scholarly journals Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+IgD+CD27+ B cell repertoire in infants

2008 ◽  
Vol 205 (6) ◽  
pp. 1331-1342 ◽  
Author(s):  
Sandra Weller ◽  
Maria Mamani-Matsuda ◽  
Capucine Picard ◽  
Corinne Cordier ◽  
Damiana Lecoeuche ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Early Stage ◽  
Cell Repertoire ◽  
Very Young Children ◽  
B Cell Repertoire ◽  
Somatic Diversification ◽  
The Many

T cell–dependent immune responses develop soon after birth, whereas it takes 2 yr for humans to develop T cell–independent responses. We used this dissociation to analyze the repertoire diversification of IgM+IgD+CD27+ B cells (also known as “IgM memory” B cells), comparing these cells with switched B cells in children <2 yr of age, with the aim of determining whether these two subsets are developmentally related. We show that the repertoire of IgM+IgD+CD27+ B cells in the spleen and blood displays no sign of antigen-driven activation and expansion on H-CDR3 spectratyping, despite the many antigenic challenges provided by childhood vaccinations. This repertoire differed markedly from those of switched B cells and splenic germinal center B cells, even at the early stage of differentiation associated with μ heavy chain expression. These data provide evidence for the developmental diversification of IgM+IgD+CD27+ B cells, at least in very young children, outside of T cell–dependent and –independent immune responses.

Impaired germinal center formation and recall T-cell–dependent immune responses in mice lacking the costimulatory ligand B7-H2

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1381-1388 ◽  
Author(s):  
Siew-Cheng Wong ◽  
Edwin Oh ◽  
Chee-Hoe Ng ◽  
Kong-Peng Lam
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Heavy Chain ◽  
Germinal Center ◽  
Critical Role ◽  
Mutant Mice ◽  
Type Ii ◽  
Germinal Center Formation

Abstract B7-H2, which is expressed constitutively on B cells and binds the inducible costimulator (ICOS) on antigen-activated T cells, is a member of the B7 family of costimulatory ligands. We have inactivated B7-H2 in the mouse. B7-H2–/– mice generate normal populations of B and T cells in their various lymphoid organs but have lower basal levels of heavy chain class–switched antibodies in their sera. These mice are able to mount normal immune responses to both type I and type II T-cell–independent antigens. However, their pattern of responses to a T-cell–dependent antigen is altered, with greatly reduced production of antigen-specific heavy chain class–switched antibodies, the levels of which could not be elevated even with repeated immunizations. This suggests a critical role for B7-H2 in the recall phases of the immune response. Germinal center formation is also impaired in the mutant mice. While B cells from the mutant mice could response normally to anti-IgM, anti-CD40, and lipopolysaccharide stimulation, the production of T-helper–type II cytokines such as interleukin-4 (IL-4) and IL-10 by primed CD4+ T cells from mutant mice were reduced. This indicated that the defects in humoral responses and germinal center formation in B7-H2–deficient mice are due to the lack of T-cell–mediated help to the B cells. Hence, B7-H2 on B cells is important for recruiting T-cell help via its interaction with ICOS and plays a critical role in costimulating humoral immune responses.

Bim establishes the B-cell repertoire from early to late in the immune response

2020 ◽  
Author(s):  
Akiko Sugimoto-Ishige ◽  
Michishige Harada ◽  
Miho Tanaka ◽  
Tommy Terooatea ◽  
Yu Adachi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Late Response ◽  
Cell Repertoire ◽  
High Affinity ◽  
B Cell Repertoire

Abstract In T cell-dependent antibody responses, some of the activated B cells differentiate along extrafollicular pathways into low-affinity memory and plasma cells, whereas others are involved in subsequent germinal center (GC) formation in follicular pathways, in which somatic hypermutation and affinity maturation occur. The present study demonstrated that Bim, a proapoptotic BH3-only member of the Bcl-2 family, contributes to the establishment of the B-cell repertoire from early to late stages of immune responses to T cell-dependent antigens. Extrafollicular plasma cells grew in the spleen during the early immune response, but their numbers rapidly declined with the appearance of GC-derived progeny in wild-type mice. By contrast, conditional Bim deficiency in B cells resulted in expansion of extrafollicular IgG1+ antibody-forming cells (AFCs) and this expansion was sustained during the late response, which hampered the formation of GC-derived high-affinity plasma cells in the spleen. Approximately 10% of AFCs in mutant mice contained mutated VH genes; thus, Bim deficiency appears not to impede the selection of high-affinity AFC precursor cells. These results suggest that Bim contributes to the replacement of low-affinity antibody by high-affinity antibody as the immune response progresses.

scholarly journals Recombinant Rabies Virus Overexpressing OX40-Ligand Enhances Humoral Immune Responses by Increasing T Follicular Helper Cells and Germinal Center B Cells

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 144 ◽  
Author(s):  
Yingying Li ◽  
Ling Zhao ◽  
Baokui Sui ◽  
Zhaochen Luo ◽  
Yachun Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Rabies Virus ◽  
Germinal Center ◽  
Rabies Vaccine ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Follicular Helper ◽  
Ox40 Ligand

Rabies, caused by the rabies virus (RABV), remains a serious threat to public health in most countries. Development of a single-dose and efficacious rabies vaccine is the most important method to restrict rabies virus transmission. Costimulatory factor OX40-ligand (OX40L) plays a crucial role in the T cell-dependent humoral immune responses through T-B cell interaction. In this work, a recombinant RABV overexpressing mouse OX40L (LBNSE-OX40L) was constructed, and its effects on immunogenicity were evaluated in a mouse model. LBNSE-OX40L-immunized mice generated a larger number of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs) than the parent virus LBNSE-immunized mice. Furthermore, LBNSE-OX40L induced significantly higher levels of virus-neutralizing antibodies (VNA) as early as seven days post immunization (dpi), which lasted for eight weeks, resulting in better protection for mice than LBNSE (a live-attenuated rabies vaccine strain). Taken together, our data in this study suggest that OX40L can be a novel and potential adjuvant to improve the induction of protective antibody responses post RABV immunization by triggering T cell-dependent humoral immune responses, and that LBNSE-OX40L can be developed as an efficacious and nonpathogenic vaccine for animals.

scholarly journals B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis—Role in Pathogenesis and Effect of Immunosuppressive Treatments

2019 ◽  
Vol 20 (24) ◽  
pp. 6231 ◽  
Author(s):  
Desmond Y. H. Yap ◽  
Tak Mao Chan
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cell ◽  
B Cells ◽  
Lupus Nephritis ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Interaction ◽  
Systemic Lupus ◽  
Cell Repertoire ◽  
B Cell Repertoire

Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell–T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell–T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.

scholarly journals The many faces of psoriatic arthritis: their genetic determinism

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_1) ◽  
pp. i4-i9 ◽  
Author(s):  
Robert Winchester ◽  
Oliver FitzGerald
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Autoimmune Response ◽  
Cell Repertoire ◽  
Immune Effector ◽  
Target Molecules ◽  
Effector Pathways ◽  
The Many ◽  
Genetically Determined ◽  
Selection Of

Abstract In this review, we propose a model of PsA as a complex genetically determined autoimmune-mediated disease having a heterogeneous variety of subphenotypes, with each subphenotype under the control of a different susceptibility-associated HLA allele. Since the specific HLA molecules encoded by each susceptibility allele dominantly select a T cell repertoire with the property of recognizing different peptides, we hypothesize each subphenotype reflects a distinct adaptive autoimmune response directed to different target molecules that is mediated by T cells within each selected repertoire. The interaction among the patients’ susceptibility alleles in the selection of their T cell repertoires determines a spectrum of overall clinical disease severity, varying from mild to severe. We further speculate that these different immune responses may result in activation of different immune effector pathways, which might therefore respond differently to various specific biologic agents.

scholarly journals Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation

2009 ◽  
Vol 206 (12) ◽  
pp. 2659-2669 ◽  
Author(s):  
Marc Seifert ◽  
Ralf Küppers
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Clone ◽  
Human Peripheral Blood ◽  
Large Population ◽  
Memory B Cells ◽  
Cell Repertoire ◽  
Memory B Cell

The origin of IgM+CD27+ B lymphocytes with mutated IgV genes, which account for ∼20% of human peripheral blood (PB) B cells, is controversially discussed. A generation in a primary diversification pathway, in T cell–independent immune responses, or in T cell–dependent germinal center (GC) reactions has been proposed. We show here that IgM+IgD+CD27+ and IgM+IgD−/lowCD27+ B cell subsets carry, like class-switched memory B cells, mutations in the Bcl6 gene as a genetic trait of a GC experience. Moreover, the identification of PB IgM+IgD+CD27+ B cells clonally related to GC-derived IgG+ memory B cells with shared and distinct IgV gene mutations demonstrates the GC origin also of the former subset. These findings provide genetic evidence for a GC derivation of somatically mutated IgM+ B cells and indicate that adult humans harbor a large population of IgM+IgD+ post-GC memory B cells. Furthermore, the analysis revealed that a highly diverse and often very large population of memory B cells is generated from a given GC B cell clone, and that (preferentially IgM) memory B cells are generated already early in the GC reaction. This provides novel insights into the dynamics of GC reactions and the generation of a memory B cell repertoire.

scholarly journals Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

1997 ◽  
Vol 185 (12) ◽  
pp. 2121-2131 ◽  
Author(s):  
Robbert van der Voort ◽  
Taher E.I. Taher ◽  
Robert M.J. Keehnen ◽  
Lia Smit ◽  
Martijn Groenink ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Germinal Center ◽  
Scatter Factor ◽  
Hepatocyte Growth

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

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