Immunoglobulin expression in the endoplasmic reticulum shapes the metabolic fitness of B lymphocytes

Jumaa, Huda; Caganova, Marieta; McAllister, Ellen; Hoenig, Laura; He, Xiaobo; Saltukoglu, Deniz; Brenker, Kathrin; Köhler, M; Leben, Ruth; Hauser, Anja E.; Niesner, Raluca; Rajewsky, Klaus; Reth, Michael; Jellusova, Julia

doi:10.26508/lsa.202000700

Cited by 11 publications

(20 citation statements)

References 51 publications

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“…OCR and ECAR were measured using Seahorse flux technology. Experiments were performed as described before ( 48 ). Detailed protocols are included in SI Appendix , Methods .…”

Section: Methodsmentioning

confidence: 99%

CD20 as a gatekeeper of the resting state of human B cells

Kläsener

Jellusova

Andrieux

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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CD20 is a B cell-specific membrane protein and represents an attractive target for therapeutic antibodies. Despite widespread usage of anti-CD20 antibodies for B cell depletion therapies, the biological function of their target remains unclear. Here, we demonstrate that CD20 controls the nanoscale organization of receptors on the surface of resting B lymphocytes. CRISPR/Cas9-mediated ablation of CD20 in resting B cells resulted in relocalization and interaction of the IgM-class B cell antigen receptor with the coreceptor CD19. This receptor rearrangement led to a transient activation of B cells, accompanied by the internalization of many B cell surface marker proteins. Reexpression of CD20 restored the expression of the B cell surface proteins and the resting state of Ramos B cells. Similarly, treatment of Ramos or naive human B cells with the anti-CD20 antibody rituximab induced nanoscale receptor rearrangements and transient B cell activation in vitro and in vivo. A departure from the resting B cell state followed by the loss of B cell identity of CD20-deficient Ramos B cells was accompanied by a PAX5 to BLIMP-1 transcriptional switch, metabolic reprogramming toward oxidative phosphorylation, and a shift toward plasma cell development. Thus, anti-CD20 engagement or the loss of CD20 disrupts membrane organization, profoundly altering the fate of human B cells.

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“…OCR and ECAR were measured using Seahorse flux technology. Experiments were performed as described before ( 48 ). Detailed protocols are included in SI Appendix , Methods .…”

Section: Methodsmentioning

confidence: 99%

CD20 as a gatekeeper of the resting state of human B cells

Kläsener

Jellusova

Andrieux

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…The maintenance of endoplasmic reticulum (ER) homeostasis shapes B-cell metabolism and metabolic stress responses by regulating mitochondrial calcium levels. 16 To further investigate the effect of SARS-CoV-2 infection on B-cell metabolism, B cells from patients and healthy controls were stimulated with F(ab′) 2 anti-human Ig(M + G) for varying times, stained with ER tracker and MITO tracker of mitochondria, and analyzed by confocal microscopy. We found that MFI of ER and MITO of patient B cell significantly increased at 0 and 5 min, but decreased at 30 min compared to that of healthy controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism

Jing

Luo

Chen

et al. 2021

Sig Transduct Target Ther

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The SARS-CoV-2 infection causes severe immune disruption. However, it is unclear if disrupted immune regulation still exists and pertains in recovered COVID-19 patients. In our study, we have characterized the immune phenotype of B cells from 15 recovered COVID-19 patients, and found that healthy controls and recovered patients had similar B-cell populations before and after BCR stimulation, but the frequencies of PBC in patients were significantly increased when compared to healthy controls before stimulation. However, the percentage of unswitched memory B cells was decreased in recovered patients but not changed in healthy controls upon BCR stimulation. Interestingly, we found that CD19 expression was significantly reduced in almost all the B-cell subsets in recovered patients. Moreover, the BCR signaling and early B-cell response were disrupted upon BCR stimulation. Mechanistically, we found that the reduced CD19 expression was caused by the dysregulation of cell metabolism. In conclusion, we found that SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism, which may provide a new intervention target to cure COVID-19.

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“…BCL-2 expression can decrease apoptosis of GC B cells by 10-fold (45) but is insufficient to prevent apoptosis due to deleterious mutations induced in BCR genes (43). Jumaa et al discovered a mechanism by which BCR expression regulates the metabolism of B cells in a BCR signaling independent manner (46). According to this mechanism, BCR regulates changes in endoplasmic reticulum that in turn controls mitochondrial activity.…”

Section: Gc B Cell Apoptosismentioning

confidence: 99%

“…Jumaa et al. discovered a mechanism by which BCR expression regulates the metabolism of B cells in a BCR signaling independent manner ( 46 ). According to this mechanism, BCR regulates changes in endoplasmic reticulum that in turn controls mitochondrial activity.…”

Section: Regulation Of B Cell Fates In the Gcsmentioning

confidence: 99%

“…According to this mechanism, BCR regulates changes in endoplasmic reticulum that in turn controls mitochondrial activity. Thus, the loss of BCR expression leads to altered B cell metabolism ( 46 ). Consequently, a similar effect might be expected in GC B cells that cannot express functional BCRs due to deleterious mutations.…”

Section: Regulation Of B Cell Fates In the Gcsmentioning

confidence: 99%

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Germinal Centre Shutdown

et al. 2021

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Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, ‘normal’ GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question – what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.

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Immunoglobulin expression in the endoplasmic reticulum shapes the metabolic fitness of B lymphocytes

Cited by 11 publications

References 51 publications

CD20 as a gatekeeper of the resting state of human B cells

CD20 as a gatekeeper of the resting state of human B cells

SARS-CoV-2 infection causes immunodeficiency in recovered patients by downregulating CD19 expression in B cells via enhancing B-cell metabolism

Germinal Centre Shutdown

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