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PubMed_Structured_Abstracts

Id Subject Object Predicate Lexical cue
T1 172-1384 BACKGROUND denotes Despite much work over past decades, whether antigen-specific immune reactions occur in rheumatoid arthritis (RA) and to what extent such reactions are directed towards joint-specific autoantigens is still questionable. One strong indicator for antigenic involvement in RA is the fact that certain major histocompatibility complex (MHC) class II genotypes [human leucocyte antigen (HLA)-DR4 and HLA-DR1[ predispose for the development of the disease [1]. In the present report, collagen type II (CII) was studied as a putative autoantigen on the basis of both clinical and experimental data that show an increased frequency of antibodies to CII in RA patients [2-4] and that show that CII can induce experimental arthritis [5]. It is evident from the literature that RA peripheral blood mononuclear cells (PBMCs) respond poorly to antigenic stimulation [6-8], and in particular evidence for a partial tolerization to CII has been presented [9]. The strategy of the present work has accordingly been to reinvestigate T-cell reactivity to CII in RA patients, to relate it to the response to commonly used recall antigens and to analyze interferon (IFN)-gamma responses as an alternative to proliferative responses.
T2 1391-1598 OBJECTIVE denotes To study cellular immune reactivity to CII in patients with RA and in healthy control individuals and to correlate this reactivity to HLA class II genotypes and to the presence of antibodies to CII in serum.
T3 1608-2722 METHODS denotes Forty-five patients who met the 1987 American college of Rheumatology classification criteria for RA [10] and 25 healthy control individuals of similar age and sex were included. Twenty-six of these patients who had low levels of anti-CII in serum were randomly chosen, whereas 19 patients with high anti-CII levels were identified by enzyme-linked immunosorbent assay (ELISA)-screening of 400 RA sera. Heparinized blood was density gradient separated and PBMCs were cultured at 1 x 10(6)/ml in RPMI-10% fetal calf serum with or without antigenic stimulation: native or denatured CII (100 microgram/ml), killed influenza virus (Vaxigrip, Pasteur Merieux, Lyon, France; diluted 1:1000) or purified protein derivative (PPD; 10 microgram/ml). CII was heat-denatured in 56 degrees C for 30 min. Cell supernatants were collected after 7 days and IFN-gamma contents were analyzed using ELISA. HLA-DR and HLA-DQ genotyping was performed utilizing a polymerase chain reaction-based technique with sequence-specific oligonucleotide probe hybridization. Nonparametric statistical analyses were utilized throughout the study.
T4 2732-5641 RESULTS denotes PBMCs from both RA patients and healthy control individuals responded with IFN-gamma production to the same degree to stimulation with native and denatured CII (Fig. 1a), giving median stimulation indexes with native CII of 4.6 for RA patients and 5.4 for health control individuals, and with denatured CII of 2.9 for RA patients and 2.6 for healthy control individuals. RA patients with elevated levels of anti-CII had a weaker IFN-gamma response to both native and denatured CII that did healthy control individuals (P-).02 and 0.04, respectively). Stimulation with the standard recall antigens PPD and killed influenza virus yielded a median stimulation index with PPD of 10.0 for RA patients and 51.3 for healthy control individuals and with influenza of 12.3 for RA patients and 25.7 for healthy, control individuals. The RA patients displayed markedly lower responsiveness to both PPD and killed influenza virus than did healthy control individuals (Fig. 1b). IFN-gamma responses to all antigens were abrogated when coincubating with antibodies blocking MHC class II. The low response to PPD and killed influenza virus in RA patients relative to that of healthy control individuals reflects a general downregulation of antigen-induced responsiveness of T cells from RA patients [6-8]. That no difference between the RA group and the control group was recorded CII-induced IFN-gamma production therefore indicates that there may be an underlying increased responsiveness to CII in RA patients, which is obscured by the general downregulation of T-cell responsiveness in these patients. In order to address this possibility, we calculated the fraction between individual values for the CII-induced IFN-gamma production and the PPD-induced and killed influenza virus-induced IFN-gamma production and the PPD-induced and killed influenza virus-induced IFN-gamma production, and compared these fractions. A highly significant difference between the RA and health control groups was apparent after stimulation with both native CII and denatured CII when expressing the response as a fraction of that with PPD (Fig. 2a). Similar data were obtained using killed influenza virus-stimulated IFN-gamma values as the denominator (Fig. 2b).When comparing the compensated IFN-gamma response to denatured CII stimulation between RA patients with different HLA genotypes, highly significant differences were evident, with HLA-DRB1*0401 patients having greater CII responsiveness than patients who lacked this genotype (Fig. 3a). HLA-DQ8 positive patients also displayed a high responsiveness to CII as compared with HLA-DQ8 negative RA patients (Fig. 3b). These associations between the relative T-cell reactivity to denatured CII and HLA class II genotypes were not seen in healthy control individuals. Similar results were achieved using influenza as denominator (P = 0.02 for HLA-DRB1*0401 and P = 0.01 for HLA-DQ8).
T5 5654-6891 CONCLUSIONS denotes No reports have previously systematically taken the general T-cell hyporesponsiveness in RA into account when investigating specific T-cell responses in this disease. In order to address this issue we used the T-cell responses to PPD and killed influenza virus as reference antigens. This was made on the assumption that exposure to these antigens is similar in age-matched and sex-matched groups of RA patients and healthy control individuals. The concept of a general hyporesponsiveness in RA T cells has been documented in several previous reports, in which both nominal antigens [6,7,8] and mitogens [11,12,13] have been used. The fact that a similar functional downregulation in RA PBMCs was obtained with both PPD and killed influenza virus as reference antigens strengthens the validity of our approach. We identified an association between the IFN-gamma response to CII and HLA-DRB1*0401 and HLA-DQ8 in the RA patient group, which is of obvious interest because both these MHC class II alleles have been associated with high responsiveness to CII in transgenic mice that express these human MHC class II molecules [14,15]. There was no association between high anti-CII levels and shared epitope (HLA-DRB1*0401 or HLA-DRB1*0404).
T6 6904-7576 CONCLUSIONS denotes CII, a major autoantigen candidate in RA, can elicit an IFN-gamma response in vitro that is associated with HLA-DRB1*0401 and HLA-DQ8 in RA patients. This study, with a partly new methodological approach to a classical problem in RA, has provided some additional support to the notion that CII may be a target autoantigen of importance for a substantial group of RA patients. Continued efforts to identify mechanisms behind the general hyporesponsiveness to antigens in RA, as well as the mechanisms behind the potential partial anergy to CII, may provide us with better opportunities to study the specificity and pathophysiological relevance of anti-CII reactivity in RA.

PMID_GLOBAL

Id Subject Object Predicate Lexical cue mondo_id
T1 89-109 DiseaseOrPhenotypicFeature denotes rheumatoid arthritis 0008383
T2 260-280 DiseaseOrPhenotypicFeature denotes rheumatoid arthritis 0008383
T3 282-284 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T5 442-444 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T7 820-822 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T9 861-864 DiseaseOrPhenotypicFeature denotes can 0012833
T10 885-894 DiseaseOrPhenotypicFeature denotes arthritis 0005578
T11 939-941 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T13 1216-1218 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T15 1451-1453 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T17 1706-1708 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T19 2002-2004 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T21 2219-2228 DiseaseOrPhenotypicFeature denotes influenza 0005812
T22 2325-2328 DiseaseOrPhenotypicFeature denotes PPD 0008827
T23 2748-2750 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T25 2964-2966 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T27 3050-3052 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T29 3103-3105 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T31 3329-3332 DiseaseOrPhenotypicFeature denotes PPD 0008827
T32 3344-3353 DiseaseOrPhenotypicFeature denotes influenza 0005812
T33 3400-3403 DiseaseOrPhenotypicFeature denotes PPD 0008827
T34 3416-3418 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T36 3478-3487 DiseaseOrPhenotypicFeature denotes influenza 0005812
T37 3500-3502 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T39 3559-3561 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T41 3619-3622 DiseaseOrPhenotypicFeature denotes PPD 0008827
T42 3634-3643 DiseaseOrPhenotypicFeature denotes influenza 0005812
T43 3826-3829 DiseaseOrPhenotypicFeature denotes PPD 0008827
T44 3841-3850 DiseaseOrPhenotypicFeature denotes influenza 0005812
T45 3860-3862 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T47 4004-4006 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T49 4054-4056 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T51 4218-4220 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T53 4463-4466 DiseaseOrPhenotypicFeature denotes PPD 0008827
T54 4486-4495 DiseaseOrPhenotypicFeature denotes influenza 0005812
T55 4539-4542 DiseaseOrPhenotypicFeature denotes PPD 0008827
T56 4562-4571 DiseaseOrPhenotypicFeature denotes influenza 0005812
T57 4682-4684 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T59 4837-4840 DiseaseOrPhenotypicFeature denotes PPD 0008827
T60 4892-4901 DiseaseOrPhenotypicFeature denotes influenza 0005812
T61 5052-5054 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T63 5355-5357 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T65 5562-5571 DiseaseOrPhenotypicFeature denotes influenza 0005812
T66 5743-5745 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T68 5884-5887 DiseaseOrPhenotypicFeature denotes PPD 0008827
T69 5899-5908 DiseaseOrPhenotypicFeature denotes influenza 0005812
T70 6054-6056 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T72 6146-6148 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T74 6338-6340 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T76 6370-6373 DiseaseOrPhenotypicFeature denotes PPD 0008827
T77 6385-6394 DiseaseOrPhenotypicFeature denotes influenza 0005812
T78 6569-6571 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T80 6942-6944 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T82 6946-6949 DiseaseOrPhenotypicFeature denotes can 0012833
T83 7041-7043 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T85 7134-7136 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T87 7267-7269 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T89 7374-7376 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383
T91 7573-7575 DiseaseOrPhenotypicFeature denotes RA 0005272|0008383

DisGeNET5_gene_disease

Id Subject Object Predicate Lexical cue
11219392-0#0#16#gene3458 4323-4519 gene3458 denotes In order to address this possibility, we calculated the fraction between individual values for the CII-induced IFN-gamma production and the PPD-induced and killed influenza virus-induced IFN-gamma
11219392-0#129#137#gene3123 6536-6544 gene3123 denotes HLA-DRB1
11219392-0#89#109#diseaseC0003873 5710-6141 diseaseC0003873 denotes ral T-cell hyporesponsiveness in RA into account when investigating specific T-cell responses in this disease. In order to address this issue we used the T-cell responses to PPD and killed influenza virus as reference antigens. This was made on the assumption that exposure to these antigens is similar in age-matched and sex-matched groups of RA patients and healthy control individuals. The concept of a general hyporesponsivenes
0#16#gene345889#109#diseaseC0003873 11219392-0#0#16#gene3458 11219392-0#89#109#diseaseC0003873 associated_with "In order to address this possibility, we calculated the fraction between individual values for the CII-induced IFN-gamma production and the PPD-induced and killed influenza virus-induced IFN-gamma",ral T-cell hyporesponsiveness in RA into account when investigating specific T-cell responses in this disease. In order to address this issue we used the T-cell responses to PPD and killed influenza virus as reference antigens. This was made on the assumption that exposure to these antigens is similar in age-matched and sex-matched groups of RA patients and healthy control individuals. The concept of a general hyporesponsivenes
129#137#gene312389#109#diseaseC0003873 11219392-0#129#137#gene3123 11219392-0#89#109#diseaseC0003873 associated_with HLA-DRB1,ral T-cell hyporesponsiveness in RA into account when investigating specific T-cell responses in this disease. In order to address this issue we used the T-cell responses to PPD and killed influenza virus as reference antigens. This was made on the assumption that exposure to these antigens is similar in age-matched and sex-matched groups of RA patients and healthy control individuals. The concept of a general hyporesponsivenes

DisGeNET

Id Subject Object Predicate Lexical cue
T0 0-16 gene:3458 denotes Interferon-gamma
T1 89-109 disease:C0003873 denotes rheumatoid arthritis
T2 129-137 gene:3123 denotes HLA-DRB1
T3 89-109 disease:C0003873 denotes rheumatoid arthritis
R1 T0 T1 associated_with Interferon-gamma,rheumatoid arthritis
R2 T2 T3 associated_with HLA-DRB1,rheumatoid arthritis