Altered B cell balance, but unaffected B cell capacity to limit monocyte activation in anti-neutrophil cytoplasmic antibody-associated vasculitis in remission

Lepse, Nikola; Abdulahad, Wayel H.; Rutgers, Abraham; Kallenberg, Cees G. M.; Stegeman, Coen A.; Heeringa, Peter

doi:10.1093/rheumatology/keu149

Cited by 50 publications

(50 citation statements)

References 34 publications

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“…In humans, B-lymphocyte clusters have been observed in rapidly progressive GN kidneys, similar to those described in lupus nephritis (170). Aberrations in circulating B cells have been described in patients with active disease in AAV with increased BCR signaling, altered proportions of CD51 B cells, and decreased Breg numbers or function (105)(106)(107)171). Not surprisingly, therefore, rituximab in combination with corticosteroids is an effective (and Food and Drug Administrationapproved) therapy for inducing remission in patients with AAV, but its efficacy in treating patients with advanced renal disease has not been established yet (172).…”

Section: Role In Gnmentioning

confidence: 73%

B Cells, Antibodies, and More

Hoffman¹,

Lakkis

Chalasani

2016

Clinical Journal of the American Society of Nephrology

352

265

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B cells play a central role in the immunopathogenesis of glomerulonephritides and transplant rejection. B cells secrete antibodies that contribute to tissue injury via multiple mechanisms. In addition, B cells contribute to disease pathogenesis in autoimmunity and alloimmunity by presenting antigens as well as providing costimulation and cytokines to T cells. B cells also play an immunomodulatory role in regulating the immune response by secreting cytokines that inhibit disease onset and/or progression. B cell-targeted approaches for treating immune diseases of the kidney and other organs have gained significant momentum. However, much remains to be understood about B-cell biology in order to determine the timing, duration, and context of optimal therapeutic response to B cell-targeted approaches. In this review, we discuss the multifaceted roles of B cells as enhancers and regulators of immunity with relevance to kidney disease and transplantation.

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Section: Role In Gnmentioning

confidence: 73%

B Cells, Antibodies, and More

Hoffman¹,

Lakkis

Chalasani

2016

Clinical Journal of the American Society of Nephrology

352

265

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“…Decreased CD5+ B cells, a B cell population enriched for regulatory cells, were found to be associated with the occurrence of relapses [33]. Additionally, two recent studies found numerical, but not functional, deficiencies in regulatory B cells [34,35]. These studies imply a role for the balance between regulatory and effector B cell functions which might have therapeutic implications.…”

Section: B Cellsmentioning

confidence: 99%

Pathogenesis of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis and Potential Targets for Biologic Treatment

et al. 2014

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Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are autoimmune diseases in which the small vessels are inflamed. Clinical observations suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data and animal models, particularly for myeloperoxidase-ANCA. An in vivo pathogenic role of ANCA directed to proteinase 3 has, however, not been fully substantiated. Additionally, the pathogenic role of B cells, T cells, and the alternative pathway of complement in AAV have been elucidated. Insight into these pathogenic pathways involved in AAV has opened and will further open new ways for targeted biologic treatment. In this review the pathogenesis of AAV and potential targets for biologic treatment are discussed.

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“…However, when excluding patients in remission with previous rituximab treatment, the differences to HC for the percentages of Breg cells were abolished (data not shown). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001. are also in line with some (Lepse et al 2014, Land et al 2015, but not all previous studies (Aybar et al 2015). In the latter study the authors did not observe any differences between patients and HC.…”

Section: Reduced Levels and Altered Phenotypes Of Breg Cells In The Csupporting

confidence: 90%

“…Both phenotypic as well as functional studies have been conducted, where the functional studies have primarily focused on measurements of IL-10 intracellularly after stimulation in vitro. However, one study measured the effect of total B cells on TNF produced by monocytes (Lepse et al 2014), whereas another study evaluated suppression on Th1 cell activation by CD24 high CD38 high B cells (Todd et al 2014). These two studies did not observe any differences between patients and HC.…”

Section: Several Studies Have Now Investigated the Frequencies And Fumentioning

confidence: 99%

“…In the latter study the authors did not observe any differences between patients and HC. CD24 high CD38 high B cells have also been investigated by others but the results have been inconclusive (Lepse et al 2014, Todd et al 2014, Aybar et al 2015, Land et al 2015, indicating that this population needs further evaluation. In addition to measurements of the frequencies of the proposed Breg cell populations, we also expanded the investigation of their phenotypes.…”

Section: Reduced Levels and Altered Phenotypes Of Breg Cells In The Cmentioning

confidence: 99%

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The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

Söderberg¹

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"Nog finns det mål och mening med vår färd -men det är vägen som är mödan värd" − Karin Boye SupervisorMårten Segelmark, Linköping University, Sweden Co-supervisorsPer Eriksson, Linköping University, Sweden Jan Ernerudh, Linköping University, Sweden Tino Kurz, Linköping University, Sweden Faculty opponentPeter Heeringa, University of Groningen, The Netherlands Abstract Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic.In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells)

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Altered B cell balance, but unaffected B cell capacity to limit monocyte activation in anti-neutrophil cytoplasmic antibody-associated vasculitis in remission

Abstract: Based on immunophenotypic classification, Bregs are numerically diminished in AAV patients. However, B cell function in terms of IL-10 production and their capacity to suppress monocyte activation is not compromised in AAV patients in remission.

Cited by 50 publications

References 34 publications

B Cells, Antibodies, and More

B Cells, Antibodies, and More

Pathogenesis of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis and Potential Targets for Biologic Treatment

The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis

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