Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses

The recruitment of tumor necrosis factor receptor–associated factors (TRAFs) 1, 2, 3, 5, and 6 to the CD40 cytoplasmic tail upon CD40 trimerization results in downstream signaling events that ultimately lead to CD40-dependent, thymus-dependent (TD) humoral immune responses. Previously, we have shown signaling through the C-terminal tail of CD40 in the absence of canonical TRAF-binding sites is capable of signaling through an alternative TRAF2-binding site. Here, we demonstrate that B cells from mice harboring CD40 with only the C-terminal tail can activate both canonical and noncanonical NFκB signaling pathways. Moreover, while lacking germinal center formation, several hallmarks of humoral immune responses including clonal B-cell activation/expansion, antibody isotype switching, and affinity maturation remain normal. This study demonstrates a new functional domain in CD40 that controls critical aspects of B-cell immunity in an in vivo setting.

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Dok-3 plays a nonredundant role in negative regulation of B-cell activation

Blood ◽

10.1182/blood-2006-10-055194 ◽

2007 ◽

Vol 110 (1) ◽

pp. 259-266 ◽

Cited By ~ 33

Author(s):

Chee-Hoe Ng ◽

Shengli Xu ◽

Kong-Peng Lam

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Cell Receptor ◽

Negative Regulation ◽

Myelogenous Leukemia ◽

Type I ◽

B Cell Activation ◽

Humoral Immune ◽

Humoral Immune Responses

p62dok and Dok-3 are members of the Dok family of adaptors found in B cells, with the former cloned as a substrate of the p210bcr/abl oncoprotein in Ph + chronic myelogenous leukemia. A role for p62dok in FcγRIIB–mediated negative regulation of B-cell proliferation had been established previously. Here, we generated Dok-3−/− mice to assess the function of Dok-3 in B cells. Mice lacking Dok-3 have normal B-cell development but possess higher level of IgM antibodies in their sera. In comparison to wild-type mice, Dok-3−/− mice mounted significantly enhanced humoral immune responses to T cell–independent type I and II antigens. Dok-3–deficient B cells hyperproliferated, exhibited elevated level of calcium signaling as well as enhanced activation of NF-κB, JNK, and p38MAPK in response to B-cell receptor (BCR) engagement. In the absence of Dok-3, the localization of the inhibitory phosphatase SHIP-1 to the plasma membrane is intact while its phosphorylation is compromised, suggesting that Dok-3 could function to facilitate or sustain the activation of SHIP-1. The phenotype and responses of Dok-3−/− mice and B cells could be differentiated from those of the Dok-1−/− counterparts. Hence, we propose that Dok-3 plays a distinct and nonredundant role in the negative regulation of BCR signaling.

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The Toll-like Receptor Protein Rp105 Regulates Lipopolysaccharide Signaling in B Cells

Journal of Experimental Medicine ◽

10.1084/jem.192.1.23 ◽

2000 ◽

Vol 192 (1) ◽

pp. 23-30 ◽

Cited By ~ 220

Author(s):

Hirotaka Ogata ◽

I-hsin Su ◽

Kensuke Miyake ◽

Yoshinori Nagai ◽

Sachiko Akashi ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

B Cell ◽

Neutralizing Antibodies ◽

Cell Activation ◽

Nuclear Factor Κb ◽

Receptor Protein ◽

B Cell Activation ◽

Toll Like Receptor ◽

Humoral Immune

The susceptibility to infections induced by Gram-negative bacteria is largely determined by innate immune responses to bacteria cell wall lipopolysaccharide (LPS). The stimulation of B cells by LPS enhances their antigen-presenting capacity and is accompanied by B cell proliferation and secretion of large quantities of LPS-neutralizing antibodies. Similar to macrophages and neutrophils, the LPS-induced activation of B cells is dependent on Toll-like receptor (TLR)4. Here, we demonstrate that the responses of B cells to LPS are also regulated by another TLR protein, RP105, which is predominantly expressed on mature B cells in mice and humans. The analysis of mice homozygous for the null mutation in the RP105 gene revealed impaired proliferative and humoral immune responses of RP105-deficient B cells to LPS. Using originally LPS-unresponsive Ba/F3 cells expressing exogenous TLR4 and RP105, we demonstrate the functional cooperation between TLR4 and RP105 in LPS-induced nuclear factor κB activation. These data suggest the existence of the TLR4–RP105 signaling module in the LPS-induced B cell activation.

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Faculty Opinions recommendation of Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717959020.793462522 ◽

2012 ◽

Author(s):

Takeshi Tsubata

Keyword(s):

Immune Responses ◽

B Cell ◽

Cell Survival ◽

Critical Role ◽

Fc Receptor ◽

Humoral Immune ◽

Humoral Immune Responses ◽

B Cell Survival

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Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1210706109 ◽

2012 ◽

Vol 109 (40) ◽

pp. E2699-E2706 ◽

Cited By ~ 77

Author(s):

R. Ouchida ◽

H. Mori ◽

K. Hase ◽

H. Takatsu ◽

T. Kurosaki ◽

...

Keyword(s):

Immune Responses ◽

B Cell ◽

Cell Survival ◽

Critical Role ◽

Fc Receptor ◽

Humoral Immune ◽

Humoral Immune Responses ◽

B Cell Survival

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Cellular and humoral immune responses associated with protection in sheep vaccinated against Teladorsagia circumcincta

Veterinary Research ◽

10.1186/s13567-021-00960-8 ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Cynthia Machín ◽

Yolanda Corripio-Miyar ◽

Julia N. Hernández ◽

Tara Pérez-Hernández ◽

Adam D. Hayward ◽

...

Keyword(s):

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Anthelmintic Resistance ◽

Gastrointestinal Nematodes ◽

Control Group ◽

Sheep Breeds ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Teladorsagia Circumcincta

AbstractDue to increased anthelmintic resistance, complementary methods to drugs are necessary to control gastrointestinal nematodes (GIN). Vaccines are an environmentally-friendly and promising option. In a previous study, a Teladorsagia circumcincta recombinant sub-unit vaccine was administered to two sheep breeds with different levels of resistance against GIN. In the susceptible Canaria Sheep (CS) breed, vaccinates harboured smaller worms with fewer eggs in utero than the control group. Here, we extend this work, by investigating the cellular and humoral immune responses of these two sheep breeds following vaccination and experimental infection with T. circumcincta. In the vaccinated CS group, negative associations between antigen-specific IgA, IgG2 and Globule Leukocytes (GLs) with several parasitological parameters were established as well as a higher CD4+/CD8+ ratio than in control CS animals, suggesting a key role in the protection induced by the vaccine. In the more resistant Canaria Hair Breed (CHB) sheep the vaccine did not significantly impact on the parasitological parameters studied and none of these humoral associations were observed in vaccinated CHB lambs, although CHB had higher proportions of CD4+ and CD8+ T cells within the abomasal lymph nodes, suggesting higher mucosal T cell activation. Each of the component proteins in the vaccine induced an increase in immunoglobulin levels in vaccinated groups of each breed. However, levels of immunoglobulins to only three of the antigens (Tci-MEP-1, Tci-SAA-1, Tci-ASP-1) were negatively correlated with parasitological parameters in the CS breed and they may be, at least partially, responsible for the protective effect of the vaccine in this breed. These data could be useful for improving the current vaccine prototype.

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Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses

Nature Communications ◽

10.1038/s41467-019-11002-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 12

Author(s):

Yuhang Jiang ◽

Cuifeng Li ◽

Qian Wu ◽

Peng An ◽

Laiquan Huang ◽

...

Keyword(s):

Cell Proliferation ◽

Immune Responses ◽

B Cell ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Histone 3

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Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation.

Journal of Experimental Medicine ◽

10.1084/jem.171.1.265 ◽

1990 ◽

Vol 171 (1) ◽

pp. 265-292 ◽

Cited By ~ 467

Author(s):

M Shlomchik ◽

M Mascelli ◽

H Shan ◽

M Z Radic ◽

D Pisetsky ◽

...

Keyword(s):

Immune Responses ◽

B Cell ◽

Cell Activation ◽

Specific Antigen ◽

B Cell Activation ◽

Spleen Cells ◽

Systemic Autoimmune Diseases ◽

Proximate Cause ◽

Arginine Residues ◽

Dna Antibodies

The proximate cause of autoantibodies characteristic of systemic autoimmune diseases has been controversial. One hypothesis is that autoantibodies are the result of polyclonal nonspecific B cell activation. Alternatively, autoantibodies could be the result of antigen-driven B cell activation, as observed in secondary immune responses. We have approached this question by studying monoclonal anti-DNA autoantibodies derived from unmanipulated spleen cells of the autoimmune MRL/lpr mouse strain. This analysis shows that anti-DNAs, like rheumatoid factors (19), are the result of specific antigen-driven stimulation. In addition, correlation of sequences with fine specificity shows that: (a) somatic mutations can cause specificity for dsDNA and that such mutations are selected for; (b) arginine residues play an important role in determining specificity; and (c) anti-idiotypes that recognize the majority of anti-DNA are probably not specific for any one family of V regions.

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