Asians, and cause abnormal RNA splicing in the CFTR gene.64,65 It is conceivable that such variations may have relevance to lung disease in Asians,66,67 although the incidence of classical cystic fibrosis is very low in many Asian populations. We also tested this hypothesis and showed that there was a significantly higher frequency of the T5 allele (containing five thymine residues) of poly-T in intron 8, in patients with pulmonary Mycobacterium avium complex infection compared with healthy control subjects.68 All T5 alleles were associated with longer TG repeats (TG12 or TG13 allele). Thus, polymorphic CFTR alleles may, at least in part, be involved in susceptibility to chronic airway infection among Asians, and we cannot exclude the possibility that accumulation of other minor mutations of the CFTR gene may account for diffuse panbronchiolitis in a small proportion of patients, or that they modify the phenotype or severity of the disease (M. Hijikata, 2011, unpubl. obs.).

CONCLUSIONS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

Nearly four decades have passed since diffuse panbronchiolitis was first described in Japan. Although neither environmental factors nor infectious agents specific to the disease have been demonstrated so far, studies on the aetiology of the disease have progressed in the context of the unique genetic predisposition of Asians. Diffuse panbronchiolitis is a complex genetic disease affecting East Asians, and is strongly associated with class I HLA-B54 in Japan and HLA-A11 in Korea. Based on the hypothesis that one of the major susceptibility genes for diffuse panbronchiolitis is probably located within a 200-kb segment in the class I region, 300 kb telomeric of the HLA-B locus on chromosome 6p21.3, we have cloned novel mucin-like genes in the candidate region. Together with newly found genes, HLA class I genes themselves and other mucin genes may also partly influence development of the disease. The functional significance of each candidate gene will be further delineated by in vitro studies.

Different mechanisms of pathogenesis resulting from different genetic or environmental backgrounds may lead to similar phenotypes of disease, as well as treatment responses, that are difficult to distinguish from the original type of diffuse panbronchiolitis. These factors should especially be considered when diffuse panbronchiolitis is reported in non-Asian patients.

Although the advent of macrolide therapy has strikingly improved the prognosis of patients with diffuse panbronchiolitis, we still do not know the true mechanism underlying the effectiveness of macrolides. We hope that our genetic approaches will also be helpful in elucidating the key molecules associated with pharmacological mechanisms, as well as the design of novel anti-inflammatory drugs to relieve chronic airway inflammation and protect the airways from harmful pathogens.

ACKNOWLEDGEMENTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES

This work was partly supported by a grant to the National Center for Global Health and Medicine and by a grant to the Diffuse Lung Diseases Research Group from the Ministry of Health, Labour and Welfare, Japan.

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. PATHOGENESIS OF DIFFUSE PANBRONCHIOLITIS
  5. GENETIC PREDISPOSITION TO DIFFUSE PANBRONCHIOLITIS
  6. ASSOCIATION WITH HUMAN LEUKOCYTE ANTIGEN
  7. CYSTIC FIBROSIS AND DIFFUSE PANBRONCHIOLITIS
  8. CONCLUSIONS
  9. ACKNOWLEDGEMENTS
  10. REFERENCES