Dataset Information

Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint.

ABSTRACT: ACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within α-enolase_326-340 in the context of HLA-DRB1*04:01 and assessed the corresponding CD4⁺ T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated α-enolase_326-340 peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of α-enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry. The native and modified peptides take a completely conserved structural conformation within the peptide-binding cleft of HLA-DRB1*04:01. The citrulline residue-327 was located N-terminally, protruding towards TCRs. The frequencies of T cells recognizing native eno_326-340 were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno_326-340 was significantly elevated in synovial fluid compared to peripheral blood (3.6-fold, p = 0.0150). Additionally, citrulline-specific T cells with a memory phenotype were also significantly increased (1.6-fold, p = 0.0052) in synovial fluid compared to peripheral blood. The native T cell epitope confined within α-enolase_326-340 does not appear to lead to complete negative selection of cognate CD4⁺ T cells. In RA patient samples, only T cells recognizing the citrullinated version of α-enolase_326-340 were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance.

SUBMITTER: Pieper J

PROVIDER: S-EPMC8259322 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:We examined the blood concentrations of neutrophil gelatinase-associated lipocalin (NGAL) and citrullinated alpha enolase peptide-1 (CEP-1) antibody in sepsis patients to evaluate their potential diagnostic, classified and prognostic utility together with C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6).Sixty-nine patients admitted at the emergency department with sepsis were studied, on admission, their demographic and clinical information were recorded. Blood levels of CRP, PCT, IL-6, NGAL, and CEP-1 antibody were measured. Relationships between sequential [sepsis-related] organ failure assessment score and blood biomarkers, between acute physiology and chronic health evaluation II score and blood biomarkers were investigated. Additionally, the mutual correlation among CRP, PCT, IL-6, NGAL, and CEP-1 antibody were investigated. Diagnostic and predictive values for clinical outcomes for biomarkers were assessed by receiver operator characteristic curve.Sixty-nine participants (38 sepsis, 31 septic shock) were compared with 40 healthy controls. The levels of CRP, PCT, IL-6, and NGAL were significantly higher in sepsis patients ([59.49 ± 48.88]; 0.71, [0.13-11.72]; 60.46, [33.26-201.20]; 265.61, [185.79-500.96], respectively) compared with healthy controls ([2.05 ± 1.85]; 0.02, [0.02-0.03]; 12.08, [7.22-16.84]; 19.73, [7.66-34.39], respectively) (P < .001). CRP, PCT, IL-6, and NGAL had better discriminatory performance with an area under the receiver operator characteristic curve (AUC) of (0.98; 0.98; 0.90; 0.97, respectively), 95% confidence interval (CI) = ([0.95; 1.00]; [0.96; 1.00]; [0.84; 0.96]; [0.94; 1.00], respectively) (P < .001), with a cut off value of (8.02 mg/L [Se = 88.40%, Sp = 100.00%]; 0.06 ng/mL [Se = 94.20%, Sp = 75.00%]; 30.63 pg/mL [Se = 78.30%, Sp = 95.00%]; 95.72 ng/mL [Se = 99.00%, Sp = 92.00%], respectively). Between the sepsis group and septic shock group, PCT and NGAL were significantly higher in septic shock group (2.44, [0.49-20.36]; 294.65 [203.34-1262.47], respectively) compared with sepsis group (0.41, [0.11-2.63]; 219.94, [146.38-385.24], respectively) (P < .05). Between survivors group and nonsurvivors group, PCT was obviously elevated in nonsurvivors group (2.47, [0.70-12.49]) compare with survivors group (0.41, [0.11-8.16]) (P < .05), with an AUC of 0.69, 95% CI = (0.57; 0.81) (P < .05), while CEP-1 antibody was decreased in nonsurvivors group (14.03, [4.94-17.17]) contrast to survivors group (18.78, [8.08-39.72]) (P < .05), with an AUC of 0.67, 95% CI = (0.54; 0.80) (P < .05). Additionally, CEP-1 antibody demonstrated a negative correlation with either sequential [sepsis-related] organ failure assessment score (r = -0.31, P < .05) or PCT (r = -0.27, P < .05).As CRP, PCT, and IL-6, NGAL was valuable in sepsis diagnosis. With a classificatory value, PCT and NGAL correlated with the degree severity of sepsis. PCT and CEP-1 antibody were meaningful in sepsis prognosis. CEP-1 antibody may be a protective factor for sepsis.

Project description:BACKGROUND:A protein exhibiting more than one biochemical function is termed a moonlighting protein. Glycolytic enzymes are typical moonlighting proteins, and these enzymes control the infection of various viruses. Previously, we reported that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and alpha-enolase (ENO1) are incorporated into human immunodeficiency virus type 1 (HIV-1) particles from viral producer cells and suppress viral reverse transcription independently each other. However, it remains unclear whether these proteins expressed in viral target cells affect the early phase of HIV-1 replication. RESULTS:Here we show that the GAPDH expression level in viral target cells does not affect the early phase of HIV-1 replication, but ENO1 has a capacity to suppress viral integration in viral target cells. In contrast to GAPDH, suppression of ENO1 expression by RNA interference in the target cells increased viral infectivity, but had no effect on the expression levels of the HIV-1 receptors CD4, CCR5 and CXCR4 and on the level of HIV-1 entry. Quantitative analysis of HIV-1 reverse transcription products showed that the number of copies of the late products (R/gag) and two-long-terminal-repeat circular forms of viral cDNAs did not change but that of the integrated (Alu-gag) form increased. In contrast, overexpression of ENO1 in viral target cells decreased viral infectivity owing to the low viral integration efficiency. Results of subcellular fractionation experiments suggest that the HIV integration at the nucleus was negatively regulated by ENO1 localized in the nucleus. In addition, the overexpression of ENO1 in both viral producer cells and target cells most markedly suppressed the viral replication. CONCLUSIONS:These results indicate that ENO1 in the viral target cells prevents HIV-1 integration. Importantly, ENO1, but not GAPDH, has the bifunctional inhibitory activity against HIV-1 replication. The results provide and new insights into the function of ENO1 as a moonlighting protein in HIV-1 infection.

Dataset Information

Memory T cells specific to citrullinated α-enolase are enriched in the rheumatic joint.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets