Which B-cell subset should we target in lupus?

Ferraccioli, Gianfranco; Houssiau, Frédéric

doi:10.1136/annrheumdis-2013-203827

Cited by 8 publications

(6 citation statements)

References 22 publications

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“…Considering the very early accumulation of autoreactive LLPCs in the bone marrow and spleen of NZB/W mice, our data suggest that a ‘clinically relevant window of opportunity’ for preventing the accumulation of autoreactive LLPCs would exist only for the kidney. However, persistent activation and accumulation of autoreactive LLPCs in the bone marrow may cause relapses in patient with SLE even after long periods of clinical inactivity [ 6 , 27 ]. Therefore other therapies aimed at targeting LLPCs are needed.…”

Section: Discussionmentioning

confidence: 99%

“…Our results provide clear evidences that targeting LLPCs in isolation would have limited efficacy in autoimmune disease. This study enters into the recent debate concerning which B cell subset should be targeted in SLE [ 13 , 27 , 32 , 41 ], and strongly suggests that combining plasma cell ablation with an efficient, preferably selective, ablation of the precursors of autoreactive LLPCs could represent a new useful strategy in antibody-mediated autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

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Long-lived plasma cells are early and constantly generated in New Zealand Black/New Zealand White F1 mice and their therapeutic depletion requires a combined targeting of autoreactive plasma cells and their precursors

Taddeo¹,

Khodadadi²,

Voigt³

et al. 2015

Arthritis Res Ther

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IntroductionAutoantibodies contribute significantly to the pathogenesis of systemic lupus erythematosus (SLE). Unfortunately, the long-lived plasma cells (LLPCs) secreting such autoantibodies are refractory to conventional immunosuppressive treatments. Although generated long before the disease becomes clinically apparent, it remains rather unclear whether LLPC generation continues in the established disease. Here, we analyzed the generation of LLPCs, including autoreactive LLPCs, in SLE-prone New Zealand Black/New Zealand White F1 (NZB/W F1) mice over their lifetime, and their regeneration after depletion.MethodsBromodeoxyuridine pulse-chase experiments in mice of different ages were performed in order to analyze the generation of LLPCs during the development of SLE. LLPCs were enumerated by flow cytometry and autoreactive anti-double-stranded DNA (anti-dsDNA) plasma cells by enzyme-linked immunospot (ELISPOT). For analyzing the regeneration of LLPCs after depletion, mice were treated with bortezomib alone or in combination with cyclophosphamide and plasma cells were enumerated 12 hours, 3, 7, 11 and 15 days after the end of the bortezomib cycle.ResultsAutoreactive LLPCs are established in the spleen and bone marrow of SLE-prone mice very early in ontogeny, before week 4 and before the onset of symptoms. The generation of LLPCs then continues throughout life. LLPC counts in the spleen plateau by week 10, but continue to increase in the bone marrow and inflamed kidney. When LLPCs are depleted by the proteasome inhibitor bortezomib, their numbers regenerate within two weeks. Persistent depletion of LLPCs was achieved only by combining a cycle of bortezomib with maintenance therapy, for example cyclophosphamide, depleting the precursors of LLPCs or preventing their differentiation into LLPCs.ConclusionsIn SLE-prone NZB/W F1 mice, autoreactive LLPCs are generated throughout life. Their sustained therapeutic elimination requires both the depletion of LLPCs and the inhibition of their regeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-lived plasma cells are early and constantly generated in New Zealand Black/New Zealand White F1 mice and their therapeutic depletion requires a combined targeting of autoreactive plasma cells and their precursors

Taddeo¹,

Khodadadi²,

Voigt³

et al. 2015

Arthritis Res Ther

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show abstract

“…[10][11][12] The various subpopulations of B lymphocytes have been identified by their phenotypic cell-surface markers and the maturation of immature or naïve B cells in memory, transitional, plasmablast and postgerminal center B cells have been characterized. Some phenotypic alterations have been correlated with periods of SLE activity and the presence of various soluble factors such as tumor necrosis factor (TNF) and B-cell activation factor (BAFF).…”

Section: The B Lymphocyte In the Etiopathogenesis Of Systemic Lupus Ementioning

confidence: 99%

Modulating the survival and maturation system of B lymphocytes: Current and future new therapeutic strategies in systemic lupus erythematosus

Valor

López‐Longo

2015

Medicina Clínica (English Edition)

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“…We read with interest the editorial by Ferraccioli and Houssiau proposing the specific targeting of long-lived plasma cells (PCs) in human lupus nephritis (LN) 1. The authors present a cogent summary of experiments showing that long-lived PCs alone are sufficient to induce murine LN, and that targeting of PCs in these models is successful.…”

mentioning

confidence: 99%

Response to: ‘Which B-cell subset should we target in lupus?’ by Ferraccioli and Houssiau

et al. 2014

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Which B-cell subset should we target in lupus?

Cited by 8 publications

References 22 publications

Long-lived plasma cells are early and constantly generated in New Zealand Black/New Zealand White F1 mice and their therapeutic depletion requires a combined targeting of autoreactive plasma cells and their precursors

Long-lived plasma cells are early and constantly generated in New Zealand Black/New Zealand White F1 mice and their therapeutic depletion requires a combined targeting of autoreactive plasma cells and their precursors

Modulating the survival and maturation system of B lymphocytes: Current and future new therapeutic strategies in systemic lupus erythematosus

Response to: ‘Which B-cell subset should we target in lupus?’ by Ferraccioli and Houssiau

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