Background
Anti-glomerular basement membrane (GBM) disease, defined by the presence of autoantibodies in the circulation against α3 chain non-collagen 1 domain of type IV collagen [α3(IV)NC1] [
1], is a severe autoimmune disease. It manifests as rapidly progressive glomerulonephritis; when accompanied by alveolar hemorrhage, it is termed Goodpasture's disease.
Human leukocyte antigen (HLA) alleles, located on the short arm of chromosome 6, have been well known to be associated with most autoimmune diseases [
2]. HLA genes encode numerous molecules including the HLA class I and II molecules, which have immunological functions. It was reported that anti-GBM disease was positively associated with HLA-DRB1*1501 and negatively associated with HLA-DRB1*07 in Caucasian population [
3]. In Asian populations, HLA-DRB1*1501 was also considered as a risk allele for Japanese [
4] and Chinese patients [
5]. These data suggested that HLA-DRB1*1501 is a common risk allele for anti-GBM disease in various populations. However, the association of anti-GBM disease and HLA class II genes, including HLA-DRB1, -DQB1, -DQA1, and -DPB1 alleles, has rarely been investigated in Asian, especially Chinese patients [
4,
5]. Since our previous study has located the risk allele of HLA-DRB1 [
5], to better understand the genetic background of this disease and prepare for the study at the level of peptide, in the current study, we further investigated the distribution and clinical association of HLA-DQB1, -DQA1 and -DPB1. Moreover, we tried to locate the potential risk amino acid residues of anti-GBM disease.
Discussion
The current study analyzed the distribution of HLA class II alleles in patients with anti-GBM disease and their potential significance. For HLA class II loci, HLA-DRB1 and -DPB1 encode relatively more variable gene products for HLA-DR and -DP molecules respectively, while both HLA-DQB1 and -DQA1 are variable in human population. Besides, previous studies have located some HLA-DRB1, -DQB1 and -DPB1 alleles with association with anti-GBM disease in Caucasian as well as Asian population [
5,
11,
12]. But in Chinese patients, few studies have been done in this topic [
5]. Therefore, we choose to type HLA-DQB1, -DQA1 and -DPB1 loci in this study, on the basis of our previous study on HLA-DRB1 [
5].
Our typing results indicated that HLA-DPB1*0401 might be non-predisposing on anti-GBM disease. We stratified by the presence of DPB1*0401 on patients with anti-GBM disease and tried to investigate how this allele has its protective influence on clinical and pathological characteristics of patients. However, we found that patients with HLA-DPB1*0401 were younger and were more likely to have hemoptysis. Since there were only three patients with positive HLA-DRB1*0401, larger sample size is needed to investigate the association between this allele and the disease.
Our previous study [
5] has located HLA-DRB1*1501 as a risky allele to anti-GBM disease in the same population. When we analyzed the combined presence of DRB1*1501 and absence of DPB1*0401, we found this combination had an even higher risk to anti-GBM disease (p = 2.0 × 10
-12) than HLA-DRB1*1501 alone (p = 1.6 × 10
-7). To further investigate how these alleles have their influence on disease, we used SKDM software to evaluate their productions at amino acid level. However, no amino acid with significant difference was found by this evaluation. Since little is known about the relation between HLA-DP and HLA-DR, it is difficult to know how these two alleles interact with each other on molecular level in the pathogenesis of anti-GBM disease.
Previous studies have focused on association between HLA-DR and -DQ genes and their haplotype with anti-GBM disease [
3,
11,
12]. The single allele DQB1*0302, haplotypes DQB1*0602-DRB1*1501 and DQB1*0201-DRB1*0301 were identified as risk alleles [
3,
11,
12], while HLA-DQB1*0501 was considered as a protective allele [
3,
12]. However, these potential associations were not observed in our study. Actually, no HLA-DQ allele was found to be significantly associated with patients with anti-GBM disease in our study.
HLA class II alleles have been demonstrated a connection with many autoimmune diseases [
13‐
15]. Nevertheless the mechanism underneath is still unknown. HLA association in anti-GBM disease is believed to reflect the ability of certain class II molecules to bind and present peptides derived from the autoantigen to T helper cells[
12]. Although at amino acid level, our study showed no significance, theories from other studies may offer us some clues. As far as we have known, the strong positive association with DRB1*1501 [
4,
5,
11,
12] as well as negative associations with DRB1*01 and DRB1*07 [
3] were found [
12,
16,
17] in many studies. According to above findings, Phelps et al. [
17] suggested that DR1/7 (encoded by DRB1*01/07) could protect by capturing α3(IV)NC1 peptides and preventing their display bound to DR15. Judging from this, we speculate that the similar protective mechanism might happen to HLA-DPB1*0401. We suppose that the beta chain of HLA-DP produced by DPB1*0401 prevents peptide such as α3(IV)NC1 from binding DR15, which leads to the disease. Nonetheless, the exact mechanism requires further research to confirm.
Conclusions
In conclusion, HLA-DPB1*0401 might be a protective allele to anti-GBM disease in Chinese patients. The combined presence of DRB1*1501 and absence of DPB1*0401 might have an even higher risk to anti-GBM disease than HLA-DRB1*1501 alone.
Acknowledgements
We are very grateful to by Dr. Ji-Chuan Liu, Ping Hou, Xin Zheng, and Ying Zhang for technique support. The study was supported by a grant from the National Science Foundation for Distinguished Young Scholars (No.30725034) and a grant of the National Natural Science Fund (No.30972733).
Authors' contributions
HL collected samples, carried out the study, analyzed the data and drafted the manuscript. MC designed and directed the study, drafted and revised the manuscript. CZ collected samples and clinical and pathological data. RY helped to draft the manuscript. PCX and XJZ helped to draft the manuscript and perform the statistical analysis. MHZ participated the designing and direction. All authors read and approved the final manuscript.