T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity

Szodoray, Péter; Stanford, Stephanie M.; Molberg, Øyvind; Munthe, Ludvig A.; Bottini, Nunzio; Nakken, Britt

doi:10.1016/j.jaci.2016.01.035

Cited by 24 publications

(37 citation statements)

References 49 publications

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“…Before these results were obtained, it has been reported that Th2 signals restore BCR signalling in a small population of anergic IgM-IgD+-naïve B cells present in blood of healthy donors and patients with SLE. 92 IL-4 or IL-21 alone led to modest effects on the pSyk(Y352) response to BCR engagement. IL-4 in combination with CD40L, however, led to higher responses than with CD40L alone.…”

Section: Co-stimulation Of Cd40 Effectively Improves B Cell Anergy Inmentioning

confidence: 93%

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

et al. 2020

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Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton’s tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically.

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Section: Co-stimulation Of Cd40 Effectively Improves B Cell Anergy Inmentioning

confidence: 93%

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

et al. 2020

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“…Anergic B cells are considered a source of self-reactive ASCs in SLE as they can persist in the mature B cell repertoire and interact with T h cells [37][38][39]; however, the exact mechanism by CXCR5 -PD-1 hi T cells. Graphs for (D), (E), (G), (I) and (J) show the proportions of T fh , T fr , CXCR5 -PD-1 hi T, T eff and T reg cells, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Anergic B cells are considered a source of self-reactive ASCs in SLE as they can persist in the mature B cell repertoire and interact with T h cells [ 37 – 39 ]; however, the exact mechanism by which anergic B cells convert to ASCs–and whether or not they are the true drivers of autoAb production–remains unclear. In this study, we found that NZB c1 lupus-prone congenic mice can breach tolerance to nuclear antigen, but that this is severely attenuated in the Vκ8/3H9 anergic model, with limited production of autoAbs despite high numbers of ssDNA-reactive cells.…”

Section: Discussionmentioning

confidence: 99%

Impaired B cell anergy is not sufficient to breach tolerance to nuclear antigen in Vκ8/3H9 lupus-prone mice

et al. 2020

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Background Systemic lupus erythematosus (SLE) is a severe autoimmune disease in which immune tolerance defects drive production of pathogenic anti-nuclear autoantibodies. Anergic B cells are considered a potential source of these autoantibodies due to their autoreactivity and overrepresentation in SLE patients. Studies of lupus-prone mice have shown that genetic defects mediating autoimmunity can breach B cell anergy, but how this breach occurs with regards to endogenous nuclear antigen remains unclear. We investigated whether B and T cell defects in congenic mice (c1) derived from the lupus-prone New Zealand Black strain can breach tolerance to nuclear self-antigen in the presence of knock-in genes (Vκ8/3H9; dKI) that generate a ssDNA-reactive, anergic B cell population. Methods Flow cytometry was used to assess splenic B and T cells from 8-month-old c1 dKI mice and serum autoantibodies were measured by ELISA. dKI B cells stimulated in vitro with anti-IgM were assessed for proliferation and activation by examining CFSE decay and CD86. Cytokine-producing T cells were identified by flow cytometry following culture of dKI splenocytes with PMA and ionomycin. dKI B cells from 6-8-week-old mice were adoptively transferred into 4-month-old wild type recipients and assessed after 7 days via flow cytometry and immunofluorescence microscopy.

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“…Importantly, oligomerized sCD40L was ineffective in a large majority of our "in vitro" experiments. Due to its effectiveness in B-cell activation, [52][53][54][55] the original CD40-mediated functional assay, oligomerized s40L is usually considered as the reference standard for CD40 triggering tests. However, the extent of CD40 polymerization has been shown to critically affect the elicitation of the multiplicity of functional effects induced by its triggering.…”

Section: Discussionmentioning

confidence: 99%

A replication-incompetent CD154/40L recombinant vaccinia virus induces direct and macrophage-mediated antitumor effects in vitro and in vivo

et al. 2019

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T-helper signals restore B-cell receptor signaling in autoreactive anergic B cells by upregulating CD45 phosphatase activity

Cited by 24 publications

References 49 publications

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus

Impaired B cell anergy is not sufficient to breach tolerance to nuclear antigen in Vκ8/3H9 lupus-prone mice

A replication-incompetent CD154/40L recombinant vaccinia virus induces direct and macrophage-mediated antitumor effects in vitro and in vivo

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