PMID- 32586370
OWN - NLM
STAT- MEDLINE
DCOM- 20210621
LR  - 20210621
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 22
IP  - 1
DP  - 2020 Jun 26
TI  - 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.
PG  - 161
LID - 10.1186/s13075-020-02251-7 [doi]
LID - 161
AB  - 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.
FAU - Ota, Toshiyuki
AU  - Ota T
AUID- ORCID: 0000-0002-4538-0137
AD  - Center for Rheumatic Diseases, Iizuka Hospital, 3-83 Yoshio-machi, Iizuka-shi, 
      Fukuoka, 820-8505, Japan. totah2@aih-net.com.
AD  - Department of Laboratory Medicine, Iizuka Hospital, 3-83 Yoshio-machi, 
      Iizuka-shi, Fukuoka, 820-8505, Japan. totah2@aih-net.com.
FAU - Ota, Shun-Ichiro
AU  - Ota SI
AD  - Center for Rheumatic Diseases, Shimonoseki City Hospital, Shimonoseki-shi, 
      Yamaguchi, 750-0041, Japan.
FAU - Uchino, Ayumi
AU  - Uchino A
AD  - Department of Internal Medicine (Rheumatic Diseases Division), Iizuka Hospital, 
      3-83 Yoshio-machi, Iizuka-shi, Fukuoka, 820-8505, Japan.
FAU - Nagano, Shuji
AU  - Nagano S
AD  - Department of Internal Medicine (Rheumatic Diseases Division), Iizuka Hospital, 
      3-83 Yoshio-machi, Iizuka-shi, Fukuoka, 820-8505, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200626
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Epitopes)
RN  - 0 (Immunoglobulin Fab Fragments)
RN  - 0 (Immunoglobulin G)
RN  - EC 3.4.23.1 (Pepsin A)
SB  - IM
MH  - *Arthritis, Rheumatoid/diagnosis
MH  - Epitopes
MH  - Humans
MH  - Immunoglobulin Fab Fragments
MH  - Immunoglobulin G
MH  - *Pepsin A
PMC - PMC7318515
OTO - NOTNLM
OT  - ACPA
OT  - Anti-hinge antibody
OT  - Diagnosis
OT  - Extended epitope recognition
OT  - IgG4
OT  - Matrix metalloproteinase
OT  - Rheumatoid arthritis
OT  - Rheumatoid factor
COIS- All authors declare that they have no competing interests.
EDAT- 2020/06/27 06:00
MHDA- 2021/06/22 06:00
PMCR- 2020/06/26
CRDT- 2020/06/27 06:00
PHST- 2020/01/20 00:00 [received]
PHST- 2020/06/16 00:00 [accepted]
PHST- 2020/06/27 06:00 [entrez]
PHST- 2020/06/27 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/06/26 00:00 [pmc-release]
AID - 10.1186/s13075-020-02251-7 [pii]
AID - 2251 [pii]
AID - 10.1186/s13075-020-02251-7 [doi]
PST - epublish
SO  - Arthritis Res Ther. 2020 Jun 26;22(1):161. doi: 10.1186/s13075-020-02251-7.