Associations of Anti-Aquaporin 5 Autoantibodies with Serologic and Histopathological Features of Sjögren’s Syndrome
Abstract
:1. Introduction
2. Experimental Section
2.1. Serum Samples and Clinical Data
2.2. Cell-Based Immunofluorescence Cytochemistry (CB-IFC)
2.3. Enzyme-Linked Immunosorbent Assay (ELISA)
2.4. Statistical Analysis
3. Results
3.1. Higher Levels of Anti-AQP5 IgG and IgA Were Detected in SS than in Non-SS by CB-IFC
3.2. Higher Levels of Anti-AQP5 IgG but Not IgA were Detected in the SS Sera by ELISA
3.3. Association between Anti-AQP5 Autoantibodies and Disease Criteria for SS
4. Discussion
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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SICCA Registry | Seoul St. Mary’s Hospital | ||||
---|---|---|---|---|---|
SS (n = 111) | Non-SS (n = 43) | SLE (n = 35) | RA (n = 35) | ||
Age (years), mean ± SD | 50.4 ± 13.6 | 53.1 ± 14.9 | 30.5 ± 9.4* | 57.0 ± 12.4 | |
anti-SSA+, n (%) | 102 (91.9) | 0 (0) | 20 (69.0), 29† | ND | |
anti-SSB+, n (%) | 61 (55.0) | 0 (0) | 6 (20.7), 29† | ND | |
RF+, n (%) | 75 (67.6) | 0 (0) | 0 (0), 22† | 27 (77.1) | |
ANA+, n (%) | 75 (67.6) | 0 (0) | 34 (97.1) | 14 (45.2), 31† | |
UWSFR ≤0.1 mL/min, n (%) | 84 (75.7) | 15 (34.9) | ND | ND | |
Labial salivary gland biopsy results | FLS score ≥1, n (%) | 80 (80), 100† | 0 (0) | ND | ND |
FLS score 0 << 1, n (%) | 7 (7), 100† | 8 (18.6) | ND | ND | |
FLS score = 0, n (%) | 13 (13), 100† | 35 (81.4) | ND | ND | |
N/SCS | 13 (13), 100† | 34 (79.0) | ND | ND | |
Schirmer’s test ≤5 mm in 5 min, n (%) | 63 (57.3), 110† | 11 (25.6) | ND | ND | |
Ocular staining score ≥3, n (%) | 105 (95.5), 110† | 0 (0) | ND | ND |
Method | Ab | Dilution of Sera | AUC | Confidence Interval | p | Cut-off Value | Sensitivity | Specificity | Accuracy |
---|---|---|---|---|---|---|---|---|---|
CB-IFC | anti-AQP5_IgG | 1:100 | 0.638 | 0.542–0.735 | 0.008 | 6.71 | 0.595 | 0.721 | 0.658 |
anti-AQP5_A IgG | 1:100 | 0.616 | 0.510–0.721 | 0.026 | 0.38 | 0.784 | 0.488 | 0.636 | |
anti-AQP5_C2 IgG | 1:100 | 0.688 | 0.595–0.781 | <0.001 | 1.79 | 0.622 | 0.721 | 0.672 | |
anti-AQP5_E1 IgG | 1:100 | 0.703 | 0.609–0.796 | <0.001 | 1.75 | 0.613 | 0.767 | 0.690 | |
anti-AQP5 IgA | 1:10 | 0.694 | 0.612–0.777 | <0.001 | 0.83 | 0.396 | 0.953 | 0.675 | |
ELISA | anti-AQP5_A IgG | 1:50 | 0.665 | 0.565–0.764 | 0.002 | 54.1 | 0.712 | 0.651 | 0.681 |
anti-AQP5_C2 IgG | 1:50 | 0.640 | 0.540–0.740 | 0.007 | 44.3 | 0.631 | 0.698 | 0.664 | |
anti-AQP5_E1 IgG | 1:50 | 0.695 | 0.593–0.798 | <0.001 | 19.3 | 0.856 | 0.558 | 0.707 | |
anti-AQP5_ACE IgG | 1:50 | 0.671 | 0.570–0.772 | 0.001 | 34.9 | 0.820 | 0.558 | 0.689 | |
anti-AQP5_A IgG | 1:100 | 0.664 | 0.567–0.762 | 0.002 | 20.3 | 0.811 | 0.465 | 0.638 | |
anti-AQP5_C2 IgG | 1:100 | 0.645 | 0.544–0.746 | 0.005 | 21.6 | 0.676 | 0.605 | 0.640 | |
anti-AQP5_E1 IgG | 1:100 | 0.649 | 0.544–0.753 | 0.004 | 26.0 | 0.739 | 0.581 | 0.660 | |
anti-AQP5_ACE IgG | 1:100 | 0.682 | 0.583–0.781 | <0.001 | 66.0 | 0.667 | 0.651 | 0.659 |
Disease Criteria for Sjogren’s Syndrome | n | Anti-AQP5_E1 IgG by CB-IFC | Anti-AQP5_E1 IgG by ELISA | |||||
---|---|---|---|---|---|---|---|---|
≥1.75 (au) | <1.75 (au) | p* | ≥19.3 (ng/mL) | <19.3 (ng/mL) | p* | |||
anti-SSA | Positive | 102 | 62 (60.8%) | 40 (39.2%) | 0.001 | 84 (82.4%) | 18 (17.6%) | <0.001 |
Negative | 52 | 17 (32.7%) | 35 (67.3%) | 27 (51.9%) | 25 (48.1%) | |||
anti-SSB | Positive | 61 | 35 (57.4%) | 26 (42.6%) | 0.222 | 50 (82.0%) | 11 (18.0%) | 0.027 |
Negative | 93 | 44 (47.3%) | 49 (52.7%) | 61 (65.6%) | 32 (34.4%) | |||
RF | Positive | 75 | 45 (60.0%) | 30 (40.0%) | 0.035 | 63 (84.0%) | 12 (16.0%) | 0.001 |
Negative | 79 | 34 (43.0%) | 45 (57.0%) | 48 (60.8%) | 31 (39.2%) | |||
ANA | Positive | 75 | 46 (61.3%) | 29 (38.7%) | 0.015 | 67 (89.3%) | 8 (10.7%) | <0.001 |
Negative | 79 | 33 (41.8%) | 46 (58.2%) | 44 (55.7%) | 35 (44.3%) | |||
UWSFR | ≤0.1 ml/min | 99 | 56 (56.6%) | 43 (43.4%) | 0.079 | 74 (74.7%) | 25 (25.3%) | 0.322 |
>0.1 ml/min | 55 | 23 (41.8%) | 32 (58.2%) | 37 (67.3%) | 18 (32.7%) | |||
FLS score | ≥1 | 80 | 50 (62.5%) | 30 (37.5%) | 0.006 | 70 (87.5%) | 10 (12.5%) | <0.001 |
0 << 1 | 15 | 7 (46.7%) | 8 (53.3%) | 10 (66.7%) | 5 (33.3%) | |||
=0 | 48 | 16 (33.3%) | 32 (66.7%) | 24 (50.0%) | 24 (50.0%) | |||
Schirmer’s test | ≤5 mm in 5 min | 74 | 36 (48.6%) | 38 (51.4%) | 0.618 | 58 (78.4%) | 16 (21.6%) | 0.391 |
>5 mm in 5 min | 79 | 39 (49.4%) | 40 (50.6%) | 55 (69.6%) | 24 (30.4%) | |||
Ocular staining score | ≥3 | 105 | 66 (62.9%) | 39 (37.1%) | <0.001 | 86 (81.9%) | 19 (18.1%) | <0.001 |
<3 | 49 | 13 (26.5%) | 36 (73.5%) | 25 (51.0%) | 24 (49.0%) |
Disease Criteria for Sjogren’s Syndrome | IgA by CB-IFC (au) | IgG by CB-IFC (au) | IgG by ELISA (ng/ml) | |||||||
---|---|---|---|---|---|---|---|---|---|---|
AQP5 | A | C2 | E1 | AQP5 | A | C2 | E1 | AC2E1 | ||
anti-SSA | Positive | 0.3 (3.7) | 2.3 (16.0) | 2.4 (16.0) | 2.5 (15.0) | 8.2 (18.3) | 67 (852) | 53 (332) | 66 (500) | 85 (975) |
Negative | 0 (3.7) | 1.5 (12.3) | 1.0 (10.3) | 1.0 (9.7) | 5.3 (12.7) | 39 (458) | 31 (271) | 35 (457) | 46 (349) | |
P† | < 0.001 | 0.099 | 0.008 | 0.002 | 0.019 | 0.005 | 0.016 | 0.002 | 0.004 | |
anti-SSB | Positive | 0.3 (3.7) | 2.3 (14.0) | 2.3 (12.8) | 2.3 (14.3) | 7.3 (18.3) | 74 (852) | 52 (332) | 78 (500) | 86 (975) |
Negative | 0.3 (3.7) | 1.8 (12.3) | 1.7 (16.0) | 1.7 (15.0) | 6.8 (18.0) | 55 (459) | 41 (298) | 52 (457) | 64 (351) | |
P† | 0.183 | 0.356 | 0.243 | 0.406 | 0.688 | 0.253 | 0.635 | 0.052 | 0.208 | |
RF | Positive | 0.3 (3.7) | 2.3 (14.0) | 2.4 (16.0) | 2.7 (14.3) | 8.3 (18.3) | 65 (852) | 45 (332) | 67 (500) | 71 (975) |
Negative | 0.0 (3.7) | 1.7 (12.3) | 1.7 (9.7) | 1.5 (15.0) | 6.3 (17.0) | 43 (768) | 30 (309) | 46 (457) | 42 (787) | |
P† | 0.099 | 0.155 | 0.035 | 0.080 | 0.247 | 0.007 | 0.254 | 0.003 | 0.002 | |
ANA | Positive | 0.3 (3.7) | 2.0 (14.0) | 2.5 (12.8) | 2.3 (15.0) | 8.3 (18.3) | 54 (852) | 44 (332) | 61 (500) | 66 (975) |
Negative | 0.0 (3.7) | 1.7 (12.3) | 1.3 (16.0) | 1.5 (14.4) | 6.0 (18.0) | 43 (628) | 25 (301) | 34 (457) | 46 (546) | |
P† | < 0.001 | 0.157 | 0.024 | 0.055 | 0.409 | 0.093 | 0.004 | < 0.001 | 0.012 | |
UWSFR | ≤ 0.1 ml/min | 0.3 (3.7) | 1.8 (14.0) | 2.3 (16.0) | 2.3 (15.0) | 6.8 (18.3) | 66 (852) | 47 (332) | 66 (500) | 82 (975) |
> 0.1 ml/min | 0.0 (3.7) | 1.8 (10.0) | 1.7 (10.3) | 1.7 (14.4) | 8.0 (16.7) | 91 (768) | 66 (309) | 64 (457) | 91 (787) | |
P† | 0.327 | 0.944 | 0.329 | 0.259 | 0.420 | 0.381 | 0.240 | 0.992 | 0.166 | |
FLS score | ≥ 1 | 0.3 (3.7) | 2.1 (19.3) | 2.5 (21.4) | 2.5 (20.7) | 8.0 (18.3) | 84 (852) | 69 (332) | 88 (500) | 102 (975) |
0 << 1 | 0.3 (3.7) | 0.0 (11.3) | 1.0 (19.0) | 1.3 (15.7) | 6.0 (18.0) | 101 (768) | 31 (309) | 37 (457) | 129 (787) | |
= 0 | 0.0 (3.3) | 1.7 (16.0) | 1.2 (9.2) | 1.0 (13.7) | 6.0 (11.7) | 38 (279) | 23 (271) | 25 (383) | 30 (349) | |
P‡ | 0.010 | 0.017 | 0.016 | 0.045 | 0.295 | 0.010 | 0.031 | < 0.001 | 0.001 | |
Schirmer’s test | < 5mm in 5min | 0.3 (3.3) | 1.8 (19.3) | 2.3 (15.8) | 1.9 (19.0) | 7.5 (18.3) | 78 (852) | 53 (332) | 80 (500) | 87 (975) |
≥ 5mm in 5min | 0 (3.7) | 1.8 (15.7) | 1.7 (24.7) | 2 (20.7) | 6.3 (18.0) | 65 (768) | 44 (309) | 61 (457) | 87 (787) | |
P† | 0.388 | 0.652 | 0.498 | 0.894 | 0.975 | 0.756 | 0.942 | 0.170 | 0.660 | |
Ocular | ≥ 3 | 0.3 (3.7) | 2.6 (14.0) | 2.7 (16.0) | 3.0 (15.0) | 8.3 (18.3) | 82 (852) | 67 (332) | 80 (500) | 101 (975) |
staining score | < 3 | 0.0 (2.7) | 1.0 (12.3) | 1.0 (7.0) | 0.3 (9.7) | 5.0 (13.0) | 48 (640) | 33 (271) | 22 (457) | 46 (647) |
P† | < 0.001 | 0.017 | < 0.001 | < 0.001 | 0.007 | 0.041 | 0.049 | 0.001 | 0.013 |
Adverse Prognostic Markers | Anti-AQP5_E1 IgG by ELISA | |||||||
---|---|---|---|---|---|---|---|---|
Positivity | High Titer (> median) | |||||||
n | ≥19.3 (ng/mL) | <19.3 (ng/mL) | p* | >79.8 (ng/mL) | ≤79.8 (ng/mL) | p* | ||
FLS | ≥3 | 41 | 35 (85.4%) | 6 (14.6%) | 0.932 | 27 (65.9%) | 14 (34.1%) | 0.013 |
<3 | 59 | 50 (84.7%) | 9 (15.3%) | 24 (40.7%) | 35 (59.3%) | |||
GC | Positive | 8 | 6 (75.0%) | 2 (25.0%) | 0.330 | 4 (50.0%) | 4 (50.0%) | 0.876 |
Negative | 87 | 76 (87.4%) | 11 (12.6%) | 46 (52.9%) | 41 (47.1%) | |||
RF | Positive | 75 | 63 (84.0%) | 12 (16.0%) | 0.652 | 40 (53.3%) | 35 (46.7%) | 0.250 |
Negative | 36 | 29 (80.6%) | 7 (19.4%) | 15 (41.7%) | 21 (58.3%) | |||
IgG | >1.445 mg/dL | 79 | 66 (83.5%) | 13 (16.5%) | 0.771 | 40 (50.6%) | 39 (49.4%) | 0.720 |
≤1.445 mg/dL | 32 | 26 (72.2%) | 6 (18.8%) | 15 (46.9%) | 17 (53.1%) | |||
C3 | <67 mg/dL | 6 | 5 (83.3%) | 1 (16.7%) | 0.976 | 3 (50%) | 3 (50%) | 0.982 |
≥67 mg/dL | 105 | 87 (82.9%) | 18 (17.1%) | 52 (49.5%) | 53 (50.5%) | |||
C4 | <16 mg/dL | 21 | 19 (90.5%) | 2 (9.5%) | 0.305 | 11 (52.4%) | 10 (47.6%) | 0.773 |
≥16 mg/dL | 90 | 73 (81.1%) | 17 (18.9%) | 44 (48.9%) | 46 (51.1%) | |||
Salivary gland enlargement | Positive | 12 | 6 (50%) | 6 (50%) | 0.974 | 6 (50.0%) | 6 (50.0%) | 0.974 |
Negative | 99 | 49 (49.5%) | 50 (50.5%) | 49 (49.5%) | 50 (50.5%) | |||
Systemic disease | Positive | 20 | 16 (80.0%) | 4 (20%) | 0.705 | 9 (45.0%) | 11 (55.0%) | 0.653 |
Negative | 91 | 76 (83.5%) | 15 (16.5%) | 46 (50.5%) | 45 (49.5%) |
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Jeon, S.; Lee, J.; Park, S.-H.; Kim, H.-D.; Choi, Y. Associations of Anti-Aquaporin 5 Autoantibodies with Serologic and Histopathological Features of Sjögren’s Syndrome. J. Clin. Med. 2019, 8, 1863. https://doi.org/10.3390/jcm8111863
Jeon S, Lee J, Park S-H, Kim H-D, Choi Y. Associations of Anti-Aquaporin 5 Autoantibodies with Serologic and Histopathological Features of Sjögren’s Syndrome. Journal of Clinical Medicine. 2019; 8(11):1863. https://doi.org/10.3390/jcm8111863
Chicago/Turabian StyleJeon, Sumin, Jennifer Lee, Sung-Hwan Park, Hyun-Duck Kim, and Youngnim Choi. 2019. "Associations of Anti-Aquaporin 5 Autoantibodies with Serologic and Histopathological Features of Sjögren’s Syndrome" Journal of Clinical Medicine 8, no. 11: 1863. https://doi.org/10.3390/jcm8111863