Scandinavian Journal of Gastroenterology. 2015; Early Online, 1–8

ORIGINAL ARTICLE

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B-cell–associated immune profiles in patients with decompensated cirrhosis

JOO YEON JHUN1,2,*, HEE YEON KIM1,3,*, JAE KYEONG BYUN1,2, BYUNG HA CHUNG1,4, SI HYUN BAE1,3, SEUNG KEW YOON1,3, DONG GOO KIM5, CHUL WOO YANG1,4, MI-LA CHO1,2,* & JONG YOUNG CHOI3,* 1

Conversant Research Consortium in Immunologic Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea, 2Rheumatism Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea, 3Division of Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea, 4 Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea, and 5Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea

Abstract Objective. Previous observations on immune dysfunction in decompensated cirrhosis have raised the possibility of B-cell impairment. Methods. B-cell subsets in decompensated cirrhotic patients were investigated. Twenty-six decompensated cirrhotic patients and 26 healthy controls were included in this study. The percentages of B-cell subsets, such as mature, memory, immature B cells, and interleukin (IL)-10+-B-cell subpopulations, were measured using fluorescent activated cell sorting. B-cell–associated cytokines (IL-10, IL-21 and IL-4) were determined using an enzyme-linked immunosorbent assay. Results. The percentage of total B cells and mature B cells increased in patients with decompensated cirrhosis compared to healthy controls. The proportions of memory B cells were significantly lower in the decompensated cirrhosis group than the control group. However, the frequency of immature B cells and the percentage of IL-10–expressing cells that were CD19+, memory, mature, or immature B cells were not significantly different between the two groups. Serum levels of IL-10, IL-21, and IL-4 were significantly lower in the decompensated cirrhosis group compared to the control group. Conclusion. These results indicate significant alterations in peripheral blood B-cell subsets in patients with decompensated cirrhosis. Specifically, a profound reduction of memory B cells was observed in spite of an increase in total B-cell populations in decompensated cirrhotic patients. This implies the underlying mechanisms of impaired immune response in these patients.

Key Words: B-lymphocyte subsets, immunity, interleukin-10, liver cirrhosis

Introduction Liver cirrhosis is the final outcome of the majority of all chronic liver diseases. With progressive portal hypertension, hepatic synthetic impairment, or cancer development, hepatic decompensation ultimately occurs in cirrhotic patients [1,2]. Patients with decompensated cirrhosis are especially in an

immunocompromised state that is at high risk for invasive bacterial infections [3]. Bacterial infections, including spontaneous bacterial peritonitis and bacteremia, account for approximately 30% of all morbidity and mortality cases [4]. Local and systemic immune dysfunction in these patients is multifactorial and mediated by portosystemic shunting, reticuloendothelial system dysfunction [5], altered neutrophil

Correspondence: Jong Young Choi, MD PhD, Professor, Division of Hepatology, Department of Internal Medicine, College of Medicine, Seoul St. Mary’s Hospital, Catholic University of Korea, #505 Banpo-Dong, Seocho-Gu, Seoul, 137-040, Korea. Tel: +82 2 2258 2073. Fax: +82 2 3481 4025. E-mail: [email protected] and Mi-La Cho PhD, Professor, Conversant Research Consortium in Immunologic disease, College of Medicine, The Catholic University of Korea, 505 Banpo-Dong, Seocho-Ku, 137-040, Seoul, Korea. Tel: +82 2 2258 7467. Fax: +82 2 599 4287. E-mail: [email protected] *Authors contributed equally to this work.

(Received 23 September 2013; revised 24 February 2014; accepted 17 March 2014) ISSN 0036-5521 print/ISSN 1502-7708 online  2015 Informa Healthcare DOI: 10.3109/00365521.2014.907335

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function [5], impaired opsonic activity, reduction in complement [6], increased intestinal permeability [7], and bacterial translocation [8]. Recent studies reported that the dysregulation between T helper 17 cells and regulatory T cells contributes to the severity of the progression of the disease in patients with liver cirrhosis [9–11]. Despite the strong functional interplay between T and B lymphocytes in immunopathological processes, whether B cells play a significant role in the development of impaired immunity in patients with decompensated cirrhosis remains unclear. Several observations suggested that the impairment of B cells also contributes to this immune dysfunction state among decompensated cirrhotic patients. For instance, merely 16% of adult chronic liver disease patients waiting for a liver transplant developed protective antibodies against the hepatitis B virus (HBV) surface antigen after vaccination with recombinant HBV vaccine [12]. Similarly, cirrhotic patients displayed impaired immunoglobulin (Ig)G production after pneumococcal vaccination [13]. Despite these observed vaccination hyporesponsiveness, serum levels of pathogen-specific Igs were paradoxically elevated in cirrhotic patients [14,15]. However, there are limited data available showing the impact of cirrhosis on B cells. Recently, Doi H et al. reported that independent of hepatitis C virus infection, there were profound defects in B-cell phenotype and its function in cirrhosis [16]. Given the limited research on B-cell phenotype and its function regardless of the immune dysfunction of decompensated liver cirrhosis, B-cell immune profiles in a group of patients with decompensated cirrhosis were investigated. Materials and methods Patient samples We prospectively recruited 26 patients with decompensated cirrhosis before they underwent the liver transplantation at Seoul St. Mary’s Hospital (Seoul, Korea) from July 2010 to February 2011. Patients with hepatitis C infection, human immunodeficiency virus infection, autoimmune liver diseases, hepatocellular carcinoma, and concurrent bacterial infection were excluded. Blood sample was collected before commencement of the immunosuppressive treatment. Twenty-six age- and sex-matched healthy donors were enrolled as controls. This study was approved by the institutional ethics committee of Seoul St. Mary’s Hospital (KC10TISI0433), and written informed consent from all patients and all clinical investigations have been conducted according

Table I. Baseline clinical and laboratory characteristics of patient population. Decompensated liver cirrhosis (n = 26) Age (years) 53.9 ± 7.9 Male (n, %) 16 (61.5%) Etiology Hepatitis B/Alcohol/others 12/8/6 (46.1%/30.8%/23.1%) 4.4 ± 2.5 White blood cell count (103/mm3) Platelet (K/mm3) 80.1 ± 56.0 Total bilirubin (mg/dl) 6.4 ± 8.5 Alanine aminotransferase (U/l) 78 ± 55 Albumin (g/dl) 2.9 ± 0.3 PT (INR) 1.6 ± 0.7 Child-Pugh class (B/C) 15/11 MELD score 12.4 ± 7.6 Continuous data are expressed as the mean values ± standard deviation. Abbreviation: MELD, model for end-stage liver disease.

to the principles expressed in the Declaration of Helsinki of 1975. Baseline clinical characteristics are summarized in Table I. PBMC isolation and FACS analysis Peripheral blood mononuclear cells (PBMCs) were isolated from heparinized venous blood by standard density gradient centrifugation over Ficoll-Paque (GE Healthcare Biosciences, Sweden, Uppsala). Cell cultures were performed in RPMI1640 medium (GibcoBRL, Carlsbad, CA, USA) containing penicillin (100 U/ml), streptomycin (100 mg/ml), and 10% fetal bovine serum (GibcoBRL) that had been inactivated by heating to 55 C for 30 min. The cell suspensions were dispensed into 48-well plates (Nunc, Roskilde, Denmark). PBMCs were stimulated with 50 ng/ml of phorbol myriste acetate (PMA) (Sigma-Aldrich, ST. Louis, MO, USA), 1 mg/ml of ionomycin (SigmaAldrich), and Golgi Stop (BD Biosciences, San Diego, CA, USA), which were added for 4 h. The cells were washed and 5  105 cells per sample were incubated for surface markers for 30 min at 4 C in the dark. The cells were then permeabilized using a Cytofix/cytoperm Plus kit (BD Bioscience) and stained with antibodies specific for intracellular markers for 30 min at 4 C in the dark. Antibodies used for flow cytometry Cells were stained with combinations of the following monoclonal antibodies (mAbs): CD38-PerCP cy5.5 (HIT2, IgG1,; PharMingen); CD19–FITC (SJ25-C1, IgG1; SouthernBiotech, Birmingham, Alabama); and CD24–PE (ML5, IgG2a,; PharMingen).

B cell subsets in decompensated LC Cells were washed, fixed, permeabilized, and stained to detect intracellular cytokines with mAbs to IL-10– APC (JES3-19F1, IgG2a,; PharMingen). Appropriate isotype controls were used for gate-setting for cytokine expression. Cells were analyzed on a FACSCalibur flow cytometry system (Becton Dickinson Systems).

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Enzyme-linked immunosorbent assay In brief, a 96-well plate (Nunc) was coated with 4 g/ml mAbs against IL-10, IL-21, and IL-4 (R&D Systems) at 4 C overnight. After blocking with phosphatebuffered saline (PBS)/1% bovine serum albumin/ 0.05% Tween 20 for 2 h at room temperature (22– 25 C), test samples and the standard recombinant IL-10, IL-21, and IL-4 were added to the 96-well plate and incubated at room temperature for 2 h. Plates were washed four times with PBS/Tween 20 and then incubated with 500 ng/ml biotinylated mouse mAbs against IL-10, IL-21, and IL-4 for 2 h at room temperature. After washing, streptavidin– alkaline phosphate–horseradish peroxidase conjugate (Sigma) was added, and the plate was incubated for 2 h. The plate was washed again and incubated with 1 mg/ml p-nitrophenyl phosphate (Sigma) dissolved in diethanolamine (Sigma) to develop the color reaction. The reaction was stopped by the addition of 1 M NaOH, and the optical density of each well was read at 405 nm. The lower limit of IL-10, IL-21, and IL-4 detection was 10 pg/ml. Recombinant human IL-10, IL-21, and IL-4 diluted in culture medium were used as the calibration standards whose concentrations ranged from 10 to 2000 pg/ml. A standard curve was drawn by plotting optical density against the log of the concentration of recombinant cytokines and was used to calculate the IL-10, IL-21, and IL-4 concentrations in the test samples. In addition, total IgG in the plasma was measured and the plasma was stored at –20 C until use. The total IgG was measured using the human IgG ELISA quantitation kit (Bethyl Lab, Montgomery, TX, USA). Cytokine assay in the culture supernatants PBMCs were activated at a concentration of 5  105/ 500 ml medium with anti-CD3 (0.5 mg/ml) for 72 h. Culture supernatants were used for IL-10, IL-21, and IL-4 assays. Statistical analysis Continuous variables were compared using Mann– Whitney U test. For categorical variables, Fisher’s exact test was used. A p value less than 0.05 was considered statistically significant. All statistical tests

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were performed using GraphPad Prism v. 4.03 software (GraphPad Software, La Jolla, CA, USA). Results Baseline clinical and laboratory findings of the patient population The baseline characteristics of the enrolled patients are presented in Table I. Mean patient age was 53.9 ± 7.9 years. The underlying causes of liver cirrhosis were hepatitis B (n = 12), alcohol (n = 8), and other causes (n = 6). Hepatic function of enrolled patients was classified as Child-Pugh class B in 15, and class C in 11 patients. Comparison of B-cell subtype (CD19+ total B cells, memory B cells, mature B cells, and immature B cells) As shown in Figures 1 and 2, the percentage of CD19+ total B cells in the blood was significantly higher in the decompensated cirrhosis group than in the healthy controls. The values were 11.9 ± 4.7% in the decompensated cirrhosis group and 8.3 ± 2.3% in the healthy controls (p = 0.009). The frequency of mature B cells was also significantly higher in the decompensated cirrhosis group than in the control group (66.5 ± 8.9% and 51.8 ± 7.6%, respectively; p < 0.001). In contrast, the frequency of memory B cells was significantly lower in the decompensated cirrhosis group compared to the healthy controls (13.4 ± 6.3% and 29.3 ± 9.7%, respectively; p = 0.003). However, the frequencies of immature B cells did not differ between the two groups (7.6 ± 3.5% and 7.6 ± 3.5%, respectively; p > 0.05). Comparison of IL-10+ B-cell subpopulations As shown in Figure 3, the percentage of IL-10+/ CD19+ B cells in the decompensated cirrhosis group (6.2 ± 4.2%) did not significantly differ compared to that in the control group (6.7 ± 3.1%; Figure 3A). In addition, the frequency of IL-10+ memory B, mature B, and immature B cells was not significantly different between the decompensated cirrhosis group (IL-10+ memory B, 10.2 ± 6.8%; IL-10+ mature B cells, 4.5 ± 3.4%; IL-10+ immature B cells, 8.1 ± 7.5%) and the control group (IL-10+ memory B, 7.6 ± 3.2%; IL-10+ mature B cells, 3.3 ± 0.9%; IL-10+ immature B cells, 11.0 ± 7.9%) (Figure 3B-D). Comparison of cytokine and IgG levels As shown in Figures 4A-C, serum levels of IL-10, IL-21, and IL-4 were significantly lower in the

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Figure 1. Flow cytometric analysis of B-cell subsets. PBMC was stained with anti-CD19 FITC, anti-CD24 PE, anti-CD38 PerCP cy5.5, and anti-IL-10 APC. CD19+ cells were gated for further analysis. B cells were divided into subpopulations according to the expression CD24+, CD38+, and IL-10+; CD19+CD24+CD38- (Memory B cells), CD19+CD24+CD38inter (Mature B cells), CD19+CD24+CD38+ (Immature B cells).

decompensated cirrhosis group than in the control group. Serum cytokine values were as follows: IL-10, decompensated cirrhosis group, 26.8 ± 4.9 pg/ml; control group, 318.9 ± 41.2 pg/ml; IL-21, decompensated cirrhosis group, 9.7 ± 7.1 pg/ml; control group, 37.4 ± 8.1 pg/ml; IL-4, decompensated cirrhosis group, 30.1 ± 8.6 pg/ml; control group, 56.5 ± 15.8 pg/ml. Concentration of IL-21 cytokine in the culture supernatants of PBMCs was substantially decreased in the decompensated cirrhosis group compared to the control group (Figure 4E). The concentrations of IL-10 and IL-4 cytokines in the culture supernatants of PBMCs showed no difference

between control and decompensated cirrhosis groups (Figure 4D and F). Serum total IgG levels increased in decompensated cirrhosis group (315.5 ± 73.4 ng/ml) compared to the control group (494.8 ± 112.6 ng/ml) (p < 0.001). Discussion In this study, we evaluated the B-cell immune profiles among decompensated cirrhosis patients, which were then compared to the general population. Our data exhibited the different distribution of B-cell subset both groups. Most notably were the increase in

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Figure 2. Distribution of CD19+ total B-cell, memory B-cell, mature B-cell, and immature B-cell subsets in the healthy control and decompensated cirrhosis group. PBMCs from healthy controls (n = 26) and decompensated cirrhotic patients (n = 26) were stimulated for 4 h ex vivo with PMA and ionomycin in the presence of GolgiStop. The percentages of CD19+ total B cells, memory B cells, mature B cells, and immature B cells were measured by flow cytometry. The frequency (%) of CD19+ lymphocytes (A), memory B cells (CD24+CD38-/CD19+ cells) (B), mature B cells (CD24+CD38inter/CD19+ cells) (C), and immature B cells (CD24+CD38+/CD19+ cells) (D) in healthy controls and patients. Bars show the means. *p < 0.05; **p < 0.01; ***p < 0.001.

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Figure 3. Distribution of IL-10+ B-cell subsets in the healthy control and decompensated cirrhosis group. PBMCs were treated as described in Figure 1 and Materials and Methods. (A) The frequency (%) of IL-10+/CD19+ cells in healthy controls and patients. (B) The frequency (%) of memory B cells IL-10+ (CD24+CD38-IL-10+/CD24+CD38-) in healthy controls and patients. (C) The frequency (%) of mature B cells IL-10+ (CD24+CD38interIL-10+/CD24+CD38inter) in healthy controls and patients. (D) The frequency (%) of immature B cells IL-10+ (CD24+CD38+IL-10+/CD24+CD38+) in healthy controls and patients. Bars show the means. *p < 0.05.

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Figure 4. Expression of IL-10, IL-21, and IL-4 in the serum in the culture supernatants of the healthy controls and decompensated cirrhosis. (A) Concentrations of IL-10 in serum samples. (B) Concentrations of IL-21 in serum samples. (C) Concentrations of IL-4 in serum samples. (D) Concentrations of IL-10 in the culture supernatants of PBMCs. (E) Concentrations of IL-21 in the culture supernatants of PBMCs. (F) Concentrations of IL-4 in the culture supernatants of PBMCs. The data represent the mean ± SD of three separate experiments. *p < 0.05; **p < 0.01.

mature B cells and the decrease in memory B cells found in the decompensated cirrhosis group. The proportion of mature B cells increased in patients with decompensated cirrhosis compared to the healthy controls (Figure 2C; p < 0.001). To establish if the enhanced mature B-cell frequency has an increased propensity to terminal differentiation or resistance to apoptosis is yet to be elucidated. Our finding of decrease in memory B cells in the decompensated cirrhosis group is in line with the recent report indicating a reduction in CD27+ memory B cells in cirrhotic patients [16]. The loss of memory B cells was also identified in patients with human immunodeficiency virus (HIV) infection, where bacterial translocation is increased through the disruption of intestinal integrity due to the infection of gastrointestinal lymphoid tissue [17,18]. Bacterial translocation causes nonspecific immune activation, thus linking to memory B-cell loss [19,20]. Similar to patients with HIV infection, bacterial translocation can occur in cirrhotic patients due to intestinal bacterial overgrowth, increased intestinal permeability, and immunological impairment [17,18]. Results showed that total serum IgG levels were elevated in decompensated cirrhotic patients. The

paradoxical state of hypergammaglobulinemia, despite the loss of memory B cells, was also observed in the previous studies. Overall, Ig levels were elevated in patients with cirrhosis in consequence of increased levels of pathogen-specific Igs [14,15]. Taken together, nonspecific immune activation and exhaustion by bacterial translocation in cirrhosis may be a possible explanation for the reduction seen in memory B cells as they are capable of mounting rapid responses to subsequent antigenic encounters [21]. Therefore, the loss of memory B cells supports the observations of the hyporesponsiveness to vaccine and an elevated incidence of infections in end-stage liver disease [12,13,22]. CD19+CD24hiCD38hi B cells have been recently identified as a particular subset of human regulatory B cells with suppressive capacity [23]. This regulatory B subset has been identified to modulate immune responses in autoimmunity, infection, and cancer [24–26]. Moreover, a recent study has investigated the regulatory B cells in the pathogenesis of chronic HBV infection [27]. However, the significance of regulatory B cells regarding liver cirrhosis has not yet been elucidated. In this study, there was no significant difference in the proportions of regulatory

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B cell subsets in decompensated LC B cells between the decompensated cirrhosis group and control group. To elucidate whether this cell type is dysregulated based on the stage of the cirrhosis still needs to be investigated. Previous research has reported that IL-10 has a role in human B-cell activation, proliferation, and differentiation [28], thus researching this cytokine of interest. Results showed that IL-10 levels were significantly lower in the decompensated cirrhosis group than in the control group in accordance with decrease in memory B cells. Serum IL-21 influences B-cell activation, proliferation, and antibody secretion [29]. And our data displayed significantly lower levels of serum IL-21 in the decompensated cirrhosis group than that of the healthy controls. It has been reported that IL-21 was found to act directly on germinal center B cells or to promote polarization toward a follicular B-helper T-like gd T cells [30,31], leading to increased memory. Therefore, the decreased serum IL-21 observed in decompensated cirrhosis group may contribute to the loss of memory B cells. Follicular B-helper T-like gd T cells help B-cells produce antibodies via IL-4 [30]. Here, IL-4 levels decreased in the decompensated cirrhosis group compared to the control group, contributing to the decreased number of memory B cells. There was some discrepancy between serum levels and concentrations in the culture supernatants of IL-21, IL-10, and IL-4. One explanation for this discrepancy could be that the cytokine environment in vivo is so complicated and influenced by other serum factors. In conclusion, patients with decompensated cirrhosis showed a significant reduction of memory B cells despite an increase in total B-cell populations. The frequency of B cells with regulatory function did not differ between the decompensated cirrhosis patients and the healthy controls. The most prominent finding of memory B-cell loss may explain one of the underlying mechanisms of impaired immune response found in decompensated cirrhosis patients. Acknowledgments This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2013R1A1A2011680) and partly supported by a grant of the Korean Health Technology R&D Project, Ministry for Health & Welfare, Republic of Korea (HI09C1555). Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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B-cell-associated immune profiles in patients with decompensated cirrhosis.

Previous observations on immune dysfunction in decompensated cirrhosis have raised the possibility of B-cell impairment...
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