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      Elevated numbers of PD-L1 expressing B cells are associated with the development of AIDS-NHL

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          Abstract

          The risk for non-Hodgkin lymphoma (NHL) is markedly increased in persons living with human immunodeficiency virus (HIV) infection, and remains elevated in those on anti-retroviral therapy (cART). Both the loss of immunoregulation of Epstein-Barr virus (EBV) infected cells, as well as chronic B-cell activation, are believed to contribute to the genesis of AIDS-related NHL (AIDS-NHL). However, the mechanisms that lead to AIDS-NHL have not been completely defined. A subset of B cells that is characterized by the secretion of IL10, as well as the expression of the programmed cell death ligand-1 (PD-L1/CD274), was recently described. These PD-L1 + B cells can exert regulatory function, including the dampening of T-cell activation, by interacting with the program cell death protein (PD1) on target cells. The role of PD-L1 + B cells in the development of AIDS-NHL has not been explored. We assessed B cell PD-L1 expression on B cells preceding AIDS-NHL diagnosis in a nested case-control study of HIV+ subjects who went on to develop AIDS-NHL, as well as HIV+ subjects who did not, using multi-color flow cytometry. Archival frozen viable PBMC were obtained from the UCLA Multicenter AIDS Cohort Study (MACS). It was seen that the number of CD19 +CD24 ++CD38 ++and CD19 +PD-L1 +cells was significantly elevated in cases 1–4 years prior to AIDS-NHL diagnosis, compared to controls, raising the possibility that these cells may play a role in the etiology of AIDS-NHL. Interestingly, most PD-L1 + expression on CD19 + cells was seen on CD19 +CD24 ++CD38 ++ cells. In addition, we showed that HIV can directly induce PD-L1 expression on B cells through interaction of virion-associated CD40L with CD40 on B cells.

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          Most cited references 26

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          Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas.

          Genomic instability promotes tumorigenesis and can occur through various mechanisms, including defective segregation of chromosomes or inactivation of DNA mismatch repair. Although B-cell lymphomas are associated with chromosomal translocations that deregulate oncogene expression, a mechanism for genome-wide instability during lymphomagenesis has not been described. During B-cell development, the immunoglobulin variable (V) region genes are subject to somatic hypermutation in germinal-centre B cells. Here we report that an aberrant hypermutation activity targets multiple loci, including the proto-oncogenes PIM1, MYC, RhoH/TTF (ARHH) and PAX5, in more than 50% of diffuse large-cell lymphomas (DLCLs), which are tumours derived from germinal centres. Mutations are distributed in the 5' untranslated or coding sequences, are independent of chromosomal translocations, and share features typical of V-region-associated somatic hypermutation. In contrast to mutations in V regions, however, these mutations are not detectable in normal germinal-centre B cells or in other germinal-centre-derived lymphomas, suggesting a DLCL-associated malfunction of somatic hypermutation. Intriguingly, the four hypermutable genes are susceptible to chromosomal translocations in the same region, consistent with a role for hypermutation in generating translocations by DNA double-strand breaks. By mutating multiple genes, and possibly by favouring chromosomal translocations, aberrant hypermutation may represent the major contributor to lymphomagenesis.
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            AID is required for c-myc/IgH chromosome translocations in vivo.

            Chromosome translocations between c-myc and immunoglobulin (Ig) are associated with Burkitt's lymphoma in humans and with pristane- and IL6-induced plasmacytomas in mice. These translocations frequently involve Ig switch regions, suggesting that they might be the result of aberrant Ig class switch recombination (CSR). However, a direct link between CSR and chromosome translocations has not been established. We have examined c-myc/IgH translocations in IL6 transgenic mice that are mutant for activation induced cytidine deaminase (AID), the enzyme that initiates CSR. Here we report that AID is essential for the c-myc/IgH chromosome translocations induced by IL6.
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              AID is required for germinal center-derived lymphomagenesis.

              Most human B cell non-Hodgkin's lymphomas (B-NHLs) derive from germinal centers (GCs), the structure in which B cells undergo somatic hypermutation (SHM) and class switch recombination (CSR) before being selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant SHM, which arise from mistakes occurring during CSR and SHM. A direct link between these DNA remodeling events and GC lymphoma development, however, has not been demonstrated. Here we have crossed three mouse models of B cell lymphoma driven by oncogenes (Myc, Bcl6 and Myc/Bcl6; refs. 5,6) with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both CSR and SHM. We show that AID deficiency prevents Bcl6-dependent, GC-derived B-NHL, but has no impact on Myc-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of CSR- and SHM-mediated structural alterations. These results show that AID is required for GC-derived lymphomagenesis, supporting the notion that errors in AID-mediated antigen-receptor gene modification processes are principal contributors to the pathogenesis of human B-NHL.
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                Author and article information

                Contributors
                mepeldegui@mednet.ucla.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                28 June 2019
                28 June 2019
                2019
                : 9
                Affiliations
                [1 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, UCLA AIDS Institute, , University of California, ; Los Angeles, California USA
                [2 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Jonsson Comprehensive Cancer Center, , University of California, ; Los Angeles, California USA
                [3 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Obstetrics and Gynecology, David Geffen School of Medicine, , University of California, ; Los Angeles, California USA
                [4 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Preventive Medicine Keck School of Medicine and Norris Comprehensive Cancer Center, , University of Southern California, ; Los Angeles, California USA
                [5 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, , University of Southern California, ; Los Angeles, California USA
                [6 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Division of Surgical Oncology, Department of Surgery, David Geffen School of Medicine, , University of California, ; Los Angeles, California USA
                [7 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, , University of California, ; Los Angeles, California USA
                [8 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, The Molecular Biology Institute, , University of California, ; Los Angeles, California USA
                [9 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, Department of Epidemiology, UCLA Fielding School of Public Health, , University of California, ; Los Angeles, California USA
                Article
                45479
                10.1038/s41598-019-45479-3
                6599055
                31253857
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100000054, U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI);
                Award ID: R01-CA168482-S
                Award ID: R21-CA220475
                Award ID: R01-CA196266
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100006492, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID);
                Award ID: P30-AI028697-S
                Award Recipient :
                Categories
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                © The Author(s) 2019

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                immunology, hiv infections

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