Soluble Herpes Virus Entry Mediator and Type II/III Interferons Are Upregulated in Primary Biliary Cholangitis
Abstract
1. Introduction
2. Results
2.1. Patient Characteristics
2.2. Soluble Immune Checkpoint Receptors Are Upregulated in Advanced PBC
Healthy Controls (n = 10) | Overall (n = 64) | p-Value | UDCR (n = 24) | UDCNR (n = 18) | ESPBC (n = 22) | p-Value | Non-Cirrhosis (n = 33) | Early Cirrhosis (n = 9) | ESPBC (n = 22) | p-Value | |
---|---|---|---|---|---|---|---|---|---|---|---|
Age at diagnosis (years) | --- | 45 (40.5–52.5) | --- | 49.5 (44–56.5) | 43.5 (38–47) | 43.5 (38–48) | 0.045 | 47 (41.5–53.5) | 44 (38–64.5) | 43.5 (38–48) | 0.283 |
Age at time of sample (years) | 34 (25.8–43.3) | 54.5 (48–60.5) | <0.0001 | 57 (48–65.5) | 51.5 (50–60) | 53.5 (48–58) | 0.473 | 55 (48.5–60.5) | 56 (47–68.5) | 53.5 (48–58) | 0.717 |
Sex as self-declared F:M count (% F) | 6:4 (60) | 62:2 (97) | 0.002 | 23:1 (96) | 18:0 (100) | 21:1 (95) | 0.666 | 33:0 (100) | 8:1 (89) | 21:1 (95) | 0.212 |
Weight (kg) | --- | 70 (63–82) | --- | 75 (67–86.8) | 66.5 (63.9–80) | 68 (55–77) | 0.048 | 73 (64–86) | 75 (58–86) | 68 (55–77) | 0.166 |
Ethnicity (counts) | |||||||||||
Caucasian | --- | 40 | 0.002 | 10 | 11 | 19 | 0.028 | 17 | 4 | 19 | 0.021 |
Black | --- | --- | --- | --- | --- | --- | --- | --- | |||
Asian | 1 | 2 | 2 | --- | --- | 2 | --- | --- | |||
Mixed | --- | --- | --- | --- | --- | --- | --- | --- | |||
Other | --- | 1 | --- | 1 | --- | --- | 1 | --- | |||
Unknown | 9 | 21 | 12 | 6 | 3 | 14 | 4 | 3 | |||
Autoimmune disease (counts) | |||||||||||
Thyroid disease (%) | --- | 8 (13) | --- | 3 | 2 | 3 | 0.308 | 5 | --- | 3 | 0.598 |
Sjögren’s or Sicca (%) | --- | 10 (16) | 3 | 4 | 3 | 6 | 1 | 3 | |||
IBD (%) | --- | 1 (2) | 1 | --- | --- | 1 | --- | --- | |||
Rheumatoid arthritis (%) | --- | 5 (8) | 2 | 3 | --- | 4 | 1 | --- | |||
Type 1 Diabetes (%) | --- | 1 (2) | 1 | --- | --- | 1 | --- | --- | |||
Other (%) | --- | 7 (11) | 6 | 1 | --- | 5 | 2 | --- | |||
WCC (109/L) | --- | 5.65 (4.62–6.92) | --- | 6.09 (5.34–7.30) | 6.11 (4.46–7.49) | 5.12 (3.37–5.74) | 0.009 | 6.39 (5.34–7.68) | 4.59 (3.51–6.60) | 5.12 (3.37–5.74) | 0.0014 |
Neutrophil (109/L) | --- | 3.32 (2.54–4.31) | --- | 3.58 (2.99–2.49) | 3.54 (2.5–4.51) | 2.92 (1.84–3.83) | 0.131 | 3.83 (3.07–4.56) | 2.70 (2.26–3.69) | 2.92 (1.84–3.83) | 0.0183 |
Lymphocyte (109/L) | --- | 1.64 (1.14–2.05) | --- | 1.98 (1.66–2.37) | 1.63 (1.27–2.06) | 1.21 (0.66–1.62) | 0.0002 | 1.85 (1.54–2.25) | 1.59 (1.14–2.03) | 1.21 (0.66–1.62) | 0.0002 |
Monocyte (109/L) | --- | 0.39 (0.31–0.46) | --- | 0.4 (0.32–0.48) | 0.39 (0.30–0.51) | 0.37 (0.21–0.42) | 0.215 | 0.41 (0.32–0.48) | 0.37 (0.25–0.51) | 0.37 (0.21–0.42) | 0.162 |
Eosinophil (109/L) | --- | 0.13 (0.08–0.21) | --- | 0.12 (0.09–0.19) | 0.12 (0.07–0.25) | 0.15 (0.08–0.23) | 0.465 | 0.13 (0.08–0.20) | 0.11 (0.05–0.25) | 0.15 (0.08–0.23) | 0.352 |
Basophil (109/L) | --- | 0.04 (0.02–0.06) | --- | 0.03 (0.02–0.04) | 0.05 (0.03–0.06) | 0.03 (0.02–0.05) | 0.263 | 0.04 (0.03–0.06) | 0.02 (0.02–0.04) | 0.03 (0.02–0.05) | 0.033 |
Haemoglobin (g/L) | --- | 128.5 (116.5–136) | --- | 135 (129–139) | 128 (118–139) | 117 (109–129) | 0.0007 | 133 (128–139) | 123 (116–141) | 117 (109–129) | 0.0008 |
Platelet (109/L) | --- | 194 (131–270.5) | --- | 216 (182–295) | 244 (175–308) | 131 (97–180) | 0.0003 | 241 (192–309) | 121 (80–276) | 131 (97–180) | <0.0001 |
INR | --- | 1.03 (0.98–1.12) | --- | 1.02 (0.99–1.04) | 0.96 (0.90–1.00) | 1.21 (1.09–1.38) | <0.0001 | 1.00 (0.95–1.03) | 1.02 (0.95–1.05) | 1.21 (1.09–1.38) | <0.0001 |
Sodium (mmol/L) | --- | 139 (137–141) | --- | 139.5 (138–141) | 139.5 (138–141) | 138.5 (136–139) | 0.104 | 140 (138–142) | 139 (136–141) | 138.5 (136–139) | 0.076 |
Creatinine (µmol/L) | --- | 62.5 (51–72) | --- | 65 (60–72) | 63 (57–76) | 49 (46–64) | 0.004 | 64 (62–77) | 60 (55–69) | 49 (46–64) | 0.002 |
Bilirubin (µmol/L) | --- | 12 (7–35) | --- | 7 (6–9) | 12 (7–17) | 59 (34–94) | <0.0001 | 7 (6–10) | 14 (7.5–26) | 59 (34–94) | <0.0001 |
ALT (IU/L) | --- | 34 (22–40) | --- | 23 (18–37) | 38 (29–87) | 48 (34–61) | 0.032 | 29 (22–40) | 30 (22–37) | 48 (34–61) | 0.648 |
AST (IU/L) | --- | 49 (30–101) | --- | 28 (21–35) | 55 (35–92) | 112 (68–156) | <0.0001 | 34 (26–49) | 45 (27–103) | 112 (68–156) | <0.0001 |
ALP (IU/L) | --- | 194 (124–348) | --- | 122 (104–139) | 283 (198–390) | 348 (175–530) | <0.0001 | 142 (116–237) | 190 (125–532) | 348 (175–530) | 0.0008 |
GGT (IU/L) | --- | 123 (45–375) | --- | 36 (19–70) | 259 (216–517) | 307 (94–480) | <0.0001 | 65 (23–238) | 211 (82–243) | 307 (94–480) | 0.011 |
Albumin (g/L) | --- | 41 (36–45) | --- | 44 (41–46) | 43 (40–45) | 34 (32–38) | <0.0001 | 44 (42–46) | 41 (38–45) | 34 (32–38) | <0.0001 |
IgM (g/L) | --- | 3.57 (2.56–4.79) | --- | 2.35 (1.3–3.64) | 3.05 (2.28–4.61) | 4.01 (2.69–6.42) | 0.131 | 2.78 (1.60–3.45) | 5.53 (3.42–8.05) | 4.01 (2.69–6.42) | 0.007 |
IgG (g/L) | --- | 16.97 (12.71–22.66) | --- | 14.63 (11.87–18.09) | 12.9 (11.47–13.31) | 21.53 (17.14–24.49) | 0.001 | 12.59 (11.30–14.35) | 13.68 (13.09–17.13) | 21.53 (17.14–24.49) | 0.0005 |
Protein (g/L) | --- | 76 (72–79) | --- | 76 (73–79) | 76.5 (71–80) | 74.5 (71–78) | 0.884 | 76 (73–80) | 72 (69–81) | 74.5 (71–78) | 0.596 |
Child–Pugh score | --- | 5 (5–7) | --- | 5 (5–5) | 5 (5–5) | 8 (7–8) | <0.0001 | - | 5 (5–5) | 8 (7–8) | <0.0001 |
MELD | --- | 7 (6–13) | --- | 7 (6–7) | 6 (5–7) | 13 (11–15) | <0.0001 | 6 (6–7) | 7 (7–8) | 13 (11–15) | <0.0001 |
UKELD | --- | 47 (45–51) | --- | 45 (43–47) | 46 (44–48) | 53 (51–54) | <0.0001 | 45 (43–47) | 47 (45–49) | 53 (51–54) | <0.0001 |
ALBI | --- | −2.84 (−3.20–−1.89) | --- | −3.18 (−3.34–−3.00) | −3.09 (−3.20–−2.65) | −1.67 (−1.91–−1.55) | <0.0001 | −3.12 (−3.35–−3.02) | −2.65 (−3.29–−2.36) | −1.67 (−1.91–−1.55) | <0.0001 |
APRI | --- | 0.55 (0.28–1.41) | --- | 0.27 (0.17–0.39) | 0.43 (0.28–0.89) | 1.72 (1.16–2.32) | <0.0001 | 0.28 (0.20–0.42) | 0.69 (0.32–1.89) | 1.72 (1.16–2.32) | <0.0001 |
UDCA (mg/kg) | --- | 13 (11–15) | --- | 12 (10–13) | 13 (12–15) | 14 (11–16) | 0.148 | 12 (11–14) | 13 (11–16) | 14 (11–16) | 0.31 |
Time from diagnosis to sample (years) | --- | 8 (4–13) | --- | 5 (3–11) | 9 (6–13) | 10 (4–13) | 0.188 | 6 (4–12) | 9 (4–13) | 10 (4–13) | 0.558 |
2.3. Pro-Inflammatory Cytokines Are Upregulated in End-Stage PBC
2.4. Bacterial Translocation Is Increased in Primary Biliary Cholangitis
2.5. Soluble Checkpoint Receptors and Cytokines Correlate with Liver Prognostic Scores
2.6. HVEM Gene Expression Is Upregulated in Immune Cells from PBC Patients
3. Discussion
4. Materials and Methods
4.1. Patients
4.2. Plasma Isolation
4.3. Luminex Assays for Soluble Immune Checkpoints and Cytokines
4.4. Plasma D-Lactate Quantification
4.5. GEO Datasets
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Chung, Y.; Tsou, H.L.P.; Heneghan, M.A.; Chokshi, S.; Riva, A. Soluble Herpes Virus Entry Mediator and Type II/III Interferons Are Upregulated in Primary Biliary Cholangitis. Int. J. Mol. Sci. 2025, 26, 605. https://doi.org/10.3390/ijms26020605
Chung Y, Tsou HLP, Heneghan MA, Chokshi S, Riva A. Soluble Herpes Virus Entry Mediator and Type II/III Interferons Are Upregulated in Primary Biliary Cholangitis. International Journal of Molecular Sciences. 2025; 26(2):605. https://doi.org/10.3390/ijms26020605
Chicago/Turabian StyleChung, Yooyun, Hio Lam Phoebe Tsou, Michael A. Heneghan, Shilpa Chokshi, and Antonio Riva. 2025. "Soluble Herpes Virus Entry Mediator and Type II/III Interferons Are Upregulated in Primary Biliary Cholangitis" International Journal of Molecular Sciences 26, no. 2: 605. https://doi.org/10.3390/ijms26020605
APA StyleChung, Y., Tsou, H. L. P., Heneghan, M. A., Chokshi, S., & Riva, A. (2025). Soluble Herpes Virus Entry Mediator and Type II/III Interferons Are Upregulated in Primary Biliary Cholangitis. International Journal of Molecular Sciences, 26(2), 605. https://doi.org/10.3390/ijms26020605