Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents

Lévy, Romain; Langlais, David; Béziat, Vivien; Rapaport, Franck; Rao, Geetha; Lazarov, Tomi; Bourgey, Mathieu; Zhou, Yu; Briand, C.; Moriya, K.; Ailal, Fatima; Avery, Danielle T.; Markle, Janet; Lim, Ai Ing; Ogishi, Masato; Yang, Rui; Pelham, Simon J.; Emam, Mehdi; Migaud, Mélanie; Deswarte, Caroline; Habib, Tanwir; Saraiva, Luís R.; Moussa, Eman Abou; Guennoun, Andrea; Boisson, Bertrand; Belkaya, Serkan; Martı́nez-Barricarte, Rubén; Rosain, Jérémie; Belkadi, Aziz; Breton, Sylvain; Payne, Kathryn; Plebani, Alessandro; Lougaris, Vassilios; Santo, James P. Di; Neven, Bénédicte; Abel, Laurent; Cindy, S.; Bousfiha, Ahmed Aziz; Marr, Nico; Bustamante, Jacinta; Liu, Kang; Gros, Philippe; Geissmann, Frédéric; Tangye, Stuart G.; Casanova, Jean Laurent; Puel, Anne

doi:10.1172/jci150143

Cited by 25 publications

(21 citation statements)

References 73 publications

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“…Additionally, six HERV elements were found to be up-regulated after the EBV-triggered immortalization of B cells ( Supplementary Table S5 ): three HERV-K elements located at chromosome 1q21.3 (JN675012.1), 12q24.11 (JN675069.1) and 22q11.23 (JN675088.1), as well as HERV-KC4 (X80240.1), HERV-9 (X57147.1) and HERV-W5 (AC117456.6:51035-52536). Interestingly, the up-regulation of these HERVs can be observed in B cell receptor (BCR) and CD40-stimulated B cells [ 42 ], but not in B cells stimulated by phorbol myristate acetate (PMA) [ 43 ] ( Supplementary Figure S5 ), suggesting activation of HERVs in B cells by stimulation of the BCR/CD40, which are pathways used by EBV for immortalization. Comparing MS and controls, we observed only six HERVs that showed an increased expression in MSLCL ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…LCL from the same PBMC donor were taken together and therefore served as biological replicates. Additional RNAseq data from activated B cells were downloaded from SRA (BioProjects PRJNA397793 [ 42 ] and PRJNA702159 [ 43 ]). Quantification of overall HERV expression was performed as described [ 44 ] by using the Galaxy server [ 45 ] for Bowtie2 mapping and quantification by FeatureCounts [ 46 ].…”

Section: Methodsmentioning

confidence: 99%

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Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis

Wieland

Schwarz

Engel

et al. 2022

Cells

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The immune pathogenesis of multiple sclerosis (MS) is thought to be triggered by environmental factors in individuals with an unfavorable genetic predisposition. Epstein–Barr virus (EBV) infection is a major risk factor for subsequent development of MS. Human endogenous retroviruses (HERVs) can be activated by EBV, and might be a missing link between an initial EBV infection and the later onset of MS. In this study, we investigated differential gene expression patterns in EBV-immortalized lymphoblastoid B cell lines (LCL) from MS-affected individuals (MSLCL) and controls by using RNAseq and qRT-PCR. RNAseq data from LCL mapped to the human genome and a virtual virus metagenome were used to identify possible biomarkers for MS or disease-relevant risk factors, e.g., the relapse rate. We observed that lytic EBNA-1 transcripts seemed to be negatively correlated with age leading to an increased expression in LCL from younger PBMC donors. Further, HERV-K (HML-2) GAG was increased upon EBV-triggered immortalization. Besides the well-known transactivation of HERV-K18, our results suggest that another six HERV loci are up-regulated upon stimulation with EBV. We identified differentially expressed genes in MSLCL, e.g., several HERV-K loci, ERVMER61-1 and ERV3-1, as well as genes associated with relapses. In summary, EBV induces genes and HERV in LCL that might be suitable as biomarkers for MS or the relapse risk.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis

Wieland

Schwarz

Engel

et al. 2022

Cells

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“…Finally, deficiency of c-REL in humans can be a cause for combined immunodeficiency (CID) [ 61 , 62 ]. The associated phenotype, which comprises lack of memory B cells, lack of isotype switched antibodies, and impaired B-cell proliferation, is consistent with the phenotype observed in the conditionally deleted Rel mice, suggesting that the observed human B-cell phenotype is cell autonomous.…”

Section: Role Of Nf-κb Signaling Pathways and Subunits In Gc B-cell D...mentioning

confidence: 99%

NF-κB Mutations in Germinal Center B-Cell Lymphomas: Relation to NF-κB Function in Normal B Cells

Pasqualucci

Klein

2022

Biomedicines

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Most B cell lymphomas arise from the oncogenic transformation of B cells that have undergone the germinal center (GC) reaction of the T cell-dependent immune response, where high-affinity memory B cells and plasma cells are generated. The high proliferation of GC B cells coupled with occasional errors in the DNA-modifying processes of somatic hypermutation and class switch recombination put the cell at a risk to obtain transforming genetic aberrations, which may activate proto-oncogenes or inactivate tumour suppressor genes. Several subtypes of GC lymphomas harbor genetic mutations leading to constitutive, aberrant activation of the nuclear factor-κB (NF-κB) signaling pathway. In normal B cells, NF-κB has crucial biological roles in development and physiology. GC lymphomas highjack these activities to promote tumour-cell growth and survival. It has become increasingly clear that the separate canonical and non-canonical routes of the NF-κB pathway and the five downstream NF-κB transcription factors have distinct functions in the successive stages of GC B-cell development. These findings may have direct implications for understanding how aberrant NF-κB activation promotes the genesis of various GC lymphomas corresponding to the developmentally distinct GC B-cell subsets. The knowledge arising from these studies may be explored for the development of precision medicine approaches aimed at more effective treatments of the corresponding tumours with specific NF-κB inhibitors, thus reducing systemic toxicity. We here provide an overview on the patterns of genetic NF-κB mutations encountered in the various GC lymphomas and discuss the consequences of aberrant NF-κB activation in those malignancies as related to the biology of NF-κB in their putative normal cellular counterparts.

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“…To what extent this reflects a preferential loss of Treg cells with high affinity TCRs as suggested from the mouse studies [ 35 ] remains to be investigated. Finally, the critical importance of c-Rel for Treg cell development was recently confirmed in a patient with inherited REL deficiency, who showed a reduction in Treg cell frequencies in the peripheral blood [ 83 ].…”

Section: Insights Into Treg Cell Differentiation From Human Patientsmentioning

confidence: 99%

NF-κB in control of regulatory T cell development, identity, and function

2022

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Regulatory T cells (Treg cells) act as a major rheostat regulating the strength of immune responses, enabling tolerance of harmless foreign antigens, and preventing the development of pathogenic immune responses in various disease settings such as cancer and autoimmunity. Treg cells are present in all lymphoid and non-lymphoid tissues, and the latter often fulfill important tasks required for the physiology of their host organ. The activation of NF-κB transcription factors is a central pathway for the reprogramming of gene expression in response to inflammatory but also homeostatic cues. Genetic mouse models have revealed essential functions for NF-κB transcription factors in modulating Treg development and function, with some of these mechanistic insights confirmed by recent studies analyzing Treg cells from patients harboring point mutations in the genes encoding NF-κB proteins. Molecular insights into the NF-κB pathway in Treg cells hold substantial promise for novel therapeutic strategies to manipulate dysfunctional or inadequate cell numbers of immunosuppressive Treg cells in autoimmunity or cancer. Here, we provide an overview of the manifold roles that NF-κB factors exert in Treg cells.

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Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents

Cited by 25 publications

References 73 publications

Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis

Epstein-Barr Virus-Induced Genes and Endogenous Retroviruses in Immortalized B Cells from Patients with Multiple Sclerosis

NF-κB Mutations in Germinal Center B-Cell Lymphomas: Relation to NF-κB Function in Normal B Cells

NF-κB in control of regulatory T cell development, identity, and function

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