Plasma Cell Survival Is Mediated by Synergistic Effects of Cytokines and Adhesion-Dependent Signals

Cassese, Giuliana; Arce, Sergio; Hauser, Anja E.; Lehnert, Katja; Moewes, Beate; Mostarac, Miro; Muehlinghaus, Gwendolin; Szyska, Martin; Radbruch, Andreas; Manz, Rudolf A.

doi:10.4049/jimmunol.171.4.1684

Cited by 424 publications

(444 citation statements)

References 45 publications

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“…Since IL-6 has been shown in animal models to be important for plasma cell differentiation and survival (22,23), further analyses were performed to determine serum levels of IgG, IgA, and IgM at weeks 4, 12, and 24. Of note, levels of serum IgG and IgA decreased significantly at week 12 and week 24 as compared to baseline (Figure 3 week 24 (P ϭ 0.06), while the frequency of naive CD27ϪIgDϩ B cells did not change during the observation period.…”

Section: Resultsmentioning

confidence: 99%

“…Within this context, B cell-targeted therapies have been widely explored in RA (30). Since IL-6 has been described as an important B cell differentiation factor with effects on plasma cell differentiation and survival in the bone marrow (22), the aim of the current study was to investigate the influence of the anti-IL-6 monoclonal antibody tocilizumab on the homeostasis of the peripheral B cell compartment as well as its effects on blood immunoglobulin levels in patients with RA.…”

Section: Discussionmentioning

confidence: 99%

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In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Roll¹,

Muhammad²,

M³

et al. 2011

Arthritis & Rheumatism

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Objective. Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature.Methods. Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24.Results. Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P ‫؍‬ 0.04). In parallel, CD19؉IgA؉ and CD19؉IgG؉ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P ‫؍‬ 0.01). IgG؉ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P ‫؍‬ 0.007) and 2.8% at week 24 (P ‫؍‬ 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA؉ B cells with serum IgA at week 24.Conclusion. Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG؉ and IgA؉ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Roll¹,

Muhammad²,

M³

et al. 2011

Arthritis & Rheumatism

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“…It is assumed that the IgG ASC detected are of memory B cell origin [as they have CD27 + memory B cell surface expression (43), and mature plasma cells are unable to survive more than 2-3 d in cell culture (33,44)]; however, there may be different populations of somatically mutated memory B cells originating from the germinal center compartments or preplasma cells (plasmablasts) involved. Further research is required to delineate the subpopulation of B cells stimulated to proliferate in the ELISPOT assay.…”

Section: Menc-specific Memory B Cell Immune Responses Postboostermentioning

confidence: 99%

B Cell Memory to a Serogroup C Meningococcal Conjugate Vaccine in Childhood and Response to Booster: Little Association with Serum IgG Antibody

Perrett

Jin

Clutterbuck

et al. 2012

The Journal of Immunology

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The maintenance of adequate serum Ab levels following immunization has been identified as the most important mechanism for individual long-term protection against rapidly invading encapsulated bacteria. The mechanisms for maintaining adequate serum Ab levels and the relationship between Ag-specific memory B cells and Ab at steady state are poorly understood. We measured the frequency of circulating serogroup C meningococcal (MenC)-specific memory B cells in 250 healthy 6- to 12-y-old children 6 y following MenC conjugate vaccine priming, before a booster of a combined Haemophilus influenzae type b–MenC conjugate vaccine and then 1 wk, 1 mo, and 1 y after the booster. We investigated the relationship between circulating MenC-specific memory B cell frequencies and Ab at baseline and following the booster vaccine. We found very low frequencies of circulating MenC-specific memory B cells at steady state in primary school-aged children and little association with MenC IgG Ab levels. Following vaccination, there were robust memory B cell booster responses that, unlike Ab levels, were not dependent on age at priming with MenC. Measurement of B cell memory in peripheral blood does not predict steady state Ab levels nor the capacity to respond to a booster dose of MenC Ag.

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“…at a 3-wk interval with tetanus toxoid (TT) (1 Lf per mouse; gift from Sanofi Pasteur, Lyon, France) absorbed to Al(OH) 3 (gift from Novartis, Siena, Italy). C57BL/6J and Blimp-1-GFP/+ mice were primed with TT/Al(OH) 3 with added CpG 1826 oligonucleotides (50 mg; Operon Biotechnologies, Cologne, Germany) (23) and boosted with TT-Al(OH) 3 5 wk after priming.…”

Section: Ags Adjuvants and Immunizationsmentioning

confidence: 99%

“…MGKs were recently described as providing critical BMPC support based on a preferential colocalization with PC compared with granulocytes (13). Yet, only 30% (and as few as 10% in some mice) of BMPCs are close to MGKs, which produce only low levels of the PC survival factor a proliferationinducing ligand (APRIL) but are an abundant source of BM IL-6, which efficiently supports PC survival in vitro (3,16,17). Doubts casted, however, over their critical in vivo role when BMPCs were found to be normal in IL-6 2/2 mice (3).…”

mentioning

confidence: 99%

Homing and Adhesion Patterns Determine the Cellular Composition of the Bone Marrow Plasma Cell Niche

Belnoue

Tougne²,

Rochat³

et al. 2012

The Journal of Immunology

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According to commonly held concepts, plasma cell (PC) longevity in bone marrow (BM) depends upon their access to survival niches. These are thought to exist in nursery cell types, which support PCs by secreting PC survival factors. To better define PC survival niches and their functioning, we adoptively transferred traceable Blimp-1-GFP PCs into recipient mice lacking a proliferation-inducing ligand (APRIL), IL-6, or macrophage migration inhibitory factor. Transferred BMPCs were preferentially associated with Ly-6Chigh monocytes (normalized colocalization index: 9.84), eosinophils (4.29), and megakaryocytes (2.12). Although APRIL was essential for BMPC survival, PC recruitment into the proximity of nursery cells was unimpaired in APRIL-deficient mice, questioning the concept that the same factors account for attraction/retention of PCs as for their local survival. Rather, the order of colocalization with BMPCs (monocytes > eosinophils > megakaryocytes) reflected these cells’ relative expression of CXCR4, VLA-4, and LFA-1, the homing and adhesion molecules that direct/retain PCs in the BM. This suggests a scenario wherein the cellular composition of the BMPC niche is defined by a common pattern of attraction/retention on CXCL12-abundant reticular docking cells. Thereby, PCs are directed to associate in a functional BM niche with hematopoietic CXCR4+VLA-4+LFA-1+ nursery cells, which provide PC survival factors.

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Plasma Cell Survival Is Mediated by Synergistic Effects of Cytokines and Adhesion-Dependent Signals

Cited by 424 publications

References 45 publications

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

B Cell Memory to a Serogroup C Meningococcal Conjugate Vaccine in Childhood and Response to Booster: Little Association with Serum IgG Antibody

Homing and Adhesion Patterns Determine the Cellular Composition of the Bone Marrow Plasma Cell Niche

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