The Maintenance of Memory Plasma Cells

Khodadadi, Laleh; Cheng, Qingyu; Radbruch, Andreas; Hiepe, Falk

doi:10.3389/fimmu.2019.00721

Cited by 169 publications

(170 citation statements)

References 217 publications

(293 reference statements)

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“…WM cells exhibited decreased levels of PRDM1 (encoding the master regulator of PC differentiation BLIMP1), TNFRSF17 (encoding BCMA, which is important for PC survival), and POU2AF1; conversely, increased levels of BACH2, STAT3, and SPIB, which are associated with the B-cell program, were observed. 37,38 This pattern supports previous phenotypic analysis and may explain the delay in differentiation that is sometimes observed in WM cells in comparison with their healthy counterparts.…”

Section: The Numbers Of Significantly Up-or Downregulated Genes Betwesupporting

confidence: 88%

TLR-mediated activation of Waldenström macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation

et al. 2020

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Waldenström macroglobulinemia (WM) is a rare malignancy in which clonal B cells infiltrate the bone marrow and give rise to a smaller compartment of neoplastic plasma cells that secrete monoclonal immunoglobulin M paraprotein. Recent studies into underlying mutations in WM have enabled a much greater insight into the pathogenesis of this lymphoma. However, there is considerably less characterization of the way in which WM B cells differentiate and how they respond to immune stimuli. In this study, we assess WM B-cell differentiation using an established in vitro model system. Using T-cell–dependent conditions, we obtained CD138+ plasma cells from WM samples with a frequency similar to experiments performed with B cells from normal donors. Unexpectedly, a proportion of the WM B cells failed to upregulate CD38, a surface marker that is normally associated with plasmablast transition and maintained as the cells proceed with differentiation. In normal B cells, concomitant Toll-like receptor 7 (TLR7) activation and B-cell receptor cross-linking drives proliferation, followed by differentiation at similar efficiency to CD40-mediated stimulation. In contrast, we found that, upon stimulation with TLR7 agonist R848, WM B cells failed to execute the appropriate changes in transcriptional regulators, identifying an uncoupling of TLR signaling from the plasma cell differentiation program. Provision of CD40L was sufficient to overcome this defect. Thus, the limited clonotypic WM plasma cell differentiation observed in vivo may result from a strict requirement for integrated activation.

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Section: The Numbers Of Significantly Up-or Downregulated Genes Betwesupporting

confidence: 88%

TLR-mediated activation of Waldenström macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation

et al. 2020

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“…The copyright holder for this preprint this version posted November 6, 2020. ; https://doi.org/10.1101/2020.11.04.20225920 doi: medRxiv preprint of antibody production may represent the switch from antibody production from short lived plasmablasts to long lived plasma cells. 33 Importantly, immune complexes are also known to regulate antibody production via inhibitory Fc receptors on plasma cells.…”

Section: Discussionmentioning

confidence: 99%

Characterising heterogeneity and sero-reversion in antibody responses to mild SARS⍰CoV-2 infection: a cohort study using time series analysis and mechanistic modelling

Manisty

Treibel

Jensen

et al. 2020

Preprint

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Background SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. Methods Health care workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n=12,990) was performed using semi quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to previously reported pseudovirus neutralising antibody measurements. Findings A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r=0.57, p<0.0001) but only anti S1 measurements correlated with near contemporary pseudovirus neutralising antibody titres (measured at 16-18 weeks, r=0.57, p<0.0001). By 21 weeks of follow-up, 31/143 (21.7%) anti S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling suggested faster clearance of anti-S1 compared to anti NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). Interpretation Mild SARS CoV 2 infection is associated with heterogenous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate after this transition. The application of individual assays for diagnostic and epidemiological serology requires validation in time series analysis.

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“…This may only be relevant with continuous treatments that maintain peripheral B cells in a nadir state and prevent antibody secreting cell (ASC) formation (Sabatino et al, 2019a;Baker et al, 2020a). However, ASC can be generated by germinal centre cells independent of the CD27+, memory B cell pathway (Baker et al, 2018;Hammarlund et al, 2017;Khodadadi et al, 2019). Novel vaccine responses will be generated from the immature/naïve B cell compartments that regenerate most rapidly following B cell depleting therapies (Baker et al, 2017b, Baker et al, 2019, Baker et al, 2020a.…”

Section: Mechanisms Driving Multiple Sclerosis May Be Distinct From Cmentioning

confidence: 99%

“…Novel vaccine responses will be generated from the immature/naïve B cell compartments that regenerate most rapidly following B cell depleting therapies (Baker et al, 2017b, Baker et al, 2019, Baker et al, 2020a. Once formed, anti-viral responses will reside within the long-lived plasma cell pool with lymphoid tissue and bone marrow (Khodadadi et al, 2019;Baker et al, 2018). Plasma cells are relatively quiescent (Khodadadi et al, 2019) and thus avoid the action of agents targeting proliferating cells and they also express low levels of CD52, deoxycytidine kinase and CD20 targeted by high-efficacy, depleting DMT (Baker et al, 2020b;Sabatino et al, 2019a, Baker et al, 2019.…”

Section: Mechanisms Driving Multiple Sclerosis May Be Distinct From Cmentioning

confidence: 99%

“…Once formed, anti-viral responses will reside within the long-lived plasma cell pool with lymphoid tissue and bone marrow (Khodadadi et al, 2019;Baker et al, 2018). Plasma cells are relatively quiescent (Khodadadi et al, 2019) and thus avoid the action of agents targeting proliferating cells and they also express low levels of CD52, deoxycytidine kinase and CD20 targeted by high-efficacy, depleting DMT (Baker et al, 2020b;Sabatino et al, 2019a, Baker et al, 2019. Furthermore, they reside predominantly in the bone marrow, a site that may not be effectively targeted by depleting antibodies as cell elimination requires entry of antibodies, complement components and effector accessory cells required for depletion (Baker et al, 2018).…”

Section: Mechanisms Driving Multiple Sclerosis May Be Distinct From Cmentioning

confidence: 99%

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The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

Baker

Amor

Kang

et al. 2020

Multiple Sclerosis and Related Disorders

104

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Background: SARS-CoV-2 viral infection causes COVID-19 that can result in severe acute respiratory distress syndrome (ARDS), which can cause significant mortality, leading to concern that immunosuppressive treatments for multiple sclerosis and other disorders have significant risks for both infection and ARDS. Objective: To examine the biology that potentially underpins immunity to the SARS-Cov-2 virus and the immunity-induced pathology related to COVID-19 and determine how this impinges on the use of current disease modifying treatments in multiple sclerosis. Observations: Although information about the mechanisms of immunity are scant, it appears that monocyte/macrophages and then CD8 T cells are important in eliminating the SARS-CoV-2 virus. This may be facilitated via anti-viral antibody responses that may prevent re-infection. However, viral escape and infection of leucocytes to promote lymphopenia, apparent CD8 T cell exhaustion coupled with a cytokine storm and vascular pathology appears to contribute to the damage in ARDS. Implications: In contrast to ablative haematopoietic stem cell therapy, most multiple-sclerosis-related disease modifying therapies do not particularly target the innate immune system and few have any major long-term impact on CD8 T cells to limit protection against COVID-19. In addition, few block the formation of immature B cells within lymphoid tissue that will provide antibody-mediated protection from (re)infection. However, adjustments to dosing schedules may help de-risk the chance of infection further and reduce the concerns of people with MS being treated during the COVID-19 pandemic. 1. SARS-Cov-2 and COVID-19 a new pandemic COVID-19 is the pandemic disease caused by severe acute respiratory syndrome (SARS) coronavirus two (SARS-CoV-2) infection (Zhu et al., 2020a; Zhou et al., 2020). About 80% of people infected with SARS-CoV-2 develop a self-limiting illness, 20% require hospitalisation, largely due to cardiovascular issues and about 5% require critical care and potential ventilatory support (Kimball et al., 2020; Day. 2020). The mortality in those requiring ventilatory support is about 40-50% (Weiss and Murdoch 2020; Zhu et al., 2020b). Death from COVID-19 is associated with older age and comorbidities such as cardiovascular disease, smoking, lung disease, obesity and diabetes (Zhu et al., 2020a; Lippi et al., 2020; Richardson et al., 2020). Mortality in young people and those without comorbidities may be related to excessive viral load (Lui et al 2020a; Chen et al., 2020a). Whilst the typical clinical features requiring self-isolation, and potentially hospitalization are fever, dry cough and shortness of breath related to respiratory tract infection, other symptoms such as headache and gastrointestinal symptoms may go unnoticed or under-appreciated leading to spreading of the virus (Zhu et al., 2020b; Richardson et al., 2020; Huang et al., 2020). People shed infective virus days before symptoms occur and continue to shed virus via the lungs and faeces whilst symptoms develo...

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The Maintenance of Memory Plasma Cells

Cited by 169 publications

References 217 publications

TLR-mediated activation of Waldenström macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation

TLR-mediated activation of Waldenström macroglobulinemia B cells reveals an uncoupling from plasma cell differentiation

Characterising heterogeneity and sero-reversion in antibody responses to mild SARS⍰CoV-2 infection: a cohort study using time series analysis and mechanistic modelling

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic

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