Faculty Opinions recommendation of IFN-γ receptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity.

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.

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Rap1 Is Essential for B-Cell Locomotion, Germinal Center Formation and Normal B-1a Cell Population

Frontiers in Immunology ◽

10.3389/fimmu.2021.624419 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sayaka Ishihara ◽

Tsuyoshi Sato ◽

Risa Sugioka ◽

Ryota Miwa ◽

Haruka Saito ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Specific Antibody ◽

Stromal Cells ◽

Germinal Center ◽

Specific Antibody Production ◽

Humoral Responses ◽

Integrin Regulation ◽

Germinal Center Formation

Integrin regulation by Rap1 is indispensable for lymphocyte recirculation. In mice having B-cell-specific Rap1a/b double knockouts (DKO), the number of B cells in lymph nodes decreased to approximately 4% of that of control mice, and B cells were present in the spleen and blood. Upon the immunization with NP-CGG, DKO mice demonstrated the defective GC formation in the spleen, and the reduced NP-specific antibody production. In vitro, Rap1 deficiency impaired the movement of activated B cells along the gradients of chemoattractants known to be critical for their localization in the follicles. Furthermore, B-1a cells were almost completely absent in the peritoneal cavity, spleen and blood of adult DKO mice, and the number of B-cell progenitor/precursor (B-p) were reduced in neonatal and fetal livers. However, DKO B-ps normally proliferated, and differentiated into IgM+ cells in the presence of IL-7. CXCL12-dependent migration of B-ps on the VCAM-1 was severely impaired by Rap1 deficiency. Immunostaining study of fetal livers revealed defects in the co-localization of DKO B-ps and IL-7-producing stromal cells. This study proposes that the profound effects of Rap1-deficiency on humoral responses and B-1a cell generation may be due to or in part caused by impairments of the chemoattractant-dependent positioning and the contact with stromal cells.

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Brg1 Supports B Cell Proliferation and Germinal Center Formation Through Enhancer Activation

Frontiers in Immunology ◽

10.3389/fimmu.2021.705848 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dominik Schmiedel ◽

Hadas Hezroni ◽

Amit Hamburg ◽

Ziv Shulman

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

B Cells ◽

B Cell ◽

Transcriptional Activation ◽

Germinal Center ◽

Cell Activation ◽

Critical Role ◽

B Cell Activation ◽

Germinal Center Formation

Activation and differentiation of B cells depend on extensive rewiring of gene expression networks through changes in chromatin structure and accessibility. The chromatin remodeling complex BAF with its catalytic subunit Brg1 was previously identified as an essential regulator of early B cell development, however, how Brg1 orchestrates gene expression during mature B cell activation is less clear. Here, we find that Brg1 is required for B cell proliferation and germinal center formation through selective interactions with enhancers. Brg1 recruitment to enhancers following B cell activation was associated with increased chromatin accessibility and transcriptional activation of their coupled promoters, thereby regulating the expression of cell cycle-associated genes. Accordingly, Brg1-deficient B cells were unable to mount germinal center reactions and support the formation of class-switched plasma cells. Our findings show that changes in B cell transcriptomes that support B cell proliferation and GC formation depend on enhancer activation by Brg1. Thus, the BAF complex plays a critical role during the onset of the humoral immune response.

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Bach2 deficiency leads autoreactive B cells to produce IgG autoantibodies and induce lupus through a T cell-dependent extrafollicular pathway

Experimental & Molecular Medicine ◽

10.1038/s12276-019-0352-x ◽

2019 ◽

Vol 51 (12) ◽

pp. 1-13 ◽

Cited By ~ 7

Author(s):

Eunkyeong Jang ◽

Un Kyo Kim ◽

Kiseok Jang ◽

Young Soo Song ◽

Ji-Young Cha ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Lupus Erythematosus ◽

Germinal Center ◽

Class Switch Recombination ◽

Helper T Cells ◽

Autoreactive B Cells ◽

Class Switch ◽

Germinal Center Formation

AbstractClass-switched IgG autoantibodies but not unswitched IgM autoantibodies play a crucial role in the development of systemic lupus erythematosus (SLE). Bach2 is known to be essential for class switch recombination of Ig genes, but recent genomic and clinical studies have suggested an association of Bach2 deficiency with SLE. This study was undertaken to examine the mechanism by which Bach2 regulates the development of SLE. Despite defects in Ig class switch recombination and germinal center formation when actively immunized, Bach2−/− mice spontaneously accumulated IgG autoantibody-secreting cells without germinal center reactions in a regulatory T cell-independent manner, and this phenomenon was accompanied by manifestations akin to SLE. Transcriptome analyses revealed that Bach2 regulated the expression of genes related to germinal center formation and SLE pathogenesis in B cells. B cell-specific deletion of Bach2 was sufficient to impair the development of germinal center B cells but insufficient to promote the production of IgG autoantibodies. Bach2 deficiency caused CD4+ T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2-deficient autoreactive B cells preferentially react at extrafollicular sites to give rise to IgG class-switched pathogenic plasma cells and that this effect requires the help of Bach2-Icoshi helper T cells. Thus, the cell-autonomous roles of Bach2 in B cells and in their cognate CD4+ T cells are required to maintain self-tolerance against SLE.

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T cell interactions with B cells during germinal center formation, a three‐step model

Immunological Reviews ◽

10.1111/imr.12737 ◽

2019 ◽

Vol 288 (1) ◽

pp. 37-48 ◽

Cited By ~ 11

Author(s):

Adi Biram ◽

Natalia Davidzohn ◽

Ziv Shulman

Keyword(s):

T Cell ◽

B Cells ◽

Germinal Center ◽

Cell Interactions ◽

Step Model ◽

Germinal Center Formation

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Prolonged Stimulation-Induced Pro-Apoptotic B Cells and Deficits in the Germinal Center Formation of Memory B Cells within One Year after Allogeneic HSCT

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2014.11.243 ◽

2015 ◽

Vol 21 (2) ◽

pp. S167

Author(s):

Angela Mensen ◽

Youngseong Oh ◽

Philipp Hemmati ◽

Christian Jehn ◽

Jörg Westermann ◽

...

Keyword(s):

B Cells ◽

Germinal Center ◽

Memory B Cells ◽

Allogeneic Hsct ◽

Prolonged Stimulation ◽

One Year ◽

Germinal Center Formation

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Germinal Centers without T Cells

Journal of Experimental Medicine ◽

10.1084/jem.191.3.485 ◽

2000 ◽

Vol 191 (3) ◽

pp. 485-494 ◽

Cited By ~ 202

Author(s):

Carola García de Vinuesa ◽

Matthew C. Cook ◽

Jennifer Ball ◽

Marion Drew ◽

Yvonne Sunners ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Germinal Center ◽

High Efficiency ◽

Germinal Centers ◽

Affinity Maturation ◽

High Affinity ◽

Safe Mechanism ◽

Germinal Center Formation

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation.

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