Maintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells

Bernasconi, Nadia L.; Traggiai, Elisabetta; Lanzavecchia, Antonio

doi:10.1126/science.1076071

Cited by 1,170 publications

(1,184 citation statements)

References 27 publications

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“…From unfractionated PBMC cultures, in vitro generation of human ASCs was especially efficient under conditions that included CD40‐ligand, IL‐2, and toll‐like receptor stimulation (R848), consistent with T‐cell help and previous reports (Fig 2A) 10. These conditions, and less so those with IL‐21, generated a substantial population of CD19 + CD27 ++ CD38 ++ ASCs at day 7 in vitro (Fig 2A), and 25% of the CD19 + CD27 ++ CD38 ++ cells (range, 15–38) expressed CD138, a known ASC‐subset marker.…”

Section: Resultssupporting

confidence: 87%

“…The NR1‐IgG were unlikely to have arisen from pre‐existing circulating ASCs derived ex vivo, given that they were not generated under conditions known to maintain ASCs in culture (IL‐6 ± BAFF) 16. By contrast, under conditions known to proliferate circulating B cells (including IL‐2 and R848),10 NR1‐IgG was consistently detected in culture supernatants both with and without CD40‐ligand (Fig 3). NR1‐IgM was also observed in several wells, typically at lower levels.…”

Section: Resultsmentioning

confidence: 96%

“…Traditional concepts in immunology outline two largely competing mechanisms of medium‐ to long‐term antibody production 10, 11. The first hypothesizes that, throughout the disease, ongoing germinal center reactions generate NR1‐specific B cells.…”

mentioning

confidence: 99%

See 2 more Smart Citations

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

107

102

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IntroductionN‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is mediated by immunoglobulin G (IgG) autoantibodies directed against the NR1 subunit of the NMDAR. Around 20% of patients have an underlying ovarian teratoma, and the condition responds to early immunotherapies and ovarian teratoma removal. However, despite clear therapeutic relevance, mechanisms of NR1‐IgG production and the contribution of germinal center B cells to NR1‐IgG levels are unknown.MethodsClinical data and longitudinal paired serum NR1‐reactive IgM and IgG levels from 10 patients with NMDAR‐antibody encephalitis were determined. Peripheral blood mononuclear cells from these 10 patients, and two available ovarian teratomas, were stimulated with combinations of immune factors and tested for secretion of total IgG and NR1‐specific antibodies.ResultsIn addition to disease‐defining NR1‐IgG, serum NR1‐IgM was found in 6 of 10 patients. NR1‐IgM levels were typically highest around disease onset and detected for several months into the disease course. Moreover, circulating patient B cells were differentiated into CD19+CD27++CD38++ antibody‐secreting cells in vitro and, from 90% of patients, secreted NR1‐IgM and NR1‐IgG. Secreted levels of NR1‐IgG correlated with serum NR1‐IgG (p < 0.0001), and this was observed across the varying disease durations, suggestive of an ongoing process. Furthermore, ovarian teratoma tissue contained infiltrating lymphocytes which produced NR1‐IgG in culture.InterpretationSerum NR1‐IgM and NR1‐IgG, alongside the consistent production of NR1‐IgG from circulating B cells and from ovarian teratomas suggest that ongoing germinal center reactions may account for the peripheral cell populations which secrete NR1‐IgG. Cells participating in germinal center reactions might be a therapeutic target for the treatment of NMDAR‐antibody encephalitis. Ann Neurol 2018;83:553–561

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 96%

See 1 more Smart Citation

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

Makuch

Wilson

Al-Diwani

et al. 2018

Annals of Neurology

107

102

View full text Add to dashboard Cite

show abstract

“…Indeed, memory B cells appear to transit between the CD27 + and CD27‐ compartments 31. DN memory B cells may acquire CD27 following polyclonal stimulation with CpG ligand32 and may play an important role in maintaining the CD27 + memory population. It remains unclear when DN peripheral B cells begin to express CD27 after transiting to the CNS.…”

Section: Discussionmentioning

confidence: 99%

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Kowarik

Astling

Gasperi

et al. 2017

Ann Clin Transl Neurol

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ObjectivesNeuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system (CNS) targeted against aquaporin‐4 (AQP4). The origin and trafficking of AQP4‐specific B cells in NMOSD remains unknown.MethodsPeripheral (n = 7) and splenic B cells (n = 1) recovered from seven NMOSD patients were sorted into plasmablasts, naïve, memory, and CD27‐IgD‐ double negative (DN) B cells, and variable heavy chain (VH) transcriptome sequences were generated by deep sequencing. Peripheral blood (PB) VH repertoires were compared to the same patient's single‐cell cerebrospinal fluid (CSF) plasmablast (PB) VH transcriptome, CSF immunoglobulin (Ig) proteome, and serum Ig proteome. Recombinant antibodies were generated from paired CSF heavy‐ and light chains and tested for AQP4 reactivity.ResultsApproximately 9% of the CSF VH sequences aligned with PB memory B cells, DN B cells, and plasmablast VH sequences. AQP4‐specific VH sequences were observed in each peripheral B‐cell compartment. Lineage analysis of clonally related VH sequences indicates that CSF AQP4‐specific B cells are closely related to an expanded population of DN B cells that may undergo antigen‐specific B‐cell maturation within the CNS. CSF and serum Ig proteomes overlapped with the VH sequences from each B‐cell compartment; the majority of matches occurring between the PB VH sequences and serum Ig proteome.InterpretationDuring an acute NMOSD relapse, a dynamic exchange of B cells occurs between the periphery and CNS with AQP4‐specific CSF B cells emerging from postgerminal center memory B cells and plasmablasts. Expansion of the PB DN B‐cell compartment may be a potential biomarker of NMOSD activity.

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“…In other words, persistent humoral antibody titers would not reflect “memory” but rather a chronic immune reaction. In a modification of this concept, Lanzavecchia and colleagues later postulated that bystander activation of memory B lymphocytes could generate plasmablasts replenishing the ranks of dying plasma cells 11. In summary, the prevailing concepts say that plasma cells have a defined, short half‐life, and that in order to maintain persistent antibody titers, ie, “humoral memory”, their numbers would have to be replenished constantly, either by cognate or bystander activation of B lymphocytes, their precursors 12…”

Section: Memory Plasma Cellsmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

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Maintenance of Serological Memory by Polyclonal Activation of Human Memory B Cells

Cited by 1,170 publications

References 27 publications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

Immunological memories of the bone marrow

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