scholarly journals The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity

2004 ◽  
Vol 200 (9) ◽  
pp. 1145-1156 ◽  
Author(s):  
Yuchun Nie ◽  
Janelle Waite ◽  
Faraha Brewer ◽  
Mary-Jean Sunshine ◽  
Dan R. Littman ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Marginal Zone ◽  
Antibody Responses ◽  
Cell Compartments ◽  
Cell Compartmentalization ◽  
B Cell Precursors ◽  
Multiple Stages

The chemokine receptor CXCR4 is expressed in B cells at multiple stages of their development. CXCR4 function in humoral immunity has not been fully investigated. We have generated gene-targeted mice in which CXCR4 can be selectively inactivated in B cells and have shown that it is required for retention of B cell precursors in the bone marrow. CXCR4-deficient B cell precursors that migrated prematurely became localized in splenic follicles despite their unresponsiveness to CXCL13. Concomitantly, mature B cell populations were reduced in the splenic marginal zone and primary follicles, and in the peritoneal cavity in the mutant animals, as were T-independent antibody responses. In addition, aberrant B cell follicles formed ectopically in intestinal lamina propria around Peyer's patches. These findings establish an important role for CXCR4 in regulating homeostasis of B cell compartmentalization and humoral immunity.

scholarly journals Antiviral Protection and Germinal Center Formation, But Impaired B Cell Memory in the Absence of CD19

1998 ◽  
Vol 188 (1) ◽  
pp. 145-155 ◽  
Author(s):  
Thomas Fehr ◽  
Robert C. Rickert ◽  
Bernhard Odermatt ◽  
Jürgen Roes ◽  
Klaus Rajewsky ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Antibody Responses ◽  
B Cell Activation ◽  
Protein Antigens ◽  
Cell Memory ◽  
B Cell Memory

Coligation of CD19, a molecule expressed during all stages of B cell development except plasmacytes, lowers the threshold for B cell activation with anti-IgM by a factor of 100. The cytoplasmic tail of CD19 contains nine tyrosine residues as possible phosphorylation sites and is postulated to function as the signal transducing element for complement receptor (CR)2. Generation and analysis of CD19 gene–targeted mice revealed that T cell–dependent (TD) antibody responses to proteinaceous antigens were impaired, whereas those to T cell–independent (TI) type 2 antigens were normal or even augmented. These results are compatible with earlier complement depletion studies and the postulated function of CD19. To analyze the role of CD19 in antiviral antibody responses, we immunized CD19−/− mice with viral antigens of TI-1, TI-2, and TD type. The effect of CD19 on TI responses was more dependent on antigen dose and replicative capacity than on antigen type. CR blocking experiments confirmed the role of CD19 as B cell signal transducer for complement. In contrast to immunization with protein antigens, infection of CD19−/− mice with replicating virus led to generation of specific germinal centers, which persisted for >100 d, whereas maintenance of memory antibody titers as well as circulating memory B cells was fully dependent on CD19. Thus, our study confirms a costimulatory role of CD19 on B cells under limiting antigen conditions and indicates an important role for B cell memory.

scholarly journals Characterization of marginal zone B cell precursors

2005 ◽  
Vol 202 (9) ◽  
pp. 1225-1234 ◽  
Author(s):  
Bhaskar Srivastava ◽  
William J. Quinn ◽  
Kristin Hazard ◽  
Jan Erikson ◽  
David Allman
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Environmental Cues ◽  
Developmental Potential ◽  
B Cell Maturation ◽  
B Cell Precursors ◽  
Follicular B Cells ◽  
Selection Of

Selection of recently formed B cells into the follicular or marginal zone (MZ) compartments is proposed to occur by way of proliferative intermediates expressing high levels of CD21/35 and CD23. However, we show that CD21/35high CD23+ splenocytes are not enriched for proliferative cells, and do not contribute substantially to the generation of follicular B cells. Instead, ontogenic relationships, steady-state labeling kinetics, and adoptive transfer experiments suggest that CD21/35high CD23+ splenocytes serve primarily as precursors for MZ B cells, although their developmental potential seems to be broader and is influenced by environmental cues that are associated with lymphopenia. Furthermore, CD21/35high CD23+ splenocytes share several key functional characteristics with MZ B cells, including their capacity to trap T-independent antigen and a heightened proliferative response to LPS. These observations challenge previous models of peripheral B cell maturation, and suggest that MZ B cells develop by way of CD21/35high CD23+ intermediates.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Compensates for Interleukin-6 in Initial B Cell Activation

2015 ◽  
Vol 90 (4) ◽  
pp. 2150-2154 ◽  
Author(s):  
Sang-Hoon Sin ◽  
Sun Ah Kang ◽  
Yongbaek Kim ◽  
Anthony Eason ◽  
Kelly Tan ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 6 ◽  
Cell Activation ◽  
Marginal Zone ◽  
Kaposi Sarcoma ◽  
B Cell Activation ◽  
Marginal Zone B Cells ◽  
Survival Factor

Interleukin 6 (IL-6) is considered a proliferation and survival factor for B cells. To assess the role of IL-6 in Kaposi sarcoma-associated herpesvirus (KSHV) latency, KSHV latency locus-transgenic mice (referred to as latency mice) lacking IL-6 were evaluated. IL-6−/−latency mice had the same phenotypes as the latency mice, i.e., increased frequency of marginal zone B cells, hyperplasia, and hyperglobulinemia, indicating that the KSHV latency locus, which includes all viral microRNAs (miRNAs), can compensate for lack of IL-6 in premalignant B cell activation.

scholarly journals ROLE OF COMPLEMENT IN INDUCTION OF ANTIBODY PRODUCTION IN VIVO

1974 ◽  
Vol 140 (1) ◽  
pp. 126-145 ◽  
Author(s):  
M. B. Pepys
Keyword(s):  
B Cells ◽  
Antibody Response ◽  
B Cell ◽  
Antibody Production ◽  
Antibody Responses ◽  
Cobra Venom ◽  
Sheep Erythrocytes ◽  
C3 Receptors

In an in vivo study in mice, suppression by the C3-cleaving protein of cobra venom (CoF), and other C3-reactive agents (zymosan, aggregated IgG, anti-C3 antibodies, and type III pneumococcal polysaccharide) of the thymus-dependent antibody responses to sheep erythrocytes, ovalbumin, and human IgG was demonstrated. The thymus-independent antibody response to polyvinyl-pyrrolidone was however unaffected by CoF. These and other published observations suggest that there may be a requirement for functional C3 in induction of thymus-dependent but not thymus-independent antibody production. A model for the role of C3 in lymphocyte cooperation is proposed based on these data analyzed in the light of existing knowledge of this process. It is postulated that fixed C3 interacting with macrophage See PDF for Structure and B-cell C3 receptors might enhance or facilitate T-dependent presentation of antigen to B cells.

scholarly journals Alterations in B Cell and Follicular T-Helper Cell Subsets in Patients with Acute COVID-19 and COVID-19 Convalescents

2021 ◽  
Vol 44 (1) ◽  
pp. 194-205
Author(s):  
Igor V. Kudryavtsev ◽  
Natalia A. Arsentieva ◽  
Oleg K. Batsunov ◽  
Zoia R. Korobova ◽  
Irina V. Khamitova ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
N Protein ◽  
Follicular Helper ◽  
Healthy Donors ◽  
Specific Igg ◽  
Sparse Methods

Background. Humoral immunity requires interaction between B cell and T follicular helper cells (Tfh) to produce effective immune response, but the data regarding a role of B cells and Tfh in SARS-CoV-2 defense are still sparse. Methods. Blood samples from patients with acute COVID-19 (n = 64), convalescents patients who had specific IgG to SARS-CoV-2 N-protein (n = 55), and healthy donors with no detectable antibodies to any SARS-CoV-2 proteins (HC, n = 44) were analyses by multicolor flow cytometry. Results. Patients with acute COVID-19 showed decreased levels of memory B cells subsets and increased proportion plasma cell precursors compared to HC and COVID-19 convalescent patients, whereas for the latter the elevated numbers of virgin naïve, Bm2′ and “Bm3+Bm4” was found if compared with HC. During acute COVID-19 CXCR3+CCR6− Tfh1-like cells were decreased and the levels of CXCR3–CCR6+ Tfh17-like were increased then in HC and convalescent patients. Finally, COVID-19 convalescent patients had increased levels of Tfh2-, Tfh17- and DP Tfh-like cells while comparing their amount with HC. Conclusions. Our data indicate that COVID-19 can impact the humoral immunity in the long-term.

scholarly journals Marginal Zone B Cells Regulate RBC Alloimmunization Toward Distinct RBC Alloantigens

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3847-3847
Author(s):  
Patricia E. Zerra ◽  
Seema R. Patel ◽  
Connie M. Arthur ◽  
Kathryn R. Girard-Pierce ◽  
Ashley Bennett ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Antibody Formation ◽  
Marginal Zone ◽  
Cd4 T Cell ◽  
Rbc Transfusion

Abstract Background: While red blood cell (RBC) transfusion can be beneficial, exposure to allogeneic RBCs can result in the development of RBC alloantibodies that can make it difficult to obtain compatible RBCs for future transfusions. Aside from phenotype matching protocols, no strategy currently exists that is capable of preventing RBC alloimmunization following therapeutic transfusion. As RBC alloantigens represent diverse determinants capable of driving distinct immune pathways, common immunological nodes must be identified in order to successfully prevent RBC alloimmunization against a variety of different alloantigens. Recent results demonstrate that marginal zone (MZ) B cells mediate anti-KEL antibody formation in the complete absence of CD4 T cells. However, whether MZ B cells similarly regulate RBC alloantibody formation against other RBC alloantigens remains unknown. As a result, we examined the role of MZ B cells and CD4 T cells in the development of RBC alloantibodies following exposure to the HOD (hen egg lysozyme, ovalbumin and duffy) antigen. Methods: Each recipient was transfused with HOD or KEL RBCs following either MZ B cell or CD4 T cell depletion using a cocktail of MZ B cell (anti-CD11a and anti-CD49d) or anti-CD4 depleting antibody, 4 and 2 days prior to transfusion. Control groups received isotype control injections in parallel. MZ B cell deficient (CD19cre/+ X Notch2flx/flx) and CD4 T cell deficient (MHC class II knockout) recipients were also used to examine the role of MZ B cells and CD4 T cells, respectively. Serum collected on days 5 and 14 post-transfusion was evaluated for anti-HOD or anti-KEL antibodies by incubating HOD or KEL RBCs with serum, followed by detection of bound antibodies using anti-IgM and anti-IgG and subsequent flow cytometric analysis. Evaluation of antibody engagement and overall survival of HOD or KEL RBCs was accomplished by labeling RBCs with the lipophilic dye, DiI, prior to transfusion, followed by examination for bound antibody and RBC clearance on days 5 and 14 post-transfusion by flow cytometry. Results: Similar to the ability of MZ B cell depletion to reduce anti-KEL antibody formation following KEL RBC exposure, depletion of MZ B cells significantly reduced anti-HOD IgM and IgG antibodies following HOD RBC transfusion. In contrast, injection of recipients with isotype control antibodies in parallel failed to prevent alloantibody formation following HOD or KEL RBC transfusion. Similar results were obtained following HOD or KEL RBC transfusion into recipients genetically deficient in MZ B cells. In contrast, although MZ B cells were required for HOD and KEL RBC-alloantibody formation, manipulation of CD4 T cells differentially impacted the ability of each antigen to induce alloantibodies. While transfusion of HOD or KEL RBCs resulted in robust IgM alloantibodies in the absence of CD4 T cells, depletion or genetic elimination of CD4 T cells significantly inhibited anti-HOD IgG antibody formation, while failing to impact IgG anti-KEL antibody formation. Consistent with this, while manipulation of CD4 T cells protected HOD RBCs from antibody deposition and subsequent RBC clearance, this same approach failed to similarly protect KEL RBCs following transfusion. In contrast, depletion of MZ B cells not only prevented detectable alloantibody production, but also completely protected HOD or KEL RBCs from antibody deposition and subsequent RBC clearance. Conclusion: These results suggest that while MZ B cells mediate a robust IgM antibody response following either KEL or HOD antigen exposure, MZ B cells appear to possess the capacity to orchestrate unique downstream IgG responses through CD4 T cell dependent and independent pathways contingent on target alloantigen. As a result, while manipulation of CD4 T cells may prevent alloantibody formation against some antigens, targeting this immune population inadequately prevents RBC alloantibody formation against all RBC antigens. As chronic transfusion therapy exposes recipients to a wide variety of alloantigens, these results suggest that MZ B cells may represent a central initiating node that governs RBC alloimmunization against a variety of RBC alloantigens, and may therefore serve as a useful target in preventing alloantibody formation in chronically transfused individuals. Disclosures No relevant conflicts of interest to declare.

Deciphering the Role of Locally Disordered DNA Methylation on CLL Development In Vivo

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1737-1737
Author(s):  
Anat Biran ◽  
Helene Kretzmer ◽  
Shanye Yin ◽  
Leah Billington ◽  
Fara Faye Regis ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Research Funding ◽  
Marginal Zone ◽  
Marginal Zone B Cells ◽  
Genome Wide ◽  
Follicular B Cells

Large-scale DNA methylation analysis of chronic lymphocytic leukemia (CLL) has identified a pervasive genome-wide level of discordance in local methylation state in leukemic cells compared to normal B cells. This is associated with variation in gene expression, increased clonal evolution and poorer clinical outcomes. We hypothesized that locally disordered methylation could lead to dysregulation of gene expression and hence contribute to cancer development and progression. To test this, we have engineered mouse lines with B-cell restricted homozygous or heterozygous knock-out of Dnmt3a by crossing Dnmt3a-floxed mice with CD19-Cre mice. Dnmt3a is a DNA methyltransferase, catalyzing the addition of a methyl group to CpG sequences in the DNA and thereby regulating gene expression. Although DNMT3A mutations are only rarely identified in CLL, RNA sequencing and protein expression analysis reveal dysregulation of DNMT3A. We confirmed partial or complete reduction in Dnmt3a protein levels in B cells from CD19-Cre;Dnmt3a heterozygous (Dnmt3a-het) and CD19-Cre;Dnmt3a homozygous mice (Dnmt3a-hom), respectively. These mice therefore provide a unique opportunity to study B cell restricted changes in locally discordant methylation over time. We first assessed the impact of Dnmt3a deletion on normal B cell development, prior to CLL development, by characterizing splenic B cell of CD19-Cre (control) or Dnmt3a-hom mice. Flow cytometry data using B220, CD21 and CD23 markers to identify B220+CD23+CD21- follicular B cells and B220+CD23+CD21high marginal zone B cells revealed elevated levels of follicular B cells (83.1% vs 87.6%, p=0.008) and reduced levels of marginal zone B cells (9.6% vs 4.1%, p=0.001) in Dnmt3a-hom mice in comparison to control mice (n=3 mice per group). These results indicate that mice with Dnmt3a deletion present with massive changes in their B cells, even prior to overt CLL development. We next monitored both Dnmt3a-het and Dnmt3a-hom cohorts over time for CLL development. We observed that 100% Dnmt3a-hom mice developed CLL-like disease by 7 months (n=23), characterized by CD5+B220+;Igk+ expression and evident within the blood, bone marrow (BM), spleen and peritoneum, suggesting a fundamental role of altered DNMT3A expression in generation of CLL. In comparison, 75% of Dnmt3a-het mice developed CLL-like disease by 18 months (n=12), with similar expansion of CD5+C220+ expansion in the BM and spleen. By RNA-sequencing analysis of normal splenic B cells from CD19-Cre and Dnmt3a-hom mice (n=3 mice, 10 weeks old), we detected substantial changes in gene expression, including 113 upregulated genes and 39 downregulated (p<0.05, FC>2). To explore the development of locally disordered methylation following transformation, CLL cells from Dnmt3a-hom mice (n=3) were subjected to reduced representation bisulfite sequencing (RRBS), a high-throughput technique to analyze genome wide methylation patterns. We found that murine CLL-like cells display locally disordered methylation, which was detected in all genomic features covered by this assay, indicating that disordered methylation is broadly affecting the murine CLL cells' epigenome. Additionally, we identified a set of differentially methylated regions (DMRs) between B cells from CD19-Cre vs CLL cells from Dnmt3a-hom (n = 2,839 DMRs), with a minimum difference of 0.2 and a minimum of 10 CpGs per DMR. Interestingly, gene ontology analysis demonstrated strong association with genes hypermethylated in TCL1 mouse model, linking this model with alternative murine models for CLL. In conclusion, we have studied B cell specific deletion of Dntm3a and showed the development of CLL in 100% of the case in Dnmt3a-hom mice. Our data suggest a fundamental role for Dnmt3a in CLL development through increased locally disordered methylation and changes in associated transcriptional signatures. This mouse model provides an exciting experimental model to undertake functional in vivo studies in order to elucidate the contribution of epigenetic changes on CLL development. Disclosures Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Wu:Neon Therapeutics: Other: Member, Advisory Board; Pharmacyclics: Research Funding.

scholarly journals A critical role of Rap1b in B-cell trafficking and marginal zone B-cell development

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4627-4636 ◽  
Author(s):  
Yuhong Chen ◽  
Mei Yu ◽  
Andrew Podd ◽  
Renren Wen ◽  
Magdalena Chrzanowska-Wodnicka ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Marginal Zone ◽  
Cell Development ◽  
B Cell Development ◽  
Cell Trafficking

Abstract B-cell development is orchestrated by complex signaling networks. Rap1 is a member of the Ras superfamily of small GTP-binding proteins and has 2 isoforms, Rap1a and Rap1b. Although Rap1 has been suggested to have an important role in a variety of cellular processes, no direct evidence demonstrates a role for Rap1 in B-cell biology. In this study, we found that Rap1b was the dominant isoform of Rap1 in B cells. We discovered that Rap1b deficiency in mice barely affected early development of B cells but markedly reduced marginal zone (MZ) B cells in the spleen and mature B cells in peripheral and mucosal lymph nodes. Rap1b-deficient B cells displayed normal survival and proliferation in vivo and in vitro. However, Rap1b-deficient B cells had impaired adhesion and reduced chemotaxis in vitro, and lessened homing to lymph nodes in vivo. Furthermore, we found that Rap1b deficiency had no marked effect on LPS-, BCR-, or SDF-1–induced activation of mitogen-activated protein kinases and AKT but clearly impaired SDF-1–mediated activation of Pyk-2, a key regulator of SDF-1–mediated B-cell migration. Thus, we have discovered a critical and distinct role of Rap1b in mature B-cell trafficking and development of MZ B cells.

scholarly journals Extra-Splenic Role of B Cell Activating Factor Blockade in Prevention of Factor VIII Inhibitors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1025-1025
Author(s):  
Bhavya S Doshi ◽  
Mostafa A Shaheen ◽  
Juliana C Small ◽  
Paris Margaritis ◽  
Valder R Arruda
Keyword(s):  
Immune Response ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
High Titer ◽  
Combined Therapy ◽  
Antibody Therapy ◽  
Marginal Zone B Cells ◽  
Fviii Inhibitor

Abstract The development of neutralizing antibodies (inhibitors) to factor VIII (FVIII) remains the most challenging complication of protein-based replacement therapy in hemophilia A (HA). Elevated levels of the B cell survival cytokine B cell activating factor (BAFF) are associated with inhibitors in HA patients and BAFF levels decrease with successful immune tolerance induction (Doshi BS et al, J Clin Invest 2021). In HA mice, localization of labeled FVIII to the spleen and subsequent depletion of splenic leukocytes has been shown to reduce and/or temporarily prevent FVIII inhibitors. In contrast, transient depletion of BAFF prevented inhibitors upfront and promoted long-term tolerance to FVIII in HA mice. Given BAFF's ability to modulate B cell pools in secondary lymphoid organs, here we compared the splenic versus extra-splenic role of BAFF in regulating the FVIII immune response in order to localize its mechanism of action. As BAFF could regulate survival of innate-like splenic-resident marginal zone B cells, initial experiments compared depletion of BAFF or marginal zone B cells in HA mice and showed more complete inhibitor prevention with BAFF depletion (median 0 vs 16.9 Bethesda Units [BU]/ml, respectively, p &lt; 0.01). These data supported our hypothesis that BAFF's regulatory effect is not solely reliant on its modulation of the splenic-resident marginal zone B cell compartment in HA mice. To further understand the extra-splenic role of BAFF in FVIII immunogenicity, wild-type (WT) or severe HA mice (with F8 exon 16 knockout) on the C57Bl/6 background, were treated according to three groups (n=9-11/group): 1) sham controls, 2) splenectomy alone, and 3) anti-BAFF monoclonal antibody (2mg/kg IP once) 4 days prior to splenectomy ("combined therapy"). Following splenectomy, mice were injected with recombinant full length human FVIII at 80 IU/kg weekly for six weeks. Bethesda titers were measured one week following the final immunization. In order to provide hemostasis in HA mice without FVIII exposure prior to splenectomy, mice were given liver-directed gene therapy with AAV8-mFVIIa at 5e11 vg/mouse two weeks prior to splenectomy. Circulating mFVIIa levels of 5.8 ± 2.4 ug/ml at day 10 were observed. These levels normalized hemostasis allowing successful splenectomy in 85% of animals, which is similar to our experience in WT mice. In the combined therapy group, only a single HA mouse developed a high titer inhibitor (7.4 BU/ml) and no WT mice developed high titer inhibitors. As the presence of endogenous FVIII antigen in WT mice does not seem to significantly alter BAFF's role in preventing the alloantibody response to xenoantigen (human FVIII protein), data for WT and HA mice were combined for analysis. Although splenectomy decreased inhibitors titers compared to sham controls (23.1 vs 78.7 BU/ml), the addition of anti-BAFF antibody therapy to splenectomy significantly reduced the risk of high titer inhibitors (RR 0.15, 95% CI 0.02-0.66, p &lt; 0.01). The median Bethesda titer in HA and WT splenectomized mice was 23.1 (0-139.4) versus 0 (0-7.4) with addition of BAFF antibody therapy. Of note, inhibitor prevention with combination splenectomy and anti-BAFF antibody therapy seen here is similar to our prior data using just anti-BAFF antibody monotherapy for FVIII inhibitor prevention in HA mice (RR 0.23, 95% CI 0.08-0.57) suggesting that splenectomy does not significantly improve FVIII inhibitor prevention in the setting of BAFF inhibition. Our data, using a challenging HA mouse model, suggest that anti-BAFF therapy may prevent FVIII inhibitors by inhibiting BAFF's function in non-splenic lymphoid compartments. As certain B cell subtypes, including marginal zone B cells, reside in non-splenic compartments in humans, our model mimics the anticipated human immune response to FVIII. Ongoing investigations into the B and T cell compartments in lymph nodes and bone marrow will provide further insights into the location of BAFF's regulatory role in the FVIII immune response and may provide insights into potential alternative pathways in the initial FVIII immune response. Disclosures Doshi: Janssen: Consultancy; Spark Therapeutics: Speakers Bureau.

scholarly journals Primary Immune Responses and Affinity Maturation Are Controlled by IgD

2021 ◽  
Vol 12 ◽  
Author(s):  
Timm Amendt ◽  
Omar El Ayoubi ◽  
Alexandra T. Linder ◽  
Gabriele Allies ◽  
Marc Young ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Autoimmune Diabetes ◽  
Affinity Maturation ◽  
Antibody Responses ◽  
Cell Functions ◽  
High Affinity ◽  
Deficient Mice

Mature B cells co-express IgM and IgD B cell antigen receptors (BCR) on their surface. While IgM BCR expression is already essential at early stages of development, the role of the IgD-class BCR remains unclear as most B cell functions appeared unchanged in IgD-deficient mice. Here, we show that IgD-deficient mice have an accelerated rate of B cell responsiveness as they activate antibody production within 24h after immunization, whereas wildtype (WT) animals required 3 days to activate primary antibody responses. Strikingly, soluble monovalent antigen suppresses IgG antibody production induced by multivalent antigen in WT mice. In contrast, IgD-deficient mice were not able to modulate IgG responses suggesting that IgD controls the activation rate of B cells and subsequent antibody production by sensing and distinguishing antigen-valences. Using an insulin-derived peptide we tested the role of IgD in autoimmunity. We show that primary autoreactive antibody responses are generated in WT and in IgD-deficient mice. However, insulin-specific autoantibodies were detected earlier and caused more severe symptoms of autoimmune diabetes in IgD-deficient mice as compared to WT mice. The rapid control of autoimmune diabetes in WT animals was associated with the generation of high-affinity IgM that protects insulin from autoimmune degradation. In IgD-deficient mice, however, the generation of high-affinity protective IgM is delayed resulting in prolonged autoimmune diabetes. Our data suggest that IgD is required for the transition from primary, highly autoreactive, to secondary antigen-specific antibody responses generated by affinity maturation.

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