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NDT Advance Access published online on April 15, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn179
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The HLA-DRB1*1501 allele is prevalent among Japanese patients with anti-glomerular basement membrane antibody-mediated disease

Wataru Kitagawa1, Hirokazu Imai1, Atsushi Komatsuda1, Nobuki Maki1, Hideki Wakui2, Yoshiyuki Hiki3 and Satoshi Sugiyama3

1 Department of Internal Medicine, Division of Nephrology and Rheumatology, Aichi Medical University School of Medicine, Aichi 480-1195 2 Third Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita City, Akita 010-8543 3 Department of Medicine, Division of Nephrology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan

Correspondence and offprint requests to: Hirokazu Imai, Nephrology and Rheumatology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan. Tel: +81-561-62-3311; Fax: +81-561-62-6694; E-mail: imaihiro{at}aichi-med-u.ac.jp



   Abstract
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 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Purpose. We aimed to clarify the relationship between HLA-DRB1*1501 and anti-glomerular basement membrane (GBM) antibody-mediated disease in Japanese patients.

Materials and methods. Samples were collected from 16 anti-GBM antibody-positive patients who were admitted to our department or related hospitals from December 1990 to October 2005. We analysed clinical and laboratory data, kidney biopsy findings, and the HLA-DR phenotypes and HLA-DRB1 alleles of the patients.

Results. Among the 16 patients, 15 had HLA-DR15 [the phenotype frequency (PF) was 93.8%], 7 were positive for DR4 (the PF was 43.8%) and 5 were positive for DR9 (the PF was 31.3%). The allele frequency of HLA-DRB1*1501 was 46.4% (13/28), which was significantly different from Japanese controls (11.6%) (P < 0.001). In contrast, the frequency of HLA-DRB1*1502 was not different from controls (0/28). The odds ratio of HLA-DRB1*1501 in these patients was 6.4 (95% CI: 2.4–16.5).

Conclusion. The present study demonstrated that Japanese patients with anti-GBM antibody-mediated disease are very likely to carry the HLA-DRB1*1501 but not the HLA-DRB1*1502 allele.

Keywords: anti-glomerular basement membrane antibody; Goodpasture's disease; HLA-DR15; HLA-DRB1*1501



   Introduction
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 Abstract
 Introduction
Materials and methods
 Results
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Human leukocyte antigen (HLA), which plays an important role in immune responses, consists of the class I and class II molecules. Class I molecules, which are composed of a heavy chain encoded by the HLA-A, HLA-B or HLA-C genes and a light chain such as β2-microglobulin, react with peptides that are 8 or 9 amino acids in length. Class II molecules, including the DR ({alpha} chain encoded by DRA and β chain encoded by DRB), DQ (DQA and DQB) and DP (DPA and DPB) subtypes, bind to peptides ~15 amino acids in length. Class II molecules, expressed on antigen-presenting cells, contribute to the production of specific antibodies.

Anti-glomerular basement membrane (GBM) antibodies, which are found in individuals with crescentic glomerulonephritis or Goodpasture's disease, react with the type IV collagen {alpha}3 NC1 domain [{alpha}3(IV)NC1]. Although the relationship between anti-GBM antibodies and HLA-DR15 has been examined in Caucasians [1–7], there are no data examining HLA phenotypes and genotypes of patients with anti-GBM antibody-mediated disease in Japan or other areas of Asia. The present study was designed to clarify the importance of the HLA DR 15 and HLA-DRB1 alleles in Japanese patients with anti-GBMantibody-mediated disease.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Samples were collected from 16 patients admitted to our department or related hospitals from December 1990 to October 2005 that were positive for anti-GBM antibodies. We analysed clinical and laboratory data, kidney biopsy findings, and the HLA-DR haplotypes and genotypes after obtaining informed consent from each patient.

We used chi-square analysis with Yates’ correction to analyse allele frequencies of DRB1 in patients with anti-GBM antibody-mediated disease compared with Japanese controls (561 persons in 159 families) [8]. A value of P < 0.05 was considered to indicate statistical significance. The 95% confidence intervals (CI) for odds ratios were calculated according to the method of Woolf without correction.



   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Clinical and laboratory data

Gender, age and clinical symptoms of the patients
Clinical and laboratory data are shown in Table 1. There was no gender bias in the patient population (eight males and eight females). Average patient age was 60.6 years. Four of the 16 patients exhibited pulmonary symptoms, such as pulmonary haemorrhage or atypical pneumonia-like shadows upon lung examination. Case 12 showed a peculiar clinical course by showing increases in anti-GBM antibody titres following pauci-immune-type crescentic glomerulonephritis combined with interstitial damage [9].


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  		Table 1 Patient profiles and outcomes

 
Laboratory findings
Fourteen of the 16 patients presented with proteinuria and haematuria, whereas 2 patients showed anuria. As indicators of kidney function, average levels of blood urea nitrogen (BUN), serum creatinine and uric acid were 25.2 ± 16.1 mmol/L, 725 ± 530 µmol/L and 523 ± 202 µmol/L (mean ± SD), respectively.

Anti-GBM and anti-neutrophil cytoplasmic antibodies
Serum titres of anti-GBM antibodies were measured. Five patients had an anti-GBM antibody titre between 14 and 88 ELISA units (EU) (normal range: <10 EU), three patients showed values between 100 and 199 EU, one patient had a titer of 284 EU and seven patients had values >300 EU. The maximum titre detected among the diluted sera of the patients was 1694 EU. Four of the 16 patients had myeloperoxidase (MPO)-ANCA (anti-neutrophil cytoplasmic antibodies); the maximum detected level was 830 EU. None of the patients were proteinase 3-ANCA positive.

Pathology
Kidney tissues were obtained from 13 of the 16 patients. One of the 13 specimens was obtained at necropsy. Kidney biopsies were not obtained from the remaining 3 patients, each of whom had severe renal failure (BUN level > 35.7 mmol/L) and anuria.

(a) Light microscopic examination. In 6 of the 13 patients, 100% of the glomeruli exhibited crescentic formations, whereas 6, 3 and 2 patients had 80–97%, 40–69% and 20–29% of glomeruli showing crescentic formations, respectively. Seven of the 13 patients showed cellular crescents, 5 patients had fibrocellular crescents and 1 had fibrocrescents.

(b) Immunofluorescence analysis. Immunofluorescence analyses were performed on 12 of the 13 kidney tissue specimens. Eleven of these 12 cases showed strong linear IgG deposition along the basement membrane. In the previously discussed case (case 12), a lack of IgG or other immunoglobulin deposition suggested that the patient had pauci-immune-type or interstitial nephritis; however, serum titres of anti-GBM antibody were elevated, even when the patient was treated with prednisolone therapy [9]. We included this peculiar case because we were able to analyse the relationship between the presence of anti-GBM antibodies and the HLA phenotype and genotype of the patient. In addition to IgG, a strong deposition of IgA was found in 2 of the 12 cases, and a weak deposition was observed in another patient.

Patient prognoses
Two patients died and nine patients required dialysis in the 3 months following treatment. Three patients responded to the initial treatment and recovered normal kidney function. Two patients responded to initial therapy, but their kidney function later deteriorated. One patient was started on haemodialysis at 2 years after the onset of the disease. The initial treatment resulted in improvements for five of the cases who had initial serum creatinine levels of 53, 88, 115, 274 and 301 µmol/L, respectively.

Human leukocyte antigen
There was no relationship between HLA-A, HLA-B and the presence of anti-GBM antibodies (Table 2). The phenotype frequency (PF) of DR15 was 93.8% (15/16). Seven patients were positive for DR4 (the PF was 43.8%), five were positive for DR9 (PF was 31.3%), two were positive for DR13 and two were positive for DR14. One of the 16 patients showed an absence of HLA-DR15; however, this patient had DR4 combined with DR9.


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  		Table 2 HLA typing

 
For the HLA genotype, the allele frequency of HLA-DRB1*1501 was 46.4% (13/28). The allele frequency of HLA-DRB1*1501 was significantly different between patients with anti-GBM antibody-mediated diseases and Japanese controls (11.6%) (P < 0.001). Even though none of the patients had the HLA-DRB1*1502 allele, there was no difference in the frequency compared to Japanese controls (8.81%). The odds ratio for HLA-DRB1*1501 was 6.4 (95% CI: 2.4–16.5).



   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The present study showed in patients with anti-GBM antibody-mediated disease that the PF of HLA-DR15 was 93.8% (15/16), whereas the allele frequency of the HLA-DRB1*1501 was 46.6% (13/28).

Previous reports revealed that the PF of HLA-DR15 in anti-GBM antibody-positive Caucasian patients (versus controls) was 63.9% versus 26.8% in Australia [2], 92% versus 21.2% in France [3], 91% versus 19.6% in the USA [4] and 79% versus 28% in the UK [7]. The odds ratios of the PF from these studies were 4.8, 42, 43 and 8.3, respectively. The present study demonstrated that the allele HLA-DRB1*1501, but not HLA-DRB1*1502, strongly associated with anti-GBM antibody-mediated disease in Japanese patients, as has been observed in Caucasian patients from diverse backgrounds.

HLA-DR2 has been divided into HLA-DR15 and HLA-DR16. In addition, HLA-DR15 is known to have two genotypes: HLA-DRB1*1501 and HLA-DRB1*1502. The allele frequencies of DRB1*1501, DRB1*1502 and DRB1*1602 in Japanese controls are 11.6%, 8.91% and 0.78%, respectively. The only difference between DRB1*1501 and DRB1*1502 is located at the 86th amino acid in pocket 4; here, a valine residue in HLA-DRB1*1501 is substituted for a glycine residue in DRB1*1502 [10]. It is noteworthy that only HLA-DRB1*1501, but not HLA-DRB1*1502, was observed in the Japanese patients with anti-GBM antibody-mediated disease.

Previous work suggesting a relationship between HLA and kidney diseases showed that HLA-B8 and HLA-DR3 are strongly related to membranous nephropathy in Caucasian subjects [11–13]. Ogahara et al. [14], however, noted a high PF of HLA-DR2 in Japanese patients with membranous nephropathy. Tomura et al. [15] confirmed the high prevalence of DR2 in these patients (74% versus 30.4% for patients versus controls; odds ratio: 6.5) and revealed that the PFs of DR4, DRw8 (DR8) and DRw9 (DR9) in the patients were significantly lower than those in controls (16% versus 39.2%, 4.0% versus 25.9% and 4.0% versus 26.6%, respectively). Hiki et al. [16] reported similar results for patients versus controls (DR4: 18.0% versus 41.4%; DRw9: 2.0% versus 23.0%). Although the present study revealed that the HLA-DRB1*1501 allele is prevalent among Japanese patients with anti-GBM antibody-mediated disease, it is still unclear whether HLA-DRB1*1501, HLA-DRB1*1502 or HLA-DRB1*1602 is associated with membranous nephropathy in the Japanese population.

A study conducted by the Ministry of Health, Labour and Welfare of Japan estimated that the number of new patients in Japan with anti-GBM antibody-mediated glomerulonephritis is 10–20 patients per year [17]. If DRB1*1501 by itself determined the occurrence of anti-GBM antibody-mediated diseases, almost 12 million people in the Japanese population would be at risk for this rapidly progressive disorder. This discrepancy suggests that although DRB1*1501 is an important factor, it does not by itself determine the occurrence of anti-GBM antibody-mediated disease. Further studies will be required to reveal other important factors for anti-GBM antibody-mediated disease in Japanese patients.



   Acknowledgments
 
The authors would like to thank Dr Daijyo Inaguma (Department of Nephrology and Rheumatology, Tosei General Hospital), Dr Hiroaki Asada (Department of Nephrology, Okazaki City Hospital), Dr Mikito Tsuyuki (Department of Nephrology and Dialysis, Cyukyo Hospital) and Dr Kenichi Asakura (Department of Internal Medicine, Yuri General Hospital). This work was supported by a grant (to H.I.) from the Progressive Renal Diseases Research Project of the Ministry of Health, Labour and Welfare of Japan (Director: Dr Yasuhiko Tomino).

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Rees AJ, Peters DK, Compston DAS, et al. Strong association between HLA-DRw2 and antibody-mediated Goodpasture's syndrome. Lancet (1978) I:966–968.
  2. Dunkley H, Chapman JR, Burke J, et al. HLA-DR and DQ genotyping in anti-GBM disease. Dis Markers (1991) 9:249–256.[Web of Science][Medline]
  3. Mercier B, Bourbigot B, Raguenes O, et al. HLA class II typing of Goodpasture's syndrome affected patients. J Am Soc Nephrol (1992) 3:658. abstract.
  4. Huey B, McCormack K, Capper J, et al. Associations of HLA-DR and HLA-DQ types with anti-GBM nephritis by sequence specific oligonucleotide probe hybridization. Kidney Int (1993) 44:307–312.[Web of Science][Medline]
  5. Burns AP, Fisher M, Li P, et al. Molecular analysis of HLA class II genes in Goodpasture's disease. Q J Med (1995) 88:93–100.
  6. Phelps RG, Turner AN, Rees AJ. Direct identification of naturally processed autoantigen-derived peptides bound to HLA-DR15. J Biol Chem (1996) 271:18549–18553.[Abstract/Free Full Text]
  7. Fisher M, Pusey CD, Vaughan RW, et al. Susceptibility to Goodpasture's disease is strongly associated with HLA-DRB1 gene. Kidney Int (1997) 51:222–229.[Web of Science][Medline]
  8. Nakajima F, Nakamura J, Yokota T. Analysis of HLA haplotypes in Japanese, using high resolution allele typing. Major Histocompatibility Complex (2001) 8:1–32.
  9. Kitagawa W, Miura N, Yamada H, et al. The increase of antiglomerular basement membrane antibody following pauci-immune-type crescentic glomerulonephritis. Clin Exp Nephrol (2005) 9:69–73.[CrossRef][Medline]
  10. Phelps RG, Rees AJ. The HLA complex in Goodpasture's disease: a model for analyzing susceptibility to autoimmunity. Kidney Int (1999) 56:1638–1653.[CrossRef][Web of Science][Medline]
  11. Klouda PT, Manos J, Acheson EJ, et al. Strong association between idiopathic membranous nephropathy and HLA Dw3. Lancet (1979) ii:770–771.
  12. Muller GA, Muller C, Liebau G, et al. Strong association of idiopathic membranous nephropathy (IMN) with HLA-DR3 and MT2 without involvement of HLA-B18 and no association of BfF1. Tissue Antigens (1981) 17:332–337.[Web of Science][Medline]
  13. Sacks SH, Warner C, Campbell D, et al. Molecular mapping of the HLA class II region in HLA-DR3 associated idiopathic membranous nephropathy. Kidney Int (1993) 39:S13–S19. Suppl.
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  17. Hirayama K, Yamagata K, Koyama A. Advances in the treatment of progressive renal dysfunction: 1. Rapidly progressive glomerular nephritis Nippon Naika Gakkai Zasshi. (2004) 93:896–905.
Received for publication: 24. 1.07
Accepted in revised form: 6. 3.08


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