Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

Merino-Vico, Ana; van Hamburg, Jan Piet; Tuijnenburg, Paul; Frazzei, Giulia; Al-Soudi, Aram; Bonasia, Carlo G.; Helder, Boy; Rutgers, Abraham; Abdulahad, Wayel H.; Stegeman, Coen A.; Sanders, Jan-Stephan; Bergamaschi, Laura; Lyons, Paul A.; Bijma, Theo; van Keep, Laura; Wesenhagen, Kirsten; Jongejan, Aldo; Olsson, Henric; de Vries, Niek; Kuijpers, Taco W.; Heeringa, Peter; Tas, Sander W.

doi:10.1016/j.jaut.2023.103133

Cited by 3 publications

(1 citation statement)

References 67 publications

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“…Investigators found an upregulated nuclear factor kappa B (NF-κB)-associated gene signature in memory B cells from patients with active AAV. Additionally, small molecule inhibitors of NF-κB and the IκB kinase complex attenuate AAV B-cell responses and reduced PR3–immunoglobulin G (IgG) production by B cells from AAV patients in vitro , suggesting NF-κB signaling pathway may be a viable therapeutic target in AAV [9,10].…”

Section: Pathogenesismentioning

confidence: 99%

Update on antineutrophil cytoplasmic autoantibody vasculitis in children

Bloom,

2024

Current Opinion in Rheumatology

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Purpose of review Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is often organ- or life-threatening in children and impacts them during important periods of psychosocial and physical development. This review covers recent advances in the pathophysiology, diagnosis, management, and outcomes of AAV in children and highlights the ongoing need for funding and increased research collaboration. Recent findings Recent work has improved our understanding of AAV disease pathogenesis, potentially identifying new biomarkers and therapeutic targets. Collaborative clinical studies have also highlighted the variable manifestations in children and identified potential factors associated with poorer outcomes. Consensus-based treatment guidelines are also appearing, but clinical trials are still essential to better understanding treatment efficacy and safety in children affected by AAV. New, validated outcome measures, including those that are patient-reported, will facilitate these much-needed clinical trials in pediatric AAV. Summary There is a continued need for more rigorous study in pediatric AAV, however, there is certainly excitement with the increase in recent research relevant to the pediatric population.

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Section: Pathogenesismentioning

confidence: 99%

Update on antineutrophil cytoplasmic autoantibody vasculitis in children

Bloom,

2024

Current Opinion in Rheumatology

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NIK Is a Mediator of Inflammation and Intimal Hyperplasia in Endothelial Denudation-Induced Vascular Injury

Baeza,

Ribagorda,

Maya-Lopez

et al. 2024

IJMS

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Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. NFκB is a key mediator of inflammation that is activated during neointimal hyperplasia following endothelial injury. However, the molecular mechanisms involved in NFκB activation are poorly understood. NFκB may be activated through canonical (transient) and non-canonical (persistent) pathways. NFκB-inducing kinase (NIK, MAP3K14) is the upstream kinase of the non-canonical pathway. We have now explored the impact of NIK deficiency on neointimal hyperplasia following guidewire-induced endothelial cell injury and on local inflammation by comparing NIK activity–deficient alymphoplasia mice (NIKaly/aly) with control wild-type (NIK+/+) mice. Guidewire-induced endothelial cell injury caused neointimal hyperplasia and luminal stenosis and upregulated the local expression of NIK and the NFκB target chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2) and chemokine ligand 5 (RANTES/CCL5). Immunohistochemistry disclosed the infiltration of the media and intima by F4/80 positive macrophages. The intima/media ratio and percentage of stenosis were milder in the NIKaly/aly than in the NIK+/+ mice. Additionally, the gene expression for MCP-1 and RANTES was lower and F4/80+ cell infiltration was milder in the NIKaly/aly than in the NIK+/+ mice. Finally, circulating MCP-1 levels were lower in the NIKaly/aly than in the NIK+/+ mice, reflecting milder systemic inflammation. In conclusion, NIK is a driver of vascular wall inflammation and stenosis following guidewire-induced endothelial cell injury. NIK targeting may be a novel therapeutic approach to limit arterial stenosis following endothelial cell injury.

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Circulating Malondialdehyde Is a Potential Biomarker for Predicting All-Cause Mortality during Follow-Up by Reflecting Comprehensive Inflammation at Diagnosis in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Chung,

Yoon,

et al. 2024

Medicina

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Background and Objectives: To investigate whether circulating malondialdehyde (cMDA) at diagnosis could contribute to reflecting cross-sectional comprehensive inflammation or vasculitis activity and further predicting all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Materials and Methods: This study included 78 patients with AAV. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were collected as indices reflecting cross-sectional comprehensive inflammation, whereas the Birmingham vasculitis activity score (bVAS), and the five-factor score (FFS) were reviewed as AAV-specific indices. All-cause mortality was considered to be a poor outcome during follow-up. cMDA was measured from stored sera. Results: The median age of the 78 patients (32 men and 46 women) was 63.0 years. The median BVAS, FFS, ESR, and CRP were 5.0, 0, 24.5 mm/h, and 3.4 mg/L, respectively. Six patients died during the median follow-up duration based on all-cause mortality at 26.7 months. At diagnosis, cMDA was significantly correlated with cross-sectional ESR but not with BVAS or FFS. Compared to patients with cMDA < 221.7 ng/mL, those with cMDA ≥ 221.7 ng/mL at diagnosis exhibited an increased relative risk (RR 12.4) for all-cause mortality and further showed a decreased cumulative patient survival rate. Cox analyses revealed that cMDA ≥ 221.7 ng/mL (hazard ratio 24.076, p = 0.007) exhibited an independent association with all-cause mortality during follow-up in patients with AAV. Conclusions: cMDA at diagnosis may be a potential biomarker for predicting all-cause mortality during follow-up by reflecting comprehensive inflammation at diagnosis in patients with AAV.

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Targeting NF-κB signaling in B cells as a potential new treatment modality for ANCA-associated vasculitis

Cited by 3 publications

References 67 publications

Update on antineutrophil cytoplasmic autoantibody vasculitis in children

Update on antineutrophil cytoplasmic autoantibody vasculitis in children

NIK Is a Mediator of Inflammation and Intimal Hyperplasia in Endothelial Denudation-Induced Vascular Injury

Circulating Malondialdehyde Is a Potential Biomarker for Predicting All-Cause Mortality during Follow-Up by Reflecting Comprehensive Inflammation at Diagnosis in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

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