Survival of Igα-Deficient Mature B Cells Requires BAFF-R Function

Levit‐Zerdoun, Ella; Becker, Marlies; Pohlmeyer, Roland; Wilhelm, Isabel; Maity, Palash C.; Rajewsky, Klaus; Reth, Michael; Hobeika, Elias

doi:10.4049/jimmunol.1501707

Cited by 14 publications

(20 citation statements)

References 97 publications

(125 reference statements)

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“…Taken together, these results might indicate a role for B cells in CFS pathophysiology, as is supported from studies of cellular immunology: Brenu and co-workers reported a decrease in immature B cells and an increase in memory B cells among CFS patients [74], whereas Bradley and co-workers [75] and Mensah and co-workers [76] found subtle distortions in the proportion of B cell subsets. Alterations of immunoglobulin levels in CFS have also been reported [77], but was not identified in the present material, which is not surprising given the strong propensity of compensatory mechanisms to ensure normal immunoglobulin levels in circulation despite changes in B cell function [78]. …”

Section: Discussionmentioning

confidence: 44%

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival

et al. 2017

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BackgroundChronic fatigue syndrome (CFS) is a prevalent and disabling condition affecting adolescents. The pathophysiology is poorly understood, but immune alterations might be an important component. This study compared whole blood gene expression in adolescent CFS patients and healthy controls, and explored associations between gene expression and neuroendocrine markers, immune markers and clinical markers within the CFS group.MethodsCFS patients (12–18 years old) were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls having comparable distribution of gender and age were recruited from local schools. Whole blood samples were subjected to RNA sequencing. Immune markers were blood leukocyte counts, plasma cytokines, serum C-reactive protein and immunoglobulins. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings.ResultsA total of 29 CFS patients and 18 healthy controls were included. We identified 176 genes as differentially expressed in patients compared to controls, adjusting for age and gender factors. Gene set enrichment analyses suggested impairment of B cell differentiation and survival, as well as enhancement of innate antiviral responses and inflammation in the CFS group. A pattern of co-expression could be identified, and this pattern, as well as single gene transcripts, was significantly associated with indices of autonomic nervous activity, plasma cortisol, and blood monocyte and eosinophil counts. Also, an association with symptoms of post-exertional malaise was demonstrated.ConclusionAdolescent CFS is characterized by differential gene expression pattern in whole blood suggestive of impaired B cell differentiation and survival, and enhanced innate antiviral responses and inflammation. This expression pattern is associated with neuroendocrine markers of altered HPA axis and autonomic nervous activity, and with symptoms of post-exertional malaise. Trial registration Clinical Trials NCT01040429Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1201-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 44%

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival

et al. 2017

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“…An alternative interpretation of these data is that the Igβ/CD19 module is also expressed on normal B cells and that it becomes detectable after BCR internalization. Continuous signaling from the Igβ/CD19 receptor module may also be the explanation for the long‐term survival of mature murine B cells that upon inducible Cre‐mediated deletion of the Igα gene, become BCR‐negative (Levit‐Zerdoun et al , 2016). Indeed, similar to what we have observed with Igβ‐only Ramos B cells, Igα‐deficient murine B cells can flux calcium upon exposure to anti‐Igβ antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…We crossed the floxed B1‐8f/Δ Ig transgenic mice (Lam et al , 1997) with mb1‐CreERT2 mice (Hug et al , 2014) to generate the B1‐8f/Δ mb1CreERT2 mice (Hobeika et al , 2015; Levit‐Zerdoun et al , 2016). The mice were induced as reported previously to generate BCR − B cells (Becker et al , 2017).…”

Section: Methodsmentioning

confidence: 99%

“…These data show that the proper expression of the BCR is required for the fitness and survival of mature B cells and it was therefore suggested that the unengaged BCR emits a maintenance or tonic survival signal. However, some mature B cells which loose BCR expression after an inducible deletion of the Igα gene survive in mice for more than 20 days, suggesting alternative signals for the survival of these B cells (Levit‐Zerdoun et al , 2016). …”

Section: Introductionmentioning

confidence: 99%

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Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

Kläsener

Iype

et al. 2018

The EMBO Journal

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Expression of the B‐cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B‐cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine‐based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B‐cell co‐receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b), and the co‐receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igβ can be expressed on the B‐cell surface, where it is found in close proximity to CD19 and signals in an ITAM‐dependent manner. These data suggest that Igβ and CD19 are part of an alternative B‐cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells.

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“…These mice express a B cell-specific Cre recombinase from the Ig-encoding mb-1 locus, which, upon tamoxifen treatment, induces the deletion of the B1-8 fl allele, resulting in the generation of HC-deficient B cells. The HC-deficient B cells were obtained at day 7 after tamoxifen treatment when an abundant number of these cells were still present in mb1-CreER T2 ; B1-8 fl mice before they were lost at later time points (44)(45)(46). These cells (denoted as HC −/− cells), identified by gating on IgM-and IgD-negative populations ( fig.…”

Section: Bambl Induces Ca 2+ Release That Is Dependent On Bcr Expressmentioning

confidence: 99%

Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins

Wilhelm

Levit‐Zerdoun

Jakob³

et al. 2019

Sci. Signal.

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Bacterial lectins are typically multivalent and bind noncovalently to specific carbohydrates on host tissues to facilitate bacterial adhesion. Here, we analyzed the effects of two fucose-binding lectins, BambL from Burkholderia ambifaria and LecB from Pseudomonas aeruginosa, on specific signaling pathways in B cells. We found that these bacterial lectins induced B cell activation, which, in vitro, was dependent on the cell surface expression of the B cell antigen receptor (BCR) and its co-receptor CD19, as well as on spleen tyrosine kinase (Syk) activity. The resulting release of intracellular Ca 2+ was followed by an increase in the cell surface abundance of the activation marker CD86, augmented cytokine secretion, and subsequent cell death, replicating all of the events that are observed in vitro upon canonical and antigen-mediated B cell activation. Moreover, injection of BambL in mice resulted in a substantial, BCR-independent loss of B cells in the bone marrow with simultaneous, transient enlargement of the spleen (splenomegaly), as well as an increase in the numbers of splenic B cells and myeloid cells. Together, these data suggest that bacterial lectins can initiate polyclonal activation of B cells through their sole capacity to bind to fucose.

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Survival of Igα-Deficient Mature B Cells Requires BAFF-R Function

Cited by 14 publications

References 97 publications

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival

Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival

Continuous signaling of CD 79b and CD 19 is required for the fitness of Burkitt lymphoma B cells

Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins

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