Management of Monogenic IL-1 Mediated Autoinflammatory Diseases in Childhood

Welzel, Tatjana; Benseler, Susanne M.; Kuemmerle‐Deschner, Jasmin

doi:10.3389/fimmu.2021.516427

Cited by 10 publications

(5 citation statements)

References 120 publications

(126 reference statements)

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“…hematopoietic stem cell transplant (HSCT) has been proved as effective treatment for patients with PAMI syndrome (24). According to previous reports, IL-1 inhibition did not resolve neutropenia in PAMI syndrome (1,25), whereas it was effectively used for pyrin inflammasome-associated inflammation control in other autoinflammatory disorders (27,28). Targeting IL-1 combination with IL-18 inhibition might be helpful for disorders with overproduction of both IL-1b and IL-18.…”

Section: Discussionmentioning

confidence: 99%

Strong inflammatory signatures in the neutrophils of PAMI syndrome

Zheng

Fan²,

Yang³

et al. 2022

Front. Immunol.

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PSTPIP1 (proline-serine-threonine phosphatase-interactive protein 1)–associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare autoinflammatory disease caused by heterozygous gain-of-function mutation in PSTPIP1. As one of the PSTPIP1-associated inflammatory diseases (PAIDs), neutropenia is a distinct manifestation to separate PAMI syndrome from other PAIDs. This study aimed to investigate the potential role of neutrophils and inflammatory signatures in the pathogenesis of PAMI. PAMI neutrophils displayed markedly increased production of interleukin-1β (IL-1β) and IL-18 by enzyme linked immunosorbent assay (ELISA) assay and intracellular cytokine staining. ASC speck formation and lactic dehydrogenase (LDH) release are also increased in patient neutrophils suggesting elevated pyrin inflammasome activation followed by upregulated cell death in PAMI neutrophils. RNA sequencing result showed strong inflammatory signals in both nuclear-factor kappa B (NF-κB) pathway and interferon (IFN) pathway in patient neutrophils. This study highlighted that elevated proinflammatory cytokines IL-1β and IL-18, increased pyrin inflammasome activation, and upregulation of NF-κB and IFN signaling pathways in neutrophils play important roles in pathogenicity of PAMI syndrome.

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Section: Discussionmentioning

confidence: 99%

Strong inflammatory signatures in the neutrophils of PAMI syndrome

Zheng

Fan²,

Yang³

et al. 2022

Front. Immunol.

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“…A "pure" placebo is typically represented by empty capsules (Welzel et al, 2021;Tsaturyan et al, 2023;Franc et al, 2022;Moerbeek, 2023) or inert substances like starch, dextromaltose, lactose, talc, mentholated water, and saline (Mitsikostas et al, 2020). The diversity of placebo effects is attributed to various biological mechanisms, influenced by the evolutionary development of the body's unique defense mechanisms (Benedetti, 2014;Buergler et al, 2023;Seneviratne et al, 2022;Pronovost-Morgan et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…While it is hypothesized that diets rich in antioxidants and supplements with anti-inflammatory properties may partially alleviate FMF symptoms and enhance the well-being of patients, research findings in this realm are contentious (Mansueto et al, 2022;Damiań et al, 2022;Mazzantini et al, 2021). The number of clinical trials on FMF is notably high, given the monogenic nature of the disease (Welzel et al, 2021;Tsaturyan et al, 2023;Pepoyan et al, 2018a;Ataya et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Placebo-resistant gut bacteria: Akkermansia muciniphila spp. and Familial Mediterranean fever disease

Pepoyan,

Marotta,

Manvelyan

et al. 2024

Front. Cell. Infect. Microbiol.

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IntroductionDespite numerous investigations into the impact of drugs/probiotics on the gut microbiota composition in Familial Mediterranean Fever (FMF) patients, the question as to whether there exists a significant bacterial diversity(ies) independent of the placebo effect that can be reliably considered in clinical and nutritional trials remains unresolved.MethodsThis study represents the in augural analysis of the placebo’s influence on the gut microbiota of both healthy individuals and FMF afflicted men, utilizing previously collected data from PhyloChip™ DNA microarray experiments. A total of 15 healthy and 15 FMF male volunteers, aged 18 to 50, participated in this partially randomized placebo trial, which is accessible through the GEO Series accession number GSE111835.Results and DiscussionKey findings from current investigations include i. the anticipated divergence in gut bacteria resistance to placebo between healthy and FMF individuals, ii. the minor impact of placebo on gut bacterial diversities in healthy individuals, with Enterobacteriaceae diversities identified as placebo-resistant among “healthy” gut bacteria, and iii. the comprehensive influence of placebo on all bacterial phyla in the gut microbiome of FMF patients, extending to nearly all bacterial genera, except for the resilience of gut Akkermansia muciniphila spp. to placebo in FMF patients. This study underscores the susceptibility of Faecalibacterium, Blautia, and Clostridium genera to placebo. Consequently, this investigation holds significance for the proper design of placebo-controlled trials and establishes a foundation for further exploration of the gut-brain axis. Furthermore, it contributes valuable insights to discussions regarding proposals for probiotic therapies, particularly focusing on Faecalibacterium spp., Blautia spp., and Clostridium spp.

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“…Direct blockade of IL-1 or its signaling pathway has become an important therapeutic strategy for these diseases, and anti–IL-1 drugs are widely used as lifelong treatments ( 12 ). Anakinra, the recombinant nonglycosylated form of IL-1RA, competes with IL-1α and IL-1β for binding to IL-1R1.…”

Section: Introductionmentioning

confidence: 99%

Constitutive IL-1RA production by modified immune cells protects against IL-1–mediated inflammatory disorders

et al. 2023

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Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients’ quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)–mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs. Transplantation of mouse and human HSPCs transduced with an IL-1RA–encoding LV ensured stable IL-1RA production while maintaining the clonogenic and differentiation capacities of HSPCs in vivo. We examined the efficacy of cell-mediated IL-1RA delivery in three models of IL-1–dependent inflammation, for which treatment hindered neutrophil recruitment in an inducible model of gout, prevented systemic and multi-tissue inflammation in a genetic model of cryopyrin-associated periodic syndromes, and reduced disease severity in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Our findings demonstrate HSPC-mediated IL-1RA delivery as a potential therapeutic modality that can be exploited to suppress tissue and organ inflammation in diverse immune-related diseases involving IL-1–driven inflammation.

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Management of Monogenic IL-1 Mediated Autoinflammatory Diseases in Childhood

Cited by 10 publications

References 120 publications

Strong inflammatory signatures in the neutrophils of PAMI syndrome

Strong inflammatory signatures in the neutrophils of PAMI syndrome

Placebo-resistant gut bacteria: Akkermansia muciniphila spp. and Familial Mediterranean fever disease

Constitutive IL-1RA production by modified immune cells protects against IL-1–mediated inflammatory disorders

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