RESUMEN
Helicobacter pylori (H. pylori) is associated with gastric inflammation and mucosal antibodies against its cytotoxin-associated gene A (CagA) are protective. Vaccine-elicited immunity against H. pylori requires MHC class II expression, indicating that CD4+ T cells are protective. We hypothesized that the HLA-DR genotypes in human populations include protective alleles that more effectively bind immunogenic CagA peptide fragments and susceptible alleles with an impaired capacity to present CagA peptides. We recruited patients (n = 170) admitted for gastroendoscopy procedures and performed high-resolution HLA-DRB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.2% positive) and H. pylori classified as positive or negative in gastric mucosal tissue slides (72.9% positive). Pearson Chi-square analysis revealed that H. pylori infection was significantly increased in DRB1*11:04-positive individuals (p = 0.027). Anti-CagA IgA was significantly decreased in DRB1*11:04 positive individuals (p = 0.041). In contrast, anti-CagA IgA was significantly increased in DRB1*03:01 positive individuals (p = 0.030). For these HLA-DRB1 alleles of interest, we utilized two in silico prediction methods to compare their capacity to present CagA peptides. Both methods predicted increased numbers of peptides for DRB1*03:01 than DRB1*11:04. In addition, both alleles preferred distinctively different CagA 15mer peptide sequences for high affinity binding. These observations suggest that DRB1*11:04 is a susceptible genotype with impaired CagA immunity, whereas DRB1*03:01 is a protective genotype that promotes enhanced CagA immunity.
Asunto(s)
Gastritis , Helicobacter pylori , Humanos , Helicobacter pylori/genética , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Cadenas HLA-DRB1/genética , Citotoxinas , Gastritis/genética , Genotipo , Péptidos/genética , Inmunoglobulina A/genéticaRESUMEN
Helicobacter pylori was reported as an important cause of gastritis, and gastric ulcers and CagA oncoprotein-producing H. pylori subgroups were blamed to increase the severity of gastritis. Disparities were reported in that the presence of serum anti-CagA IgA was not parallel with CagA-positive H. pylori cohabitation. We hypothesized that the HLA-DQA1 ~ DQB1 haplotypes in human populations include protective haplotypes that more effectively present immunogenic CagA peptides and susceptible haplotypes with an impaired capacity to present CagA peptides. We recruited patients (n = 201) admitted for gastroendoscopy procedures and performed high-resolution HLA-DQA1 and DQB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.0% positive), and H. pylori was classified as positive or negative in gastric mucosal tissue slides (72.6% positive). The HLA DQA1*05:05 allele (29.1%) and HLA DQB1*03:01 allele (32.8%) were found at the highest frequency among gastritis patients of Turkish descent. In HLA DQA1*05:05 ~ DQB1*03:01 double homozygous (7.3%) and heterozygous (40.7%) haplotype carriers, the presence of anti-CagA IgA decreased dramatically, the presence of H. pylori increased, and the presence of metaplasia followed a decreasing trend. The DQ protein encoded by HLA DQA1*05:05-DQ*03:01 showed a low binding affinity to the CagA peptide when binding capacity was analyzed by the NetMHCIIPan 4.0 prediction method. In conclusion, HLA DQA1 ~ DQB1 polymorphisms are crucial as host defense mechanisms against CagA H. pylori since antigen binding capacity plays a crucial role in anti-CagA IgA production.
