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B Cells and Immunological Tolerance
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B Cells and Immunological Tolerance

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (25 September 2018) | Viewed by 42131

Special Issue Editors

Dr. Marcos López-Hoyos

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Guest Editor
1. Immunology Service, University Hospital Marqués de Valdecilla-IDIVAL, 39008 Santander, Spain
2. Molecular Biology Department, Universidad de Cantabria, 39005 Santander, Spain
Interests: immunology; autoimmunity; transplantation; tolerance; human pathology; biomarkers
Special Issues, Collections and Topics in MDPI journals
Dr. Ramón Merino

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Guest Editor
Instituto de Biomedicina y Biotecnología de Cantabria, Consejo Superior de Investigaciones Científicas-Universidad de Cantabria, Molecular Biology Department, Universidad de Cantabria, 39011 Santander, Spain
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The main goal of the immune system is to protect the body against foreign agents. To achieve this mission, the immune system acquires an advanced degree of specialization that allows it to recognize and neutralize any pathogen and danger signal present in the organism. The immune response must be capable of being triggered by harmful extraneous stimuli and, once the danger is eliminated, it must be silenced and not perpetuated over time. A failure in the correct shutdown of the immune response may be the basis of many inflammatory processes. On the other hand, this high degree of specialization increases the risk of systemic ruptures of the physiological mechanisms controlling immunological tolerance and anomalous or unanticipated responses are induced, as in the case of autoimmune diseases, where some "misguided" immune cells attack their own antigens (autoantigens). To counter these effects, the immune system has established a balanced equilibrium between the effector and the inhibitor mechanisms of the immune response. This issue focuses on tolerance mechanisms affecting B cell responses from the molecular level (microRNA, microbiota…) to the cellular level (apoptosis, Bregs). These are targets for the development of diagnostic and/or therapeutic approaches in human inflammatory, autoimmune or alloimmune processes.

Dr. Marcos López-Hoyos
Dr. Ramón Merino
Guest Editors

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Keywords

  • B cell tolerance
  • autoimmune
  • alloimmune
  • mechanisms
  • diagnostic
  • therapeutics

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Related Special Issue

Published Papers (7 papers)

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Research

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14 pages, 2299 KiB  
Article
The Role of CD38 on the Function of Regulatory B Cells in a Murine Model of Lupus
by Brianna Burlock, Gabrielle Richardson, Sonia García-Rodríguez, Salvador Guerrero, Mercedes Zubiaur and Jaime Sancho
Int. J. Mol. Sci. 2018, 19(10), 2906; https://doi.org/10.3390/ijms19102906 - 25 Sep 2018
Cited by 14 | Viewed by 5638
Abstract
Previous work from our group has shown that Cd38−/− mice develop a milder pristane-induced lupus disease than WT or Art2−/− counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 [...] Read more.
Previous work from our group has shown that Cd38−/− mice develop a milder pristane-induced lupus disease than WT or Art2−/− counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 (TRPM2)-dependent apoptosis-driven mechanism. In this study we asked whether CD38 may play a role in the expression and function of regulatory B cells (IL-10-producing B cells or B10 cells). In pristane-treated mice the frequency of spleen CD19+CD1dhiCD5+ B cells, which are highly enriched in B10 cells, was significantly increased in Cd38−/− splenocytes compared to WT, while the frequency of peritoneal plasmacytoid dendritic cells (pDCs), which are major type I Interferon (IFN) producers, was greatly diminished. The low proportion of pDCs correlated with lower amounts of IFN-α in the peritoneal lavage fluids of the Cd38−/− mice than of WT and Art2−/− mice. Functional ex vivo assays showed increased frequencies of IL-10-producing B cells in Cd38−/− splenocytes than in WT upon stimulation with an agonist anti-CD40 mAb. Overall these results strongly suggest that Cd38−/− mice are better suited than WT mice to generate and expand regulatory B10 cells following the appropriate stimulation. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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20 pages, 2504 KiB  
Article
Trans-Ethnic Mapping of BANK1 Identifies Two Independent SLE-Risk Linkage Groups Enriched for Co-Transcriptional Splicing Marks
by Manuel Martínez-Bueno, Nina Oparina, Mikhail G. Dozmorov, Miranda C. Marion, Mary E. Comeau, Gary Gilkeson, Diane Kamen, Michael Weisman, Jane Salmon, Joseph W. McCune, John B. Harley, Robert Kimberly, Judith A. James, Joan Merrill, Courtney Montgomery, Carl D. Langefeld and Marta E. Alarcón-Riquelme
Int. J. Mol. Sci. 2018, 19(8), 2331; https://doi.org/10.3390/ijms19082331 - 8 Aug 2018
Cited by 13 | Viewed by 4013
Abstract
BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the [...] Read more.
BANK1 is a susceptibility gene for several systemic autoimmune diseases in several populations. Using the genome-wide association study (GWAS) data from Europeans (EUR) and African Americans (AA), we performed an extensive fine mapping of ankyrin repeats 1 (BANK1). To increase the SNP density, we used imputation followed by univariate and conditional analysis, combined with a haplotypic and expression quantitative trait locus (eQTL) analysis. The data from Europeans showed that the associated region was restricted to a minimal and dependent set of SNPs covering introns two and three, and exon two. In AA, the signal found in the Europeans was split into two independent effects. All of the major risk associated SNPs were eQTLs, and the risks were associated with an increased BANK1 gene expression. Functional annotation analysis revealed the enrichment of repressive B cell epigenomic marks (EZH2 and H3K27me3) and a strong enrichment of splice junctions. Furthermore, one eQTL located in intron two, rs13106926, was found within the binding site for RUNX3, a transcriptional activator. These results connect the local genome topography, chromatin structure, and the regulatory landscape of BANK1 with co-transcriptional splicing of exon two. Our data defines a minimal set of risk associated eQTLs predicted to be involved in the expression of BANK1 modulated through epigenetic regulation and splicing. These findings allow us to suggest that the increased expression of BANK1 will have an impact on B-cell mediated disease pathways. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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12 pages, 2288 KiB  
Article
Generation of Human Breg-Like Phenotype with Regulatory Function In Vitro with Bacteria-Derived Oligodeoxynucleotides
by Jorge Gallego-Valle, Verónica Astrid Pérez-Fernández, Rafael Correa-Rocha and Marjorie Pion
Int. J. Mol. Sci. 2018, 19(6), 1737; https://doi.org/10.3390/ijms19061737 - 12 Jun 2018
Cited by 24 | Viewed by 4592
Abstract
Regulatory B cells (Bregs) participate in auto-tolerance maintenance and immune homeostasis. Despite their impact on many diseases and due to the difficulty to define them, knowledge about their origin and their physiological inducers is still unclear. The incomplete understanding about the generation of [...] Read more.
Regulatory B cells (Bregs) participate in auto-tolerance maintenance and immune homeostasis. Despite their impact on many diseases and due to the difficulty to define them, knowledge about their origin and their physiological inducers is still unclear. The incomplete understanding about the generation of Bregs and their limited numbers in periphery make it difficult to develop Breg-based therapy. Therefore, identifying factors that promote their development would allow their ex-vivo production in order to create new immunotherapy. This project aims to test the capacity of several cytokines (Interleukin 1-beta (IL-1β), Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), and Cluster of differentiation 40 ligand (CD40L)) and bacteria-derived oligodeoxynucleotides (CpG-ODN), alone or in combination, to generate B cells with regulatory phenotype and function. We have demonstrated that the Breg-associated phenotypes were heterogeneous between one and other stimulation conditions. However, the expression of other markers related to Bregs such as IL-10, CD80, CD86, CD71, Programmed cell death-1 (PD-1), and Programmed death-ligand 1 (PD-L1) was increased when cells were stimulated with CpG alone or in combination. Moreover, stimulated B cells presented a suppressive function on autologous activated peripheral blood mononuclear cells (PBMC) proliferation. Therefore, this work is the first step to demonstrate the feasibility to induce functional Breg-like cells in vitro and will then facilitate the way to produce Breg-like cells as a potential future cellular therapy. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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11 pages, 1694 KiB  
Article
Peripheral B-Cell Subset Distribution in Primary Antiphospholipid Syndrome
by Lorena Álvarez-Rodríguez, Leyre Riancho-Zarrabeitia, Jaime Calvo-Alén, Marcos López-Hoyos and Víctor Martínez-Taboada
Int. J. Mol. Sci. 2018, 19(2), 589; https://doi.org/10.3390/ijms19020589 - 16 Feb 2018
Cited by 19 | Viewed by 5089
Abstract
Background: B-cell differentiation and B-cell tolerance checkpoints may be different in antiphospholipid syndrome (APS) from systemic lupus erythematosus (SLE) and can help to understand differences between them. Our aim was to define alterations of B-cell subsets in patients with primary APS (pAPS) and [...] Read more.
Background: B-cell differentiation and B-cell tolerance checkpoints may be different in antiphospholipid syndrome (APS) from systemic lupus erythematosus (SLE) and can help to understand differences between them. Our aim was to define alterations of B-cell subsets in patients with primary APS (pAPS) and to compare them with SLE patients and healthy controls (HC). Methods: Cross-sectional study including three study groups: 37 patients with pAPS, 11 SLE patients, and 21 age- and gender-matched HC. We determined the frequencies of different B-cell subsets in peripheral blood naïve and memory compartments. In addition, we measured serum B cell-activating factor (BAFF) levels and circulating pro-inflammatory cytokines, such as IL-6, by commercial ELISA and CBA, respectively. Results: Patients with pAPS showed a lower percentage of immature and naïve B cells than patients with SLE (p = 0.013 and p = 0.010, respectively) and a higher percentage of non-switched memory B cells than patients with SLE (p = 0.001). No differences either in the percentage of switched memory cells or plasma cells were found among the different groups. Serum BAFF levels were higher in SLE patients than in healthy controls and pAPS patients (p = 0.001 and p = 0.017, respectively). A significant increase in the serum BAFF levels was also observed in pAPS patients compared to HC (p = 0.047). Circulating IL-6 levels were higher in SLE and pAPS patients than HC (p = 0.036 and p = 0.048, respectively). A positive correlation was found between serum BAFF and IL-6 levels in patients with SLE but not in pAPS (p = 0.011). Conclusions: Our characterization of peripheral blood B-cell phenotypes in pAPS demonstrates different frequencies of circulating B cells at different stages of differentiation. These differences in the naïve B-cell repertoire could explain the higher number and variety of autoantibodies in SLE patients in comparison to pAPS patients, especially in those with obstetric complications. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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Review

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18 pages, 1315 KiB  
Review
TGFβ Superfamily Members as Regulators of B Cell Development and Function—Implications for Autoimmunity
by Esther Tamayo, Pilar Alvarez and Ramón Merino
Int. J. Mol. Sci. 2018, 19(12), 3928; https://doi.org/10.3390/ijms19123928 - 7 Dec 2018
Cited by 49 | Viewed by 6597
Abstract
The TGFβ superfamily is composed of more than 33 growth and differentiation factors, including TGFβ1, β2, β3, BMPs, GDFs, nodal-related proteins, and activins. These members usually exert pleiotropic actions on several tissues and control multiple cellular processes, such as cell growth, cell survival, [...] Read more.
The TGFβ superfamily is composed of more than 33 growth and differentiation factors, including TGFβ1, β2, β3, BMPs, GDFs, nodal-related proteins, and activins. These members usually exert pleiotropic actions on several tissues and control multiple cellular processes, such as cell growth, cell survival, cell migration, cell fate specification, and differentiation, both during embryonic development and postnatal life. Although the effects of these factors on immune responses were elucidated long ago, most studies have been focused on the actions of TGFβs on T cells, as major regulators of adaptive immunity. In this review, we discuss new findings about the involvement of TGFβ superfamily members in the control of B cell development and function. Moreover, the potential contribution of TGFβ signaling to control B cell-mediated autoimmune diseases and its utility in the design of new therapies are also discussed. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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17 pages, 865 KiB  
Review
B Regulatory Cells: Players in Pregnancy and Early Life
by Ana Esteve-Solé, Yiyi Luo, Alexandru Vlagea, Ángela Deyà-Martínez, Jordi Yagüe, Ana María Plaza-Martín, Manel Juan and Laia Alsina
Int. J. Mol. Sci. 2018, 19(7), 2099; https://doi.org/10.3390/ijms19072099 - 19 Jul 2018
Cited by 37 | Viewed by 6762
Abstract
Pregnancy and early infancy represent two very particular immunological states. During pregnancy, the haploidentical fetus and the pregnant women develop tolerance mechanisms to avoid rejection; then, just after birth, the neonatal immune system must modulate the transition from the virtually sterile but haploidentical [...] Read more.
Pregnancy and early infancy represent two very particular immunological states. During pregnancy, the haploidentical fetus and the pregnant women develop tolerance mechanisms to avoid rejection; then, just after birth, the neonatal immune system must modulate the transition from the virtually sterile but haploidentical uterus to a world full of antigens and the rapid microbial colonization of the mucosa. B regulatory (Breg) cells are a recently discovered B cell subset thought to play a pivotal role in different conditions such as chronic infections, autoimmunity, cancer, and transplantation among others in addition to pregnancy. This review focuses on the role of Breg cells in pregnancy and early infancy, two special stages of life in which recent studies have positioned Breg cells as important players. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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15 pages, 1959 KiB  
Review
Immunomodulatory Function of Myeloid-Derived Suppressor Cells during B Cell-Mediated Immune Responses
by Bilgenaz Özkan, Heejin Lim and Sung-Gyoo Park
Int. J. Mol. Sci. 2018, 19(5), 1468; https://doi.org/10.3390/ijms19051468 - 15 May 2018
Cited by 41 | Viewed by 8474
Abstract
Myeloid-derived suppressor cells (MDSCs) play roles in immune regulation during neoplastic and non-neoplastic inflammatory responses. This immune regulatory function is directed mainly toward T cells. However, MDSCs also regulate other cell populations, including B cells, during inflammatory responses. Indeed, B cells are essential [...] Read more.
Myeloid-derived suppressor cells (MDSCs) play roles in immune regulation during neoplastic and non-neoplastic inflammatory responses. This immune regulatory function is directed mainly toward T cells. However, MDSCs also regulate other cell populations, including B cells, during inflammatory responses. Indeed, B cells are essential for antibody-mediated immune responses. MDSCs regulate B cell immune responses directly via expression of effector molecules and indirectly by controlling other immune regulatory cells. B cell-mediated immune responses are a major component of the overall immune response; thus, MDSCs play a prominent role in their regulation. Here, we review the current knowledge about MDSC-mediated regulation of B cell responses. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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