China is a relatively high endemic area of HBV infection, there are many HBV carriers, chronic hepatitis patients, cirrhosis and hepatocellular carcinoma patients caused by HBV infection, which cause heavy social burden. After the introduction of the HBV vaccine into the immunization program in China in 1992, the government administered free HBV vaccine to newborns to reduce the spread of HBV. At the same time, China has adopted a variety of methods to prevent and control HBV, strengthen the standardized management of HBV screening and medical treatment for blood donors, and effectively control iatrogenic HBV infection. All the above measures have significantly reduced the infection rate of new HBV infections, and the total HBV prevalence rate in China has dropped to 5.49% by 2015. Therefore, it is of great significance to study the infection mechanism of hepatitis B for the prevention and treatment of hepatitis B.
HLA-II genes play a key role in viral antigen presentation to mediate cellular and humoral immune responses. Since Kamatani and his colleagues did GWAS in large HBV infection cohort shown that HLA-DPB1 and related single nucleotide polymorphism rs9277535A/G are a strongly risk factors for persistent infection with hepatitis B virus. Thereafter, many researches focused on and successfully repeated the association between HLA-DPB1 and HBV infection and infection outcomes. they found that HLA-DPB1 *09:01 increased HBV susceptibility, DPB1*02:01 was not susceptible to HBV, and DPB1*02:01 was also associated with reduced risk of HBV progression to chronic HBV. Studies in American populations also found that the allele with the greatest risk of infection for HBV was DPB1*01:01, and the allele with the greatest protection against HBV infection was DPB1*04:01. Subsequently, the genotypes of DPB1 * 05:01, 09:01, and DPB1 * 02:01, 04:01, and 04:02 were again found to be susceptible to HBV in Japanese and Chinese populations. The studies also found that some DPB1 alleles and rs9277535G related to weak HBV vaccines response, low sensitive of HBV drug therapy, incidence of occult HBV infection, and also prone to hepatocellular carcinoma development. In our study, we found the strongly association between rs9277535 and HLA-DPB1 alleles and HBV infection susceptibility. We found the rs9277535A, HLA-DPB1*04:02 were protective factors for chronic HBV infection in this study population, the results were accordingly to previously. rs9277535G and HLA-DPB1*05:01 were significantly associated with HBV susceptibility in Sichuan Han population. Evidence reported here in suggests that HLA-DP have key role in HBV infection progression.
The influence of the HLA-DPB1 region on HBV recovery is due to levels of HLA-DPB1 expression and less likely to differences in the peptides presented by different HLA-DPB1 alleles. The HLA-DPB1 expression were significantly different rs9277535AA and rs9277535GG, the protect genotype 9277535AA has significantly lower HLA-DPB1 mRNA expression level compared than the risk genotype rs9277535GG in healthy controls, Thomas and his colleagues also demonstrated that rs9277534GG genotype, which confers susceptibility to HBV persistence with significantly higher levels of HLA-DP surface protein and transcript level expression in healthy donors, rs9277534GG have lower levels of HLA-DPB1 mRNA in HBV group, O’Brien had reported that rs9277535AA with higher HLA-DPB1 mRNA expression in liver associated with lower HBV odds ratios with chronic HBV, our study also get a similar result with HLA-DPB1 expression in PBMC. The HLA-DPB1*05:01 and DPB1*21:01 in HBV group showed significantly lower HLA-DPB1 mRNA expression levels compared to the healthy control groups. Previous research  observed that decreased expression levels of DPA1 and DPB1 mRNA were correlated with the HBV activation after 2 years of treatment with HBV drugs, the high expression of DPA1 mRNA was associated with lower HBV viral load . These results suggesting that the persistence HBV infection may influenced by differences HLA-DPB1 expression, lower HLA-DPB1 expression may lower the function of antigen peptide present, at last, decrease the immune response to HBV viral, resulting HBV persistence infection risks.
Studies also found that amino acids at position 84–87 of the second exon antigen presentation sequence of DPB1 had a complete linkage with the DPB1 alleles, and there were two major amino acids at position 84–87 with GGPA and DENA, through bioinformatics analysis found that the four amino acids is located at the groove contacting peptide residues pocket-1, can be caused different antigen presenting functions, at last, caused different immunity function to HBV infection. Class II HLA molecules expression on the surface of antigen-presenting cells, to combine with antigenic peptide to CD4 + T helper cells. The T cell paly a crucial role in HBV response in host immune response.
Usually, HLA class II molecules present exogenous antigen peptide, However, HLA-DP molecules with beta-chains encoding DPGly84 does not bind invariant chain (Ii) via the class II-associated invariant chain peptide (CLIP) region to constitutively present endogenous peptides. And processed by the proteasome and transported to the ER by the transporter associated with antigen processing (TAP). Therefore, DP84Gly can uniquely uses both class I and II antigen processing pathways to present peptides derived from intracellular and extracellular sources, DP84Asp has not such endogenous antigen presentation function. Therefore, this polymorphism has different functions in autoimmune, antiviral and tumor mechanisms through the different function of antigen presentation .
The DP84Gly genotype not only plays a unique antiviral function in adaptive immunity, but also as a ligand of NKp44 to activate NKT cells to play an antiviral role in natural immune function. Compared with healthy controls, NK cells in CHB patients show inhibitory phenotypes, in which the expression of activated receptors NKp44 and NKp46 are down-regulated. Whether the DP84Gly genotype can promote the spontaneous clearance of HBV by binding NKp44 to activated NK after HBV infection has not been studied.
HLA-DPB1 expression associated with HBV infection was not verified in Chinese population, to the best of our knowledge, this is the first research to investigate the HLA-DPB1 mRNA expression in different HLA-DPB1 alleles and SNPs alleles, and the association between mRNA expression and HBV infection. Further research should be clearly to verified the role of NK cells and CD4 + T cells in DP84Gly including DPB1*04:01, DPB1*04:02 DPB1*02:01 and DPB1*02:02 in HBV protection and clearance.