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      B cell-associated immune profiles in patients with end-stage renal disease (ESRD)

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          Abstract

          Most of the previous studies on immune dysregulation in end-stage renal disease (ESRD) have focused on T cell immunity. We investigated B cell subpopulations in ESRD patients and the effect of hemodialysis (HD) on B cell-associated immune profiles in these patients. Forty-four ESRD [maintenance HD patients ( n = 27) and pre-dialysis patients ( n = 17)] and 27 healthy volunteers were included in this study. We determined the percentage of B cell subtypes, such as mature and immature B cells, memory B cells, and interleukin (IL)-10 + cells, as well as B cell-producing cytokines (IL-10, IL-4 and IL-21) by florescent activated cell sorting (FACS). B cell-associated gene expression was examined using real-time PCR and B cell producing cytokines (IL-10, IL-4 and IL-21) were determined using an enzyme-linked immunosorbent assay (ELISA). The percentage of total B cells and mature B cells did not differ significantly among the three groups. The percentages of memory B cells were significantly higher in the pre-dialysis group than in the HD group ( P < 0.01), but the percentage of immature B cells was significantly lower in the pre-dialysis group than in the other groups. The percentages of IL-10-expressing cells that were CD19 + or immature B cells did not differ significantly ( P > 0.05) between the two subgroups within the ESRD group, but the serum IL-10 concentration was significantly lower in the pre-dialysis group ( P < 0.01). The results of this study demonstrate significantly altered B cell-associated immunity. Specifically, an imbalance of immature and memory B cells in ESRD patients was observed, with this finding predominating in pre-dialysis patients.

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          Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6.

          IL-21 is a type I cytokine whose receptor is expressed on T, B, and NK cells. Within the B cell lineage, IL-21 regulates IgG1 production and cooperates with IL-4 for the production of multiple Ab classes in vivo. Using IL-21-transgenic mice and hydrodynamics-based gene delivery of IL-21 plasmid DNA into wild-type mice as well as in vitro studies, we demonstrate that although IL-21 induces death of resting B cells, it promotes differentiation of B cells into postswitch and plasma cells. Thus, IL-21 differentially influences B cell fate depending on the signaling context, explaining how IL-21 can be proapoptotic for B cells in vitro yet critical for Ag-specific Ig production in vivo. Moreover, we demonstrate that IL-21 unexpectedly induces expression of both Blimp-1 and Bcl-6, indicating mechanisms as to how IL-21 can serve as a complex regulator of B cell maturation and terminal differentiation. Finally, BXSB-Yaa mice, which develop a systemic lupus erythematosus-like disease, have greatly elevated IL-21, suggesting a role for IL-21 in the development of autoimmune disease.
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            BLNK: a central linker protein in B cell activation.

            Linker or adapter proteins provide mechanisms by which receptors can amplify and regulate downstream effector proteins. We describe here the identification of a novel B cell linker protein, termed BLNK, that interfaces the B cell receptor-associated Syk tyrosine kinase with PLCgamma, the Vav guanine nucleotide exchange factor, and the Grb2 and Nck adapter proteins. Tyrosine phosphorylation of BLNK by Syk provides docking sites for these SH2-containing effector molecules that, in turn, permits the phosphorylation and/or activation of their respective signaling pathways. Hence, BLNK represents a central linker protein that bridges the B cell receptor-associated kinases with a multitude of signaling pathways and may regulate the biologic outcomes of B cell function and development.
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              Effect of end-stage renal disease on B-lymphocyte subpopulations, IL-7, BAFF and BAFF receptor expression

              Background. End-stage renal disease (ESRD) results in increased susceptibility to infections, impaired response to vaccination and diffuse B-cell lymphopenia. However, the precise nature and mechanism of ESRD-induced B-cell lymphopenia remains unclear. Therefore, we studied the distribution of major B-cell subsets, B-cell growth, differentiation and survival factors, IL-7 and BAFF, and their receptors in 21 haemodialysis patients and 21 controls. Methods. Innate B1 cells (CD19+, CD5+), conventional B2 cells (CD19+, CD5−), newly formed transitional B cells (CD19+, CD10+, CD27−), naïve B cells (CD19+, CD27−) and memory B cells (CD19+, CD27+) and BAFF receptor were quantified by flow cytometry. Plasma IL-7, BAFF, IL-6, TNF-α and IL-10 were measured by ELISA. Results. The ESRD group exhibited significant reductions of all B-cell subpopulations except for transitional B cells that were less severely affected. No significant difference was found in B-cell apoptosis between the ESRD and control groups. Moreover, plasma IL-7 and BAFF levels were elevated in ESRD patients, therefore excluding their deficiencies as a possible culprit. However, BAFF receptor expression was significantly reduced in transitional but not mature B cells in the ESRD group. Interestingly, B-cell activation with the TLR9 agonist resulted in significantly greater production of IL-6 and TNF alpha but not IL-10 in the ESRD group. Conclusions. Thus, despite elevation of B-cell growth, differentiation and survival factors, ESRD patients exhibited diffuse reduction of B-cell subpopulations. This was associated with the down-regulation of BAFF receptor in transitional B cells. The latter can, in part, contribute to B-cell lymphopenia by promoting resistance to the biological actions of BAFF that is a potent B-cell differentiation and survival factor.
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                Author and article information

                Journal
                Exp Mol Med
                Exp. Mol. Med
                EMM
                Experimental & Molecular Medicine
                Korean Society for Biochemistry and Molecular Biology
                1226-3613
                2092-6413
                31 August 2012
                23 May 2012
                : 44
                : 8
                : 465-472
                Affiliations
                [1 ]Conversant Research Consortium in Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-040, Korea.
                [2 ]Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-040, Korea.
                [3 ]Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-040, Korea.
                [4 ]Rheumatism Research Center, Catholic Institute of Medical Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-040, Korea.
                [5 ]Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 137-040, Korea.
                Author notes
                Corresponding authors: Tel, 82-2-536-0323; Fax, 82-2-2258-6037; yangch@ 123456catholic.ac.kr (C.W.Y.), Tel, 82-2-599-4287; Fax, 82-2-2258-7467; iammila@ 123456catholic.ac.kr (M.L.C.)

                *These authors contributed equally to this work.

                Article
                10.3858/emm.2012.44.8.053
                3429810
                22617684
                c403a27f-5922-40cc-bf8e-8fe86d881104
                Copyright © 2012 by the Korean Society for Biochemistry and Molecular Biology

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 May 2012
                Categories
                Original Article

                Molecular medicine
                precursor cells, b-lymphoid,renal dialysis,b-lymphocyte subsets,kidney failure, chronic

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