Identification of a High‐Frequency Somatic <i>NLRC4</i> Mutation as a Cause of Autoinflammation by Pluripotent Cell–Based Phenotype Dissection

Kawasaki, Yoshihisa; Oda, Hirotsugu; Ito, Jun; Niwa, Akira; Tanaka, Takayuki; Hijikata, Atsushi; Seki, Ryosuke; Nagahashi, Ayako; Osawa, Mitsujiro; Asaka, Isao; Watanabe, Akira; Nishimata, Shigeo; Shirai, Tomoyuki; Kawashima, Hisashi; Ohara, Osamu; Nakahata, Tatsutoshi; Nishikomori, Ryuta; Heike, Toshio; Saito, Megumu K.

doi:10.1002/art.39960

Cited by 113 publications

(94 citation statements)

References 41 publications

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“…One, discussed above, presented with prenatal AIFEC (31), the other presented with cardinal NOMID features (fever, rash, inflammatory bone lesions, sensory neural hearing loss and structural brain defects) but he was NLPR3 -mutation negative and he displayed chronically elevated serum IL-18 (37). Functional analysis of patient pluripotent stem cell-derived monocytes revealed two distinct populations, one with aberrant and the other with normal IL-1β secretion.…”

Section: Extended Nlrc4 Phenotypesmentioning

confidence: 99%

“…Other non-AIFEC patients were treated with recombinant IL-1RA (anakinra) and although skin manifestations were completely responsive, other disease features were not. Anakinra was also highly effective in treating NOMID-like symptoms due to NLRC4 mutation (37). Used prophylactically, anakinra reduced the severity and frequency of MAS episodes more effectively than low-dose steroids and colchicine in one AIFEC patient with mild gastrointestinal disease (2), but was not efficacious treating another AIFEC patient in flare (30).…”

Section: Treatment Of Nlrc4 Inflammasomopathiesmentioning

confidence: 99%

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NLRC4 inflammasomopathies

Romberg¹,

Vogel

Canna

2017

Current Opinion in Allergy &Amp; Clinical Immunology

114

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Purpose of review The purpose of the review is to highlight developments in autoinflammatory diseases associated with gain-of-function mutations in the gene encoding NLR-family CARD domain-containing protein 4 (NLRC4), the NLRC4-inflammasomopathies. Recent findings Three years since the identification of the first autoinflammation with infantile enterocolitis (AIFEC) patients, there is an improved understanding of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and also intestinal epithelial cells. This information has opened new therapeutic avenues to treat AIFEC patients with targeted agents like recombinant IL-18 binding protein and anti-interferon-γ antibodies. Additional phenotypes traditionally associated with NLRP3 mutations like familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), have now also been associated with gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has now been identified in a NOMID and an AIFEC patient, a finding emphasizing nontraditional modes of inheritance in autoinflammatory diseases. Summary The NLRC4 inflammasomopathies comprise a growing autoinflammatory disease category that spans a broad clinical spectrum from cold urticaria to NOMID and the often-fatal disease AIFEC. Rapid case identification with biomarkers like elevated serum IL-18 concentrations and early intervention with targeted immunomodulatory therapies are key strategies to improving outcomes for AIFEC patients.

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Section: Extended Nlrc4 Phenotypesmentioning

confidence: 99%

Section: Treatment Of Nlrc4 Inflammasomopathiesmentioning

confidence: 99%

NLRC4 inflammasomopathies

Romberg¹,

Vogel

Canna

2017

Current Opinion in Allergy &Amp; Clinical Immunology

114

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“…This method of reprogramming somatic cells to pluripotency [142] allows for indefinite propagation as well as differentiation to a variety of human cell types that would previously have been unobtainable [143–145]. Saito et al utilised this method in the investigation of autoinflammatory disorders involving NLRP3 [146] and NLRC4 [147]. Two individuals with somatic mutations in NLRP3 had both wild-type (WT) and mutant NLRP3 iPSC lines generated [146].…”

Section: Modelling Monogenic Autoinflammatory Disordersmentioning

confidence: 99%

“…The WT iPSC lines served as a comparator, with the authors able to determine that only macrophages differentiated from mutant NLRP3 iPSC lines showed abnormal IL-1β secretion. A subsequent publication generated iPSC lines from an individual suspected of CAPS but without pathogenic mutations in NLRP3 [147] . Heterogeneous responses to LPS stimulation in the iPSC clones prompted WES, with clones having a robust response to LPS possessing a mutation in NLRC4 .…”

Section: Modelling Monogenic Autoinflammatory Disordersmentioning

confidence: 99%

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Moghaddas

Masters

2018

Clinical Science

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Monogenic autoinflammatory disorders are an increasingly heterogeneous group of conditions characterised by innate immune dysregulation. Improved genetic sequencing in recent years has led not only to the discovery of a plethora of conditions considered to be ‘autoinflammatory’, but also the broadening of the clinical and immunological phenotypic spectra seen in these disorders. This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models. Furthermore, the use of the term ‘autoinflammatory’ is discussed in relation to disorders that cross the innate and adaptive immune divide. The utilisation of next-generation sequencing (NGS) in this population is examined, as are potential in vivo and in vitro methods of modelling to determine pathogenicity of novel genetic findings. Finally, areas where our understanding can be improved are highlighted, such as phenotypic variability and genotype–phenotype correlations, with the aim of identifying areas of future research.

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“…Differential responses to lithium were detected in neurons from patients with bipolar disorder and they matched well with clinical outcomes [58]. Clonal analysis and directed differentiation of iPS cells from neonatal-onset multisystem inflammatory disease (NOMID) patients elucidated heterogeneity of monocytes from a single patient [59]. Subsequent identification of unexpected somatic mosaicism of NLRC4 mutation demonstrated the significance of prospective genetic screening, combined with iPS cell-based phenotypic dissection for individualized diagnoses.…”

Section: Use Of Induced Pluripotent Stem (Ips) Cells To Understandmentioning

confidence: 99%

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

Hashimoto

Czysz

2016

Cells

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Despite continuous efforts to improve the process of drug discovery and development, achieving success at the clinical stage remains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS) cells has brought new hope to the drug discovery field because they enable scientists to humanize a variety of pharmacological and toxicological models in vitro. The availability of human iPS cell-derived cells, particularly as an alternative for difficult-to-access tissues and organs, is increasing steadily; however, their use in the field of translational medicine remains challenging. Biomarkers are an essential part of the translational effort to shift new discoveries from bench to bedside as they provide a measurable indicator with which to evaluate pharmacological and toxicological effects in both the preclinical and clinical settings. In general, during the preclinical stage of the drug development process, in vitro models that are established to recapitulate human diseases are validated by using a set of biomarkers; however, their translatability to a clinical setting remains problematic. This review provides an overview of current strategies for human iPS cell-based drug discovery from the perspective of translational research, and discusses the importance of early consideration of clinically relevant biomarkers.

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Identification of a High‐Frequency Somatic NLRC4 Mutation as a Cause of Autoinflammation by Pluripotent Cell–Based Phenotype Dissection

Cited by 113 publications

References 41 publications

NLRC4 inflammasomopathies

NLRC4 inflammasomopathies

The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

Translational Prospects and Challenges in Human Induced Pluripotent Stem Cell Research in Drug Discovery

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