Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

Berkowska, Magdalena A.; Driessen, Gertjan J.; Bikos, Vasilis; Großerichter-Wagener, Christina; Stamatopoulos, Kostas; Cerutti, Andrea; He, Bing; Biermann, Katharina; Lange, Johan F.; Burg, Mirjam van der; Dongen, Jacques J. M. van; Zelm, Menno C. van

doi:10.1182/blood-2011-04-345579

Cited by 326 publications

(459 citation statements)

References 54 publications

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“…DN B cells are elevated in the elderly and in inflammatory diseases including established RA, SLE, and Alzheimer's disease, suggesting their contribution to pathology in disease and in immune changes associated with aging (8,11,109,110). There are several hypotheses on the origin of DN B cells including that they are exhausted memory B cells that have downregulated CD27 (109), memory B cell precursors that have not acquired CD27 yet (111), or an entirely new B cell population that has undergone low levels of somatic hypermutation (111,112). DN B cells show an activated phenotype where levels of these cells are associated with higher levels of circulating autoantibodies in SLE (8,106) and have a proinflammatory phenotype in Alzheimer's disease (110).…”

Section: Discussionmentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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“…Sequences were analyzed with IgBLAST (http://www.ncbi.nlm.nih.gov/ igblast/) and JOINSOLVER (http://joinsolver.niaid.nih.gov) programs, as described previously. 11,16,17 Statistics Median values were compared by Mann-Whitney or Wilcoxon matchedpairs signed rank test where appropriate, using Prism Version 6 (GraphPad). Three-way analyses were compared simultaneously by either KruskalWallis or Friedman test and, if significant, prompted appropriate pairwise comparisons.…”

Section: Ig Gene Sequence Analysismentioning

confidence: 99%

“…9 More recently, IgG ϩ /CD27 Ϫ B cells were identified and characterized by more direct methods that revealed a level of SHM that was higher than in IgG Ϫ /CD27 Ϫ but lower than in IgG ϩ /CD27 ϩ B cells. 10,11 In the present study, we investigated memory B cells in the blood of CGD patients and evaluated their functional capabilities.…”

Section: Introductionmentioning

confidence: 99%

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

Moir¹,

Ravin²,

Santich³

et al. 2012

Blood

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“…In humans, CD27 expression correlates with the presence of somatic hypermutations in the variable (V) region of the Ig genes (19). However, memory B cells also include CD27 2 class-switched cells (20,21), as well as CD27 + IgM-expressing B cells (22). Whether high proportions of Ag-experienced memory B cells early in life reduce the risk for development of allergic disease and/or sensitization later in childhood has not been examined.…”

mentioning

confidence: 99%

High Proportion of CD5+ B Cells in Infants Predicts Development of Allergic Disease

Lundell

Johansen

Adlerberth

et al. 2014

The Journal of Immunology

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Delayed maturation of the immune system has been proposed to be a risk factor for development of allergy, but B cell maturation in relation to allergic disease has not been examined. B cells lose CD5 and acquire CD27 during maturation from immature via mature/naive to Ig-secreting cells and memory cells. We sought to investigate B cell maturation in relation to development of allergic disease and sensitization in the FARMFLORA birth cohort including 65 Swedish children. Total B cell numbers, proportions of CD5+ and CD27+ B cells, and levels of IgM, IgG, IgA, and IgE were measured in blood on repeated occasions from birth to 36 mo of age, and related to allergic disease and sensitization at 18 and 36 mo of age with multivariate discriminant analysis. We also compared the expression of CD24 and CD38 within CD5+ and CD5neg B cells in children and in adults. We found that infants with a high proportion of CD5+ B cells at birth and at 1 mo of age had an increased risk for having allergic disease at 18 and 36 mo of life. Further, the proportions of CD5+ B cells at 1 mo of age were inversely correlated with total IgG levels at 18 and 36 mo of age. The majority of the CD5+ B cells were of a CD24hi/+CD38hi/+ immature/naive phenotype at birth (97%), 7 y of age (95%), and in adults (86%). These results suggest that development of allergic disease is preceded by an immaturity in neonatal B cell phenotype.

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Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

Cited by 326 publications

References 54 publications

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

High Proportion of CD5+ B Cells in Infants Predicts Development of Allergic Disease

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