RESUMO
A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X-Pro and X-Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD.
Assuntos
Aminopeptidases/imunologia , Síndrome de Behçet/imunologia , Antígeno HLA-B51/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Peptídeos/imunologia , Polimorfismo Genético/imunologia , Aminopeptidases/genética , Síndrome de Behçet/genética , Linhagem Celular , Antígeno HLA-B51/genética , Humanos , Células Matadoras Naturais/imunologia , Antígenos de Histocompatibilidade Menor/genética , Peptídeos/genética , Domínios Proteicos , Linfócitos T/imunologiaRESUMO
The red cell acid phosphatase (ACP1) gene, which encodes a low-molecular-weight phosphotyrosine phosphatase, has been suggested as a common genetic factor of autoimmunity. In the present study, we aim to investigate the possible association of ACP1 with the susceptibility of systemic lupus erythematosus (SLE). A total of 1,546 SLE patients and 1,947 healthy individuals from 4 Caucasians populations were included in the present study. Four single-nucleotide polymorphisms (SNPs) were genotyped in this study: rs10167992, rs11553742, rs7576247, and rs3828329. ACP1*A, ACP1*B, and ACP1*C codominant ACP1 alleles were determined using 2 of the SNPs and analyzed. After the meta-analysis test was performed, a significant association of rs11553742*T was observed (p(pooled) = 0.005, odds ratios = 1.37 [1.10-1.70]), retaining significance after multiple testing was applied (p(FDR) = 0.019). Our data indicate for first time the association of rs11553742*T with increased susceptibility in SLE patients.
Assuntos
Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Alelos , Argentina , Estudos de Coortes , Frequência do Gene , Genótipo , Alemanha , Haplótipos , Humanos , Itália , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/etnologia , Razão de Chances , Espanha , População Branca/genéticaRESUMO
The vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic mediators related to inflammation-associated synovial angiogenesis. The aim of this study was to asses the role of -1154 G-->A (rs1570360) and -634 G-->C (rs2010963) VEGF gene functional variants with rheumatoid arthritis (RA). The population under study was composed of a total of 753 unrelated RA patients and 801 healthy controls. The VEGF -1154 G-->A and -634 G-->C polymorphism genotyping was performed by real-time polymerase chain reaction technology, using TaqMan 5' allelic discrimination assay. No evidence of association was observed between the -1154 G-->A and the -634 G-->C VEGF polymorphisms, or inferred VEGF haplotypes with RA susceptibility or clinical manifestations. Our results suggest that the analyzed VEGF promoter polymorphisms may not play a relevant role in RA pathogenesis in our population.
Assuntos
Artrite Reumatoide/genética , Polimorfismo Genético/genética , Fator A de Crescimento do Endotélio Vascular/genética , Alelos , Artrite Reumatoide/metabolismo , DNA/metabolismo , Predisposição Genética para Doença/genética , Humanos , Fator Reumatoide/genética , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
BACKGROUND: The role of human leukocyte antigen (HLA)-DPB1 as a transplantation antigen is controversial. A higher incidence of acute graft-versus-host disease (aGVHD) has been described after unrelated donor bone marrow transplant when both HLA-DPB1 alleles were mismatched. METHODS: We investigated the impact of a single HLA-DPB1 mismatch after HLA-A-B-DRB1 identical sibling donor transplantation on aGVHD. We analyzed 627 adult patient-donor pairs and identified 30 pairs without HLA-DPB1 identity (4.78%). In 17 cases, the patient had an allele that was not shared by the donor. RESULTS: The cumulative incidence of grades II-IV aGVHD was higher in the HLA-DPB1 mismatched group (66.7% vs. 35.7%, p=0.012). The HLA-DPB1 mismatch was identified by multivariate analysis as an independent risk factor for aGVHD (p=0.020, RR=2.68, 95% CI: 1.73-3.62). CONCLUSIONS: HLA-DPB1 can mediate alloreactive responses. A single HLA-DPB1 mismatch increases the risk of aGVHD after sibling donor stem cell transplantation.