PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis
Abstract
:1. Introduction
2. Results
2.1. Characteristics of Basic Parameters in Patients and Healthy Controls
2.2. PGN Patients Have a More “Exhausted” Lymphocyte Profile than NPGN Patients and Healthy Controls
2.3. Understanding the Phenomenon of Lymphocyte Exhaustion in PGN Patients and NPGN Patients
2.4. Correlation of PD-1 and PD-L1—Positive Cells and EBV DNA Copy Numbers
2.5. ROC Analyses of PD-1 and PD-L1—Positive Cells as Possible Non-Invasive Markers to Distinguish Type of Primary Glomerulonephritis
3. Discussion
Limitations of the Study
4. Materials and Methods
4.1. Patients and Controls
4.2. Preparation of Material
4.3. Immunophenotyping
4.4. Patients’ Infection Status Assessment
4.5. DNA Isolation and Calculation of EBV Load and Assessment of Anti-EBV Antibody Status
4.6. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
EBV | Epstein-Barr virus |
GN | Glomerulonephritis |
Ig | Immunoglobulin |
NPGN | nonproliferative glomerulonephritis |
PD-1 | programmed cell death protein 1 |
PD-L1 | programmed death-ligand 1 |
PGN | proliferative glomerulonephritis |
ROC | receiver operating characteristic |
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Parameters | Study Group (n = 45) | Control Goup (n = 20) | t/Z | p Value | ||
---|---|---|---|---|---|---|
Mean ± SD | Median (Range) | Mean ± SD | Median (Range) | |||
WBC [103/mm3] | 6.8 ± 1.7 | 6.6 (4.3–9.9) | 6.8 ± 0.4 | 6.7 (6.3–7.6) | −0.55 | 0.58 |
LYM [103/mm3] | 2.1 ± 0.7 | 1.96 (1.2–3.7) | 2.5 ± 0.6 | 2.5 (1.5–3.7) | −2.53 | 0.011 |
RBC [106/mm3] | 4.7 ± 1.6 | 4.4 (3.3–11.8) | 5.2 ± 0.4 | 5.12 (4.5–5.8) | −4.7 | <0.0001 |
HGB [g/dL] | 13.2 ± 1.6 | 13.2 (9.3–16.4) | 14.3 ± 1.2 | 14.35 (12.5–16.9) | −2.85 | 0.0058 |
PLT [103/mm3] | 238.9 ± 61.3 | 222.0 (147.0–410.0) | 279.0 ± 57.0 | 281.5 (186.0–403.0) | −2.49 | 0.013 |
Urea [mg/dL] | 51.9 ± 28.6 | 44.3 (13.0–115.7) | 31.4 ± 6.9 | 32.0 (18.0–42.0) | 2.59 | 0.0097 |
BUN [mg/dL] | 24.3 ± 13.4 | 20.7 (6.1–54.0) | 14.7 ± 3.2 | 14.95 (8.4–19.6) | 2.59 | 0.0097 |
Serum creatinine [mg/dL] | 1.2 ± 0.6 | 0.96 (0.37–2.3) | 0.9 ± 0.1 | 0.9 (0.7–1.1) | 1.07 | 0.29 |
eGRF [ml/min/1.73 m2] | 86.1 ± 33.1 | 81.5 (26.7–146.8) | 125.6 ± 10.3 | 121.1 (115.0–148.2) | −5.2 | <0.0001 |
Serum uric acid [mg/dL] | 6.9 ± 1.7 | 7.1 (3.8–11.9) | 6.2 ± 1.4 | 6.95 (3.7–7.9) | 1.73 | 0.083 |
Total quantity of protein in a 24-h urine collection test [g/24 h] | 5.7 ± 5.6 | 4.8 (0.01–24.9) | 0.0 ± 0 | 0.0 | 6.39 | <0.0001 |
Serum IgG [g/L] | 6.6 ± 2.8 | 6.3 (2.8–15.7) | 12.7 ± 1.4 | 12.79 (10.1–15.5) | −5.79 | <0.0001 |
Serum IgM [g/L] | 1.7 ± 1.1 | 1.2 (0.2–3.98) | 1.7 ± 0.3 | 1.6 (1.2–2.2) | −1.02 | 0.31 |
Serum IgA [g/L] | 2.4 ± 1.6 | 2.0 (0.3–6.1) | 2.4 ± 0.8 | 2.56 (0.9–3.9) | −0.76 | 0.45 |
Serum total protein [g/dL] | 5.4 ± 1.0 | 5.4 (3.2–7.4) | 7.4 ± 0.6 | 7.35 (6.4–8.2) | −8.0 | <0.0001 |
Serum albumin [g/L] | 2.6 ± 0.9 | 2.8 (0.6–4.1) | 4.2 ± 0.4 | 4.2 (3.5–4.75) | −7.75 | <0.0001 |
Serum complement component C3 [g/L] | 1.2 ± 0.3 | 1.2 (0.4–2.0) | 1.3 ± 0.2 | 1.2 (0.95–1.8) | −0.85 | 0.40 |
Serum complement component C4 [g/L] | 0.3 ± 0.08 | 0.28 (0.11–0.55) | 0.3 ± 0.08 | 0.3 (0.15–0.4) | 0.82 | 0.42 |
Parameters | NPGN (n = 22) | PGN (n = 23) | t/Z | p Value | ||
---|---|---|---|---|---|---|
Mean ± SD | Median (Range) | Mean ± SD | Median (Range) | |||
Male/Female, n (%) | 14 (63.6)/8 (36.4) | 14 (60.9)/9 (39.1) | 1.0 | |||
Age [years] | 42.8 ± 13.2 | 37.4 (19.0–70.0) | 37.4 ± 14.3 | 35.0 (20.0–70.0) | 1.31 | 0.20 |
Arterial hypertension, n (%) | 2 (9.1) | 13 (56.5) | 0.0012 | |||
Urea [mg/dL] | 55.2 ± 31.5 | 45.1 (17.8–115.7) | 48.8 ± 25.9 | 44.3 (13.0–115.7) | 0.74 | 0.46 |
BUN [mg/dL] | 25.8 ± 14.7 | 21.1 (8.3–54.0) | 22.8 ± 12.1 | 20.7 (6.1–54.0) | 0.74 | 0.46 |
Serum creatinine [mg/dL] | 1.1 ± 0.6 | 0.9 (0.37–2.3) | 1.3 ± 0.6 | 1.2 (0.5–2.3) | −0.9 | 0.37 |
eGRF [ml/min/1.73 m2] | 106. ± 28.2 | 115.7 (54.6–146.8) | 66.7 ± 25.1 | 69.9 (26.7–117.3) | 4.99 | <0.0001 |
Serum uric acid [mg/dL] | 6.6 ± 1.9 | 6.4 (3.8–11.9) | 7.2 ± 1.5 | 7.6 (4.0–9.3) | −1.19 | 0.24 |
Serum IgG [g/L] | 6.5 ± 2.1 | 6.7 (3.2–11.4) | 6.7 ± 3.4 | 6.1 (8.8–15.7) | −0.25 | 0.80 |
Serum IgM [g/L] | 2.2 ± 1.1 | 2.7 (0.4–3.98) | 1.1 ± 0.7 | 1.1 (0.2–3.2) | 3.87 | 0.0004 |
Serum IgA [g/L] | 2.0 ± 0.95 | 2.1 (0.6–3.6) | 2.6 ± 1.9 | 1.9 (0.3–6.1) | −1.34 | 0.19 |
Serum total protein [g/dL] | 5.4 ± 1.0 | 5.2 (4.0–7.4) | 5.5 ± 1.0 | 5.7 (3.2–6.9) | −0.57 | 0.57 |
Serum albumin [g/L] | 2.5 ± 0.8 | 2.6 (0.8–3.8) | 2.8 ± 0.9 | 2.8 (0.6–4.1) | −0.86 | 0.40 |
Total quantity of protein in a 24-hour urine collection test [g/24 h] | 8.5 ± 6.1 | 6.3 (3.0–24.9) | 3.0 ± 3.6 | 0.9 (0.01–10.3) | 3.46 | 0.0005 |
Serum complement component C3 [g/L] | 1.4 ± 0.3 | 1.3 (0.9–2.0) | 1.1 ± 0.3 | 1.2 (0.4–1.7) | 3.29 | 0.002 |
Serum complement component C4 [g/L] | 0.32 ± 0.1 | 0.28 (0.2–0.55) | 0.3 ± 0.07 | 0.3 (0.1–0.5) | 1.32 | 0.19 |
Variable (Unit) | Study Group (n = 45) | Control Goup (n = 20) | t/Z | p Value |
---|---|---|---|---|
Median (Range) | Median (Range) | |||
Frequencies of T CD3+ lymphocytes (%) | 74.4 (5.2–87.98) | 72.4 (70.0–74.75) | 1.36 | 0.17 |
Frequencies of B CD19+ lymphocytes (%) | 10.98 (1.7–70.3) | 10.8 (6.0–14.5) | 0.23 | 0.82 |
Frequencies of NK cells (%) | 12.6 (1.9–36.8) | 14.5 (12.6–19.8) | −2.42 | 0.016 |
Frequencies of T CD3+/CD4+ cells (%) | 43.1 (26.1–63.4) | 41.5 (40.5–44.2) | 0.68 | 0.50 |
Frequencies of T CD3+/CD8+ cells (%) | 28.0 (18.1–48.7) | 29.97 (28.9–33.2) | −2.30 | 0.022 |
T CD3+/CD4+: T CD3+/CD8+ ratio | 1.6 (0.7–3.2) | 1.4 (1.2–1.5) | 1.73 | 0.084 |
CD4+/PD-1+ (%) | 24.7 (10.3–57.3) | 5.3 (2.65–7.7) | 6.39 | <0.0001 |
CD8+/PD-1+ (%) | 18.0 (1.5–64.8) | 3.7 (1.4–6.2) | 5.55 | <0.0001 |
CD19+/PD-1+ (%) | 10.8 (0.6–45.6) | 1.9 (0.4–3.4) | 5.31 | <0.0001 |
CD4+/PD-L1+ (%) | 17.8 (1.4–49.8) | 1.7 (1.0–4.5) | 6.16 | <0.0001 |
CD8+/PD-L1+ (%) | 12.8 (0.9–40.7) | 0.4 (0.3–0.7) | 6.39 | <0.0001 |
CD19+/PD-L1+ (%) | 15.7 (0.7–43.0) | 0.2 (0.07–1.0) | 6.37 | <0.0001 |
Variable (Unit) | NPGN (n = 22) | PGN (n = 23) | t/Z | p Value |
---|---|---|---|---|
Median (Range) | Median (Range) | |||
Frequencies of T CD3+ lymphocytes (%) | 76.9 (5.2–87.98) | 73.3 (63.3–85.1) | −0.32 | 0.75 |
Frequencies of B CD19+ lymphocytes (%) | 9.5 (1.7–70.3) | 11.3 (7.0–19.1) | 0.19 | 0.85 |
Frequencies of NK cells (%) | 10.2 (1.9–36.8) | 12.9 (7.3–35.3) | −0.76 | 0.89 |
Frequencies of T CD3+/CD4+ cells (%) | 44.7 (26.1–63.4) | 41.4 (34.5–53.3) | 1.06 | 0.45 |
Frequencies of T CD3+/CD8+ cells (%) | 27.3 (18.4–48.7) | 28.9 (18.1–42.1) | −0.40 | 0.77 |
T CD3+/CD4+: T CD3+/CD8+ ratio | 1.6 (0.7–3.2) | 1.4 (0.8–2.7) | 0.73 | 0.47 |
CD4+/PD-1+ (%) | 18.6 (10.3–32.6) | 30.8 (16.3–57.3) | −5.38 | <0.0001 |
CD8+/PD-1+ (%) | 13.2 (4.0–27.8) | 23.9 (1.5–64.28) | −3.22 | 0.0025 |
CD19+/PD-1+ (%) | 7.9 (0.6–14.0) | 14.0 (0.9–45.6) | −2.99 | 0.0046 |
CD4+/PD-L1+ (%) | 16.7 (9.0–28.7) | 27.7 (1.4–49.8) | −2.74 | 0.0088 |
CD8+/PD-L1+ (%) | 12.1 (1.4–35.5) | 16.8 (0.9–40.7) | −1.39 | 0.17 |
CD19+/PD-L1+ (%) | 14.4 (1.7–26.8) | 15.9 (0.7–43.0) | −1.56 | 0.13 |
Parameter | Prognostic Value | AUC | 95% CI | p Value |
---|---|---|---|---|
CD4+/PD-1+ (%) | 27.68 | 0.89 | 0.79–0.98 | <0.0001 |
CD8+/PD-1+ (%) | 20.4 | 0.80 | 0.66–0.95 | <0.0001 |
CD19+/PD-1+ (%) | 14.2 | 0.74 | 0.59–0.88 | 0.002 |
CD4+/PD-L1+ (%) | 21.73 | 0.70 | 0.54–0.88 | 0.017 |
CD8+/PD-L1+ (%) | 15.51 | 0.62 | 0.45–0.79 | 0.15 |
CD19+/PD-L1+ (%) | 20.27 | 0.62 | 0.45–0.78 | 0.18 |
Parameter | Study Group (n = 45) | Control Group (n = 20) | t/Z | p Value | ||
---|---|---|---|---|---|---|
Mean ± SD | Median (Range) | Mean ± SD | Median (Range) | |||
Age (years) | 40.0 ± 13.9 | 41.0 (19.0–70.0) | 41.4 ± 13.1 | 42.5 (20.0–60.0) | −0.38 | 0.71 |
Diagnosis, n (%): | NA | NA | NA | |||
Membranous glomerulonephritis | 11 (24.4) | |||||
Minimal change disease | 11 (24.4) | |||||
Membranoproliferative | 11 (24.4) | |||||
glomerulonephritis | ||||||
IgA nephropathy | 12 (26.7) | |||||
Type of glomerulonephritis, n (%): | NA | NA | NA | |||
Nonproliferative | 22 (48.9) | |||||
Proliferative | 23 (51.1) |
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Grywalska, E.; Smarz-Widelska, I.; Korona-Głowniak, I.; Mertowski, S.; Gosik, K.; Hymos, A.; Ludian, J.; Niedźwiedzka-Rystwej, P.; Roliński, J.; Załuska, W. PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis. Int. J. Mol. Sci. 2020, 21, 8001. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218001
Grywalska E, Smarz-Widelska I, Korona-Głowniak I, Mertowski S, Gosik K, Hymos A, Ludian J, Niedźwiedzka-Rystwej P, Roliński J, Załuska W. PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis. International Journal of Molecular Sciences. 2020; 21(21):8001. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218001
Chicago/Turabian StyleGrywalska, Ewelina, Iwona Smarz-Widelska, Izabela Korona-Głowniak, Sebastian Mertowski, Krzysztof Gosik, Anna Hymos, Jarosław Ludian, Paulina Niedźwiedzka-Rystwej, Jacek Roliński, and Wojciech Załuska. 2020. "PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis" International Journal of Molecular Sciences 21, no. 21: 8001. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218001