IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopes
Abstract Background Pepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region...
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| Format: | Article |
| Language: | English |
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BMC
2020-06-01
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| Series: | Arthritis Research & Therapy |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13075-020-02251-7 |
| _version_ | 1819080235280236544 |
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| author | Toshiyuki Ota Shun-ichiro Ota Ayumi Uchino Shuji Nagano |
| author_facet | Toshiyuki Ota Shun-ichiro Ota Ayumi Uchino Shuji Nagano |
| author_sort | Toshiyuki Ota |
| collection | DOAJ |
| description | Abstract Background Pepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHAs have different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since the expression of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), AHA production could also be increased. The purpose of this study was to determine whether the levels of AHAs against IgG hinge epitopes produced by MMP-3 are elevated in RA. Methods The serum levels of IgG or IgA AHAs against the IgG1/IgG4 F(ab’)2 fragments, generated by either MMP-3 or pepsin, were measured using ELISA in 111 patients with RA and 81 healthy controls (HC). Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (> 95%) of the AHA. The targeted epitope of a specific AHA was investigated through inhibition ELISA. Results Seven AHAs were statistically higher in RA patients than in HC, except IgG AHA against IgG1 F(ab’)2, which was generated by MMP-3 proteolytic cleavage. The areas under the ROC curve were 0.66–0.80, although the sensitivities at high specificity were low (5.4–24.3%). The cumulative number of positive AHAs in each individual was statistically higher in RA patients than in HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHAs against IgG4 F(ab’)2 fragments generated by pepsin cross-reacted with IgG1 F(ab’)2 fragments generated by pepsin. Multivariate logistic regression analysis identified the IgG AHA against IgG4 F(ab’)2 fragments generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA (odds ratio 1.18, 95% CI 1.06–1.32; P = 0.003). Additional experiments using non-RA patients finally strengthened the diagnostic utility. Conclusion In RA patients, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab’)2 fragments generated by pepsin but not MMP-3. |
| first_indexed | 2024-12-21T19:41:39Z |
| format | Article |
| id | doaj.art-370c242bec31491eac23aa0183ad62bd |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-12-21T19:41:39Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-370c242bec31491eac23aa0183ad62bd2022-12-21T18:52:26ZengBMCArthritis Research & Therapy1478-63622020-06-0122111110.1186/s13075-020-02251-7IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopesToshiyuki Ota0Shun-ichiro Ota1Ayumi Uchino2Shuji Nagano3Center for Rheumatic Diseases, Iizuka HospitalCenter for Rheumatic Diseases, Shimonoseki City HospitalDepartment of Internal Medicine (Rheumatic Diseases Division), Iizuka HospitalDepartment of Internal Medicine (Rheumatic Diseases Division), Iizuka HospitalAbstract Background Pepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHAs have different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since the expression of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), AHA production could also be increased. The purpose of this study was to determine whether the levels of AHAs against IgG hinge epitopes produced by MMP-3 are elevated in RA. Methods The serum levels of IgG or IgA AHAs against the IgG1/IgG4 F(ab’)2 fragments, generated by either MMP-3 or pepsin, were measured using ELISA in 111 patients with RA and 81 healthy controls (HC). Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (> 95%) of the AHA. The targeted epitope of a specific AHA was investigated through inhibition ELISA. Results Seven AHAs were statistically higher in RA patients than in HC, except IgG AHA against IgG1 F(ab’)2, which was generated by MMP-3 proteolytic cleavage. The areas under the ROC curve were 0.66–0.80, although the sensitivities at high specificity were low (5.4–24.3%). The cumulative number of positive AHAs in each individual was statistically higher in RA patients than in HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHAs against IgG4 F(ab’)2 fragments generated by pepsin cross-reacted with IgG1 F(ab’)2 fragments generated by pepsin. Multivariate logistic regression analysis identified the IgG AHA against IgG4 F(ab’)2 fragments generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA (odds ratio 1.18, 95% CI 1.06–1.32; P = 0.003). Additional experiments using non-RA patients finally strengthened the diagnostic utility. Conclusion In RA patients, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab’)2 fragments generated by pepsin but not MMP-3.http://link.springer.com/article/10.1186/s13075-020-02251-7Anti-hinge antibodyMatrix metalloproteinaseIgG4Rheumatoid factorACPARheumatoid arthritis |
| spellingShingle | Toshiyuki Ota Shun-ichiro Ota Ayumi Uchino Shuji Nagano IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopes Arthritis Research & Therapy Anti-hinge antibody Matrix metalloproteinase IgG4 Rheumatoid factor ACPA Rheumatoid arthritis |
| title | IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopes |
| title_full | IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopes |
| title_fullStr | IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopes |
| title_full_unstemmed | IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopes |
| title_short | IgG anti-hinge antibodies against IgG4 F(ab’)2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis: implications of the possible roles of metalloproteinases and IgG subclasses in generating immunogenic hinge epitopes |
| title_sort | igg anti hinge antibodies against igg4 f ab 2 fragments generated using pepsin are useful diagnostic markers for rheumatoid arthritis implications of the possible roles of metalloproteinases and igg subclasses in generating immunogenic hinge epitopes |
| topic | Anti-hinge antibody Matrix metalloproteinase IgG4 Rheumatoid factor ACPA Rheumatoid arthritis |
| url | http://link.springer.com/article/10.1186/s13075-020-02251-7 |
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