Responsiveness of B cells is regulated by the hinge region of IgD

Übelhart, Rudolf; Hug, Eva; Bach, M.; Wossning, Thomas; Minden, Marcus Dühren-von; Horn, Anselm H. C.; Tsiantoulas, Dimitrios; Kometani, Kohei; Kurosaki, Tomohiro; Binder, Christoph J.; Sticht, Heinrich; Nitschke, Lars; Reth, Michael; Jumaa, Hassan

doi:10.1038/ni.3141

Cited by 108 publications

(155 citation statements)

References 50 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…31), potentially explaining the unresponsive state of anergic B cells. The intracellular calcium increase elicited by monomeric HEL was directly compared in splenic B cells from MM4 and DD6 transgenic mice, which respectively express the IgM HEL or IgD HEL antigen receptors studied in ref.…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, hen egg lysozyme (HEL) antigen signalling induced CD86 identically through IgD or IgM on splenic B cells expressing one or other isotype21. However, when the same IgM HEL and IgD HEL BCRs were expressed separately in a pro-B cell line with a partially crippled BLNK (SLP65) intracellular signalling adaptor, soluble monovalent HEL antigen signalled an increase in intracellular calcium when it bound IgM but induced no calcium signalling when it bound IgD, whereas multivalent HEL-antigen signalled through both isotypes31. Extrapolating the findings from the BLNK mutant cell line, it was concluded that the predominant expression of IgD on anergic cells prevents any response to monovalent self-antigens, ascribing the in vivo state of anergy to the change in BCR isotype31.…”

mentioning

confidence: 99%

See 1 more Smart Citation

IgD attenuates the IgM-induced anergy response in transitional and mature B cells

et al. 2016

View full text Add to dashboard Cite

Self-tolerance by clonal anergy of B cells is marked by an increase in IgD and decrease in IgM antigen receptor surface expression, yet the function of IgD on anergic cells is obscure. Here we define the RNA landscape of the in vivo anergy response, comprising 220 induced sequences including a core set of 97. Failure to co-express IgD with IgM decreases overall expression of receptors for self-antigen, but paradoxically increases the core anergy response, exemplified by increased Sdc1 encoding the cell surface marker syndecan-1. IgD expressed on its own is nevertheless competent to induce calcium signalling and the core anergy mRNA response. Syndecan-1 induction correlates with reduction of surface IgM and is exaggerated without surface IgD in many transitional and mature B cells. These results show that IgD attenuates the response to self-antigen in anergic cells and promotes their accumulation. In this way, IgD minimizes tolerance-induced holes in the pre-immune antibody repertoire.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

IgD attenuates the IgM-induced anergy response in transitional and mature B cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…It is relevant to point out that the Fab stimulating reagents that are used in these and previously published in vitro studies (8–15, 18, 19, 45) differ from the ligands that CLL-BCRs encounter in vivo , and that additional characteristics of the stimulating antigen, including affinity (46, 47) and valency (48, 49), may influence the BCR signaling outcome.…”

Section: Discussionmentioning

confidence: 99%

Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia

Hacken

Sivina

Kim

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

B-cell receptor (BCR) signaling is a central pathogenetic pathway in chronic lymphocytic leukemia (CLL). Most CLL cells express BCRs of IgM and IgD isotypes, but the contribution of these isotypes to functional responses remains incompletely defined. We therefore investigated differences between IgM and IgD signaling in freshly isolated peripheral blood CLL cells and in CLL cells cultured with nurselike cells (NLC), a model that mimics the lymph node microenvironment. IgM signaling induced prolonged activation of ERK kinases, promoted CLL cell survival, CCL3 and CCL4 chemokine secretion, and down-regulation of BCL6, the transcriptional repressor of CCL3. In contrast, IgD signaling induced activation of the cytoskeletal protein HS1, along with F-actin polymerization, which resulted in rapid receptor internalization, and failure to support downstream responses including CLL cell survival and chemokine secretion. IgM and IgD receptor down-modulation, HS1 and ERK activation, chemokine secretion and BCL6 down-regulation were also observed when CLL cells were co-cultured with NLC. The BTK kinase inhibitor ibrutinib effectively inhibited both, IgM and IgD isotype signaling. In conclusion, through a variety of functional readouts, we demonstrate very distinct outcomes of IgM and IgD isotype activation in CLL cells, providing novel insight into the regulation of BCR signaling in CLL.

show abstract

“…The computational investigation of linear peptides with the sequence METPSQRRATRSGAQASSTPLSPTRITRLQ followed an approach similar to earlier work [66]. Three systems were set up in an initial extended conformation, differing in the phosphorylation state of Ser22 and the configuration of Pro23: (1) Ser22 not phosphorylated, Pro23 in trans configuration (Ser22/Pro23 trans ); (2) Ser22 phosphorylated, Pro23 in trans configuration (Ser22 phos/Pro23 trans ); and (3) Ser22 phosphorylated, Pro23 in cis configuration (Ser22 phos/Pro23 cis ).…”

Section: Methodsmentioning

confidence: 99%

The Prolyl Isomerase Pin1 Promotes the Herpesvirus-Induced Phosphorylation-Dependent Disassembly of the Nuclear Lamina Required for Nucleocytoplasmic Egress

et al. 2016

Self Cite

View full text Add to dashboard Cite

The nuclear lamina lines the inner nuclear membrane providing a structural framework for the nucleus. Cellular processes, such as nuclear envelope breakdown during mitosis or nuclear export of large ribonucleoprotein complexes, are functionally linked to the disassembly of the nuclear lamina. In general, lamina disassembly is mediated by phosphorylation, but the precise molecular mechanism is still not completely understood. Recently, we suggested a novel mechanism for lamina disassembly during the nuclear egress of herpesviral capsids which involves the cellular isomerase Pin1. In this study, we focused on mechanistic details of herpesviral nuclear replication to demonstrate the general importance of Pin1 for lamina disassembly. In particular, Ser22-specific lamin phosphorylation consistently generates a Pin1-binding motif in cells infected with human and animal alpha-, beta-, and gammaherpesviruses. Using nuclear magnetic resonance spectroscopy, we showed that binding of Pin1 to a synthetic lamin peptide induces its cis/trans isomerization in vitro. A detailed bioinformatic evaluation strongly suggests that this structural conversion induces large-scale secondary structural changes in the lamin N-terminus. Thus, we concluded that a Pin1-induced conformational change of lamins may represent the molecular trigger responsible for lamina disassembly. Consistent with this concept, pharmacological inhibition of Pin1 activity blocked lamina disassembly in herpesvirus-infected fibroblasts and consequently impaired virus replication. In addition, a phospho-mimetic Ser22Glu lamin mutant was still able to form a regular lamina structure and overexpression of a Ser22-phosphorylating kinase did not induce lamina disassembly in Pin1 knockout cells. Intriguingly, this was observed in absence of herpesvirus infection proposing a broader importance of Pin1 for lamina constitution. Thus, our results suggest a functional model of similar events leading to disassembly of the nuclear lamina in response to herpesviral or inherent cellular stimuli. In essence, Pin1 represents a regulatory effector of lamina disassembly that promotes the nuclear pore-independent egress of herpesviral capsids.

show abstract

Responsiveness of B cells is regulated by the hinge region of IgD

Cited by 108 publications

References 50 publications

IgD attenuates the IgM-induced anergy response in transitional and mature B cells

IgD attenuates the IgM-induced anergy response in transitional and mature B cells

Functional Differences between IgM and IgD Signaling in Chronic Lymphocytic Leukemia

The Prolyl Isomerase Pin1 Promotes the Herpesvirus-Induced Phosphorylation-Dependent Disassembly of the Nuclear Lamina Required for Nucleocytoplasmic Egress

Contact Info

Product

Resources

About