scholarly journals Genetic mapping reveals Nfkbid as a central regulator of humoral immunity to Toxoplasma gondii

2021 ◽  
Vol 17 (12) ◽  
pp. e1010081
Author(s):  
Scott P. Souza ◽  
Samantha D. Splitt ◽  
Juan C. Sanchez-Arcila ◽  
Julia A. Alvarez ◽  
Jessica N. Wilson ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
B Cell ◽  
Humoral Immunity ◽  
Cell Activation ◽  
Secondary Infection ◽  
Forward Genetics ◽  
Parasitic Infections ◽  
B Cell Activation ◽  
Class Switch ◽  
Secondary Infections

Protective immunity to parasitic infections has been difficult to elicit by vaccines. Among parasites that evade vaccine-induced immunity is Toxoplasma gondii, which causes lethal secondary infections in chronically infected mice. Here we report that unlike susceptible C57BL/6J mice, A/J mice were highly resistant to secondary infection. To identify correlates of immunity, we utilized forward genetics to identify Nfkbid, a nuclear regulator of NF-κB that is required for B cell activation and B-1 cell development. Nfkbid-null mice (“bumble”) did not generate parasite-specific IgM and lacked robust parasite-specific IgG, which correlated with defects in B-2 cell maturation and class-switch recombination. Though high-affinity antibodies were B-2 derived, transfer of B-1 cells partially rescued the immunity defects observed in bumble mice and were required for 100% vaccine efficacy in bone marrow chimeric mice. Immunity in resistant mice correlated with robust isotype class-switching in both B cell lineages, which can be fine-tuned by Nfkbid gene expression. We propose a model whereby humoral immunity to T. gondii is regulated by Nfkbid and requires B-1 and B-2 cells for full protection.

scholarly journals PTIP chromatin regulator controls development and activation of B cell subsets to license humoral immunity in mice

2017 ◽  
Vol 114 (44) ◽  
pp. E9328-E9337 ◽  
Author(s):  
Dan Su ◽  
Stijn Vanhee ◽  
Rebeca Soria ◽  
Elin Jaensson Gyllenbäck ◽  
Linda M. Starnes ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Cell Activation ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Transactivation Domain ◽  
B Cell Activation ◽  
Chromatin Regulator ◽  
B Cell Subsets

B cell receptor signaling and downstream NF-κB activity are crucial for the maturation and functionality of all major B cell subsets, yet the molecular players in these signaling events are not fully understood. Here we use several genetically modified mouse models to demonstrate that expression of the multifunctional BRCT (BRCA1 C-terminal) domain-containing PTIP (Pax transactivation domain-interacting protein) chromatin regulator is controlled by B cell activation and potentiates steady-state and postimmune antibody production in vivo. By examining the effects of PTIP deficiency in mice at various ages during ontogeny, we demonstrate that PTIP promotes bone marrow B cell development as well as the neonatal establishment and subsequent long-term maintenance of self-reactive B-1 B cells. Furthermore, we find that PTIP is required for B cell receptor- and T:B interaction-induced proliferation, differentiation of follicular B cells during germinal center formation, and normal signaling through the classical NF-κB pathway. Together with the previously identified role for PTIP in promoting sterile transcription at the Igh locus, the present results establish PTIP as a licensing factor for humoral immunity that acts at several junctures of B lineage maturation and effector cell differentiation by controlling B cell activation.

HIV-1 induces B-cell activation and class switch recombination via spleen tyrosine kinase and c-Jun N-terminal kinase pathways

AIDS ◽  
2014 ◽  
Vol 28 (16) ◽  
pp. 2365-2374 ◽  
Author(s):  
Ana Judith Perisé-Barrios ◽  
Rafael Correa-Rocha ◽  
Susana Álvarez ◽  
Maria Ángeles Muñoz-Fernandez ◽  
Marjorie Pion
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Activation ◽  
Class Switch Recombination ◽  
B Cell Activation ◽  
Spleen Tyrosine Kinase ◽  
Class Switch ◽  
Hiv 1

scholarly journals LT-K63 Enhances B Cell Activation and Survival Factors in Neonatal Mice That Translates Into Long-Lived Humoral Immunity

2020 ◽  
Vol 11 ◽  
Author(s):  
Audur Anna Aradottir Pind ◽  
Jenny Lorena Molina Estupiñan ◽  
Gudbjorg Julia Magnusdottir ◽  
Giuseppe Del Giudice ◽  
Ingileif Jonsdottir ◽  
...  
Keyword(s):  
B Cell ◽  
Humoral Immunity ◽  
Cell Activation ◽  
B Cell Activation ◽  
Survival Factors ◽  
Neonatal Mice

scholarly journals AID-dependent histone acetylation is detected in immunoglobulin S regions

2006 ◽  
Vol 203 (1) ◽  
pp. 215-226 ◽  
Author(s):  
Lili Wang ◽  
Naree Whang ◽  
Robert Wuerffel ◽  
Amy L. Kenter
Keyword(s):  
B Cells ◽  
B Cell ◽  
Histone Acetylation ◽  
Cell Activation ◽  
Strongly Correlated ◽  
B Cell Activation ◽  
Histone H4 ◽  
Class Switch ◽  
Damage Repair ◽  
Activation Induced Deaminase

Class switch recombination (CSR) is regulated by the expression of activation-induced deaminase (AID) and germline transcripts (GLTs). AID-dependent double-strand breaks (DSBs) are introduced into switch (S) regions and stimulate CSR. Although histone acetylation (Ac) has been well documented in transcription regulation, its role in DNA damage repair remains largely unexplored. The 1B4.B6 B cell line and normal splenic B cells were activated to undergo CSR and analyzed for histone Ac by chromatin immunoprecipitation (ChIP). A detailed study of the Iγ3-Sγ3-Cγ3 locus demonstrated that acetylated histones are focused to the Iγ3 exon and the Sγ3 region but not to the intergenic areas. Histone H3 Ac is strongly correlated with GLT expression at four S regions, whereas H4 Ac was better associated with B cell activation and AID expression. To more directly examine the relationship between H4 Ac and AID, LPS-activated AID KO and WT B cells were analyzed and express comparable levels of GLTs. In AID-deficient B cells, both histones H3 and H4 are reduced where H4 is more severely affected as compared with WT cells. Our findings raise the intriguing possibility that histone H4 Ac at S regions is a marker for chromatin modifications associated with DSB repair during CSR.

scholarly journals E2A activity is induced during B-cell activation to promote immunoglobulin class switch recombination

1999 ◽  
Vol 18 (22) ◽  
pp. 6307-6318 ◽  
Author(s):  
Melanie W. Quong ◽  
David P. Harris ◽  
Susan L. Swain ◽  
Cornelis Murre
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Class Switch Recombination ◽  
B Cell Activation ◽  
Immunoglobulin Class ◽  
Class Switch

scholarly journals STAT6-Deficient Mice Exhibit Normal Induction of Murine AIDS and Expression of Immunoglobulin E following Infection with LP-BM5 Murine Leukemia Viruses

1999 ◽  
Vol 73 (8) ◽  
pp. 7093-7095 ◽  
Author(s):  
Herbert C. Morse ◽  
Thomas McCarty ◽  
Nathalia A. Giese ◽  
Lekidelu Taddesse-Heath ◽  
Michael J. Grusby
Keyword(s):  
B Cell ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Receptor Activation ◽  
Interleukin 4 ◽  
B Cell Activation ◽  
Class Switch ◽  
Murine Aids ◽  
Leukemia Viruses ◽  
Deficient Mice

ABSTRACT The unique Gag polyprotein of the replication-defective virus responsible for murine AIDS (MAIDS) induces B-cell activation, proliferation, and differentiation, including immunoglobulin class switch-recombination to immunoglobulin E (IgE). Secretion of IgE normally requires the serial induction of interleukin 4 (IL-4), engagement of the IL-4 receptor, activation of signal transducer and activator of transcription (STAT) 6, and induction of Iɛ germline transcripts as a prelude to switching. Remarkably, expression of IgE is equivalent in normal and IL-4-deficient mice with MAIDS (Morawetz et al., J. Exp. Med. 184:1651–1661, 1996). To understand this anomaly, we studied mice with a null mutation of STAT6. Lymphoproliferation and immunodeficiency, the hallmarks of MAIDS, developed with comparable kinetics and degree in normal and mutant mice. In addition, serum IgE levels were indistinguishable in mice of either genotype. We conclude that B cells from mice with MAIDS activate unique IL-4- and STAT6-independent signaling pathways for B-cell activation and differentiation.

scholarly journals Substrate stiffness regulates B-cell activation, proliferation, class switch, and T-cell-independent antibody responses in vivo

2015 ◽  
Vol 45 (6) ◽  
pp. 1621-1634 ◽  
Author(s):  
Yingyue Zeng ◽  
Junyang Yi ◽  
Zhengpeng Wan ◽  
Kai Liu ◽  
Ping Song ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Activation ◽  
Antibody Responses ◽  
Substrate Stiffness ◽  
B Cell Activation ◽  
Class Switch

scholarly journals Locus Suicide Recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues

2018 ◽  
Author(s):  
Iman Dalloul ◽  
François Boyer ◽  
Zeinab Dalloul ◽  
Amandine Pignarre ◽  
Gersende Lacombe ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Memory B Cells ◽  
B Cell Activation ◽  
Class Switch ◽  
Super Enhancer ◽  
Activation Induced Deaminase

AbstractB-cell activation yields abundant cell death in parallel to clonal amplification and remodeling of immunoglobulin (Ig) genes by activation-induced deaminase (AID). AID promotes affinity maturation of Ig variable regions and class switch recombination (CSR) in mature B lymphocytes. In the IgH locus, these processes are under control by the 3’ regulatory region (3’RR) super-enhancer, a region demonstrated in the mouse to be both transcribed and itself targeted by AID-mediated recombination. Alternatively to CSR, IgH deletions joining Sμ to “like-switch” DNA repeats that flank the 3’ super-enhancer can thus accomplish so-called “locus suicide recombination” (LSR) in mouse B-cells. We now show that AID-mediated LSR also actively occurs in humans, and provides an activation-induced cell death pathway in multiple conditions of B-cell activation. LSR deletions either focus on the functional IgH allele or are bi-allelic, since they can only be detected when they are ongoing and their signature vanishes from fully differentiated plasma cells or from “resting” blood memory B-cells, but readily reappears when such memory B-cells are re-stimulatedin vitro. Highly diversified breakpoints are distributed either within the upstream (3’RR1) or downstream (3’RR2) copies of the IgH 3’ super-enhancer and all conditions activating CSRin vitroalso seem to trigger LSR.Author SummaryClass switch recombination, initiated by the activation-induced deaminase enzyme rearranges immunoglobulin (Ig) genes in order to replace expression of IgM by IgG, IgA or IgE. A variant form of this event, locus suicide recombination (LSR), was previously reported in mouse B-lymphocytes and simply deletes all functional Ig constant genes, thus terminating B-cell function. This study first demonstrates that the structure of the human Ig heavy chain locus provides an ideal target for LSR, and is thus actively (but transiently) affected by this deletional process at the activated B-cell stage. LSR then yields recombined genes that do not support B-cell survival and which thus become undetectable among long-lived memory B-cells or plasma cells.

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