Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

Wada, Taizo; Kanegane, Hirokazu; Ohta, Kazuhide; Katoh, Fumiyo; Imamura, Toshihiko; Nakazawa, Yozo; Miyashita, Ritsuko; Hara, Junichi; Hamamoto, Kazuko; Yang, Xi; Filipovich, Alexandra H.; Marsh, Rebecca; Yachie, Akihiro

doi:10.1016/j.cyto.2013.09.007

Cited by 126 publications

(94 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The presence of similar activating mutations in these NLRs, the strong species conservation of the NBD domain, and the role of the NBD in mediating autoinhibition 6 support constitutive NLR oligomerization as an important mechanism in these three diseases. Unlike in CAPS/NOMID patients, the NLRC4 mutation in our patient causes very high circulating and stimulated levels of IL-18, similar to levels seen in other MAS-prone conditions 26–28,37 . The factors and molecular mechanisms that differentially regulate NLRC4 versus NLRP3 inflammasome activation are largely unknown and require further study.…”

supporting

confidence: 79%

“…3a). Comparably high levels of serum IL-18 have also been associated with MAS in systemic JIA 25 , AOSD 26 , infection 27 , and XIAP deficiency 28 . Other serum markers that clustered distinctly in NLRC4-MAS included macrophage stimulating cytokines (M-CSF, IL-12p40 29 ), apoptotic factors (TRAIL, LTα), chemokines (CCL7, CXCL12, IL-16), and hematopoietic growth factors (SCF, IL-3) (Fig.3a and Supplementary Fig.…”

mentioning

confidence: 99%

See 1 more Smart Citation

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

et al. 2014

View full text Add to dashboard Cite

Inflammasomes are innate immune sensors that respond to pathogen and damage-associated signals with caspase-1 activation, IL-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the Cryopyrin Associated Periodic Syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion, led to successful treatment with IL-1 blocking agents1. Herein, we report a de novo missense mutation, c.1009A>T, p.Thr337Ser, in the nucleotide-binding domain of inflammasome component NLRC4 (IPAF/CARD12) that causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, the latter exceeding levels in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in transduced cells and increased production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests novel targets for therapy.

show abstract

supporting

confidence: 79%

mentioning

confidence: 99%

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

et al. 2014

View full text Add to dashboard Cite

show abstract

“…More recently, Shimizu et al described the presence of two different cytokine profiles in SJIA with an IL-6 signature in patients with arthritis-related disease manifestations and an IL-18 predominate cytokine profile in patients with MAS (32). In contrast, Wada et al recently demonstrated IL-6, IL-18, tumor necrosis factor (TNF)α, and interferon (IFN)γ elevations in patients with active FHL, Epstein-Barr Virus (EBV)-HLH, and IDAHS (33). In a patient with SLE-related MAS, Shimizu et al demonstrated a more striking TNFα cytokine signature compared to the cytokine profiles from patients with other forms of hyperinflammatory disease (31, 32).…”

Section: Pathogenesismentioning

confidence: 96%

Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis

Weaver

Behrens

2014

Current Opinion in Rheumatology

View full text Add to dashboard Cite

Purpose of Review Macrophage activation syndrome is the rheumatic disease-associated member of a group of hyperinflammatory syndromes characterized by uncontrolled cytokine storm. In this review, we highlight recent publications related to the pathoetiology of hyperinflammatory syndromes with an emphasis on how this new knowledge will guide our diagnosis, treatment, and future research efforts to better understand these deadly conditions. Recent findings The heterogeneity of clinical manifestations seen in patients with hyperinflammatory syndromes continues to grow as novel genetic and immunotherapeutic triggers of cytokine storm have been identified. Recent studies characterize unique cytokine and gene expression profiles from patients with different hyperinflammatory syndromes, while novel murine models begin to define networks of immune dysregulation thought to drive excessive inflammationin cytokine storm. Summary Emerging evidence suggests hypercytokinemia is the driving cause of pathology and morbidity/mortality in hyperinflammatory syndromes. Therefore, approaches to block cytokine function may be fruitful in treating hyperinflammatory syndromes with less toxicity than current therapies. However, not all hyperinflammatory syndromes result in the same pathogenic cytokine profile implying a personalized approach will be required for effective use of anti-cytokine therapies in the treatment of hyperinflammatory syndromes.

show abstract

“…Thus, impaired killing of activated macrophages may be a common factor driving macrophage activation in both paradigms. The serum levels of IL-18 associated with XIAP deficiency and NLRC4-MAS are usually in the nanogram-per-milliliter range (the normal range is generally less than 200 pg/mL) and rise during flares (67, 155). Extraordinarily high IL-18 elevation is also seen in some patients with systemic juvenile idiopathic arthritis (sJIA) (156) and Still disease (157) who have had MAS.…”

Section: Autoinflammatory Diseases Caused By Persistent Macrophagementioning

confidence: 99%

Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling

Jesús

Canna

Liu

et al. 2015

Annu. Rev. Immunol.

246

197

View full text Add to dashboard Cite

Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.

show abstract

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

Cited by 126 publications

References 34 publications

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome

Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis

Molecular Mechanisms in Genetically Defined Autoinflammatory Diseases: Disorders of Amplified Danger Signaling

Contact Info

Product

Resources

About