Regulatory B Cells and Their Cytokine Profile in HCV-Related Hepatocellular Carcinoma: Association with Regulatory T Cells and Disease Progression
Abstract
:1. Introduction
2. Patients and Methods
2.1. Study Definitions and Patients‘ Selection
- CHC was defined when HCV-Ab and HCV-RNA-PCR was positive for more than 6 months. HCV viral load was determined by using Artus1 HCV-RG RT-PCR Kit (cat#4518265, QIAGEN, Germany) according to the manufacturer’s protocol. QRT-PCR was performed on 7500 Fast real-time PCR Thermal cycler (Applied Biosystems, CA, USA).
- HCV-related Liver cirrhosis (HCV-related LC) was diagnosed based on the results of clinical evaluation, laboratory tests (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, albumin, and estimation of prothrombin time), and imaging (using well-defined criteria of liver cirrhosis). Severity of liver cirrhosis was assessed by the Child–Pugh score (CPS) [24].
- HCC diagnosis was also based on both laboratory testing for alpha-fetoprotein (AFP; using Access 2 tumor marker analyzer, Beckman Coulter, USA S.N.: 510552), and imaging (using CT-scan and/or MRI study). Staging of HCC was in concordance with the Barcelona Clinic Liver Cancer (BCLC) staging system [25,26]. HCC-patients were classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system into A, B, and C classes. Early stage (A) includes patients with asymptomatic early tumors suitable for radical therapies-resection, transplantation or percutaneous treatments. Intermediate stage (B) comprises patients with asymptomatic multinodular HCC. Advanced stage (C) includes patients with symptomatic tumors and/or an invasive tumoral pattern [27].
- Exclusion criteria: Patients co-infected with hepatitis B virus, with other co-morbid extrahepatic neoplasms, or patients with chronic autoimmune diseases were excluded from the study.
2.2. Evaluation of the Freuency of Bregs by Flow Cytometry
2.3. Evaluation of the Frequency of Tregs by Flow Cytometry
2.4. Serum Cytokine Measurements
2.5. Statistical Analysis
3. Results
3.1. Demographic Data
3.2. Frequency of Bregs and Tregs c among the Studied Groups
3.3. IL-10, IL-35 and BAFF Serum Levels
3.4. Correlation of the Frequency of Bregs with the Frequency of Tregs, IL-10, IL-35 and BAF Serum Levels among HCV-HCC Patients
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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CHC (n = 35) | HCV-LC (n = 35) | HCV–HCC (n = 60) | Healthy Controls (n = 20) | p-Value | |
---|---|---|---|---|---|
Age (range, years) | 45–65 | 50–65 | 50–70 | 40–60 | 0.4 |
Sex (male/female) | 25/10 | 20/15 | 40/20 | 14/6 | 0.2 |
Hb (g/dL) | 11.37 ± 2.5 | 10 ± 1.57 | 12.68 ± 1.55 | 13.7 ± 2.1 | 0.41 |
Total bilirubin(mg/dL) [Normal range: 0.1 to 1.2] | 1.43 ± 0.92 | 1.66 ± 1.33 | 1.62 ± 1.67 | 0.77 ± 0.08 | <0.001 |
Albumin(g/dL) [Normal range: 3.4 to 5.4] | 3.15 ± 1.42 | 3.56 ± 1.22 | 3.04 ± 0.7 | 4.08 ± 0.41 | <0.001 |
ALT [Normal: up to 40 IU/L] | 48.6 ± 42 | 51.2 ± 47 | 71.1 ± 12 | 22.1 ± 5.6 | <0.001 |
AST (IU/L) [Normal: up to 40 IU/L] | 71.4 ± 58 | 76.4 ± 58 | 81.4 ± 75 | 21.2 ± 3.9 | <0.001 |
AFP (IU/L) [Normal range <10] | 3.5 ± 1.2 | 8.45 ± 7.43 | 785.3 ± 203.3 | 1.1 ± 0.3 | <0.001 |
Prothrombin concentration (%) | 85.4% ± 3.01 | 56.8% ± 18.2 | 72.53% ± 17.5 | 90.6 ± 5.2 | <0.00001 |
INR | 1.05 ± 0.051 | 1.45 ± 0.33 | 1.2 ± 0.177 | 1.15 ± 0.03 | <0.00001 |
HCV-RNA copy number/mL | 1.3 × 106 ± 2 × 106 | 2.7 × 106 ± 2 × 106 | 7 × 106 ± 16 × 106 | NA | NA |
Child–Pugh class | NA | Class A (n = 15) | Class A (n = 30) | NA | NA |
Class B (n = 13) | Class B (n = 20) | ||||
Class C (n = 7) | Class C (n = 10) | ||||
Hepatic focal lesions | NA | NA | single < 5 cm (n = 30) | NA | NA |
single > 5 cm (n = 18) | |||||
multiple (n = 12) | |||||
BCLC staging | NA | NA | NA | NA | |
Stage-A | 20 | ||||
Stage-B | 15 | ||||
Stage-C | 25 |
Variable (Mean ± SD) | CHC (n = 35) | HCV-LC (n = 35) | HCV-HCC (n = 60) | Healthy Controls (n = 20) | P 1 Value | P 2 Value | P 3 Value |
---|---|---|---|---|---|---|---|
%CD 19+B cell | 10.90 ± 1.78 | 11.56 ± 1.71 | 11.75 ± 1.81 | 12.11 ± 1.79 | 0.03 | ns | ns |
%Bregs | 5.13 ± 2.01 | 5.62 ± 1.90 | 6.26 ± 2.71 | 3.71 ± 0.9 | 0.01 | ns | <0.0001 |
%Tregs (CD4+CD25+high FoxP3+cells) | 1.67 ± 0.35 | 1.89 ± 0.37 | 2.04 ± 0.34 | 1.51 ± 0.29 | 0.0002 | 0.02 | <0.0001 |
IL-10 pg/mL | 4 ± 1.83 | 6.27 ± 2 | 10.25 ± 3.69 | 3.72 ± 2.43 | <0.0001 | <0.0001 | <0.0001 |
IL-35 pg/mL | 108.9 ± 43. 7 | 136.4 ± 73.2 | 154.6 ± 87.5 | 65.6 ± 45.4 | 0.04 | 0.03 | <0.0001 |
BAFF pg/mL | 348.5 ± 292.1 | 451.7 ± 379 | 772 ± 463.6 | 272 ± 267.2 | <0.0001 | 0.001 | <0.0001 |
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Hetta, H.F.; Mekky, M.A.; Zahran, A.M.; Abdel-Malek, M.O.; Ramadan, H.K.; Shafik, E.A.; Abbas, W.A.; Abbas El-Masry, M.; Mohamed, N.A.; Kamel, A.A.; Marraiki, N.; Beshbishy, A.M.; Batiha, G.E.-S.; Osman, H.A.; Koneru, G.; El-Mokhtar, M.A. Regulatory B Cells and Their Cytokine Profile in HCV-Related Hepatocellular Carcinoma: Association with Regulatory T Cells and Disease Progression. Vaccines 2020, 8, 380. https://doi.org/10.3390/vaccines8030380
Hetta HF, Mekky MA, Zahran AM, Abdel-Malek MO, Ramadan HK, Shafik EA, Abbas WA, Abbas El-Masry M, Mohamed NA, Kamel AA, Marraiki N, Beshbishy AM, Batiha GE-S, Osman HA, Koneru G, El-Mokhtar MA. Regulatory B Cells and Their Cytokine Profile in HCV-Related Hepatocellular Carcinoma: Association with Regulatory T Cells and Disease Progression. Vaccines. 2020; 8(3):380. https://doi.org/10.3390/vaccines8030380
Chicago/Turabian StyleHetta, Helal F., Mohamed A. Mekky, Asmaa M. Zahran, Mohamed O. Abdel-Malek, Haidi K. Ramadan, Engy A. Shafik, Wael A. Abbas, Muhammad Abbas El-Masry, Nahed A. Mohamed, Amira A. Kamel, Najat Marraiki, Amany Magdy Beshbishy, Gaber El-Saber Batiha, Heba A. Osman, Gopala Koneru, and Mohamed A. El-Mokhtar. 2020. "Regulatory B Cells and Their Cytokine Profile in HCV-Related Hepatocellular Carcinoma: Association with Regulatory T Cells and Disease Progression" Vaccines 8, no. 3: 380. https://doi.org/10.3390/vaccines8030380