Proinflammatory cytokines and response to molds in mononuclear cells of patients with Meniere disease

Frejo, Lidia; Gallego‐Martinez, Alvaro; Requena, Teresa; Martín-Sanz, Eduardo; Amor-Dorado, Juan Carlos; Soto-Varela, Andrés; Santos-Pérez, Sofía; Espinosa-Sánchez, Juan Manuel; Batuecas‐Caletrío, Ángel; Arán, Ismael; Fraile, J.; Rossi-Izquierdo, Marcos; Lopez-Escamez, José A.

doi:10.1038/s41598-018-23911-4

Cited by 65 publications

(62 citation statements)

References 36 publications

(30 reference statements)

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“…Frejo et al used disease laterality (uni vs. bilateral) as a principal group classifier, and, in a second step, applied data mining procedures (cluster analysis) to identify clinical features (autoimmune disorders, migraine, MD family history, synchronic vs. metachronic onset of hearing loss) that segregated five discrete subgroups of uni and bilateral MD patients, respectively (40, 41). In a follow-up study, Frejo et al then used an etiology-based approach and distinguished two subgroups with different cytokine profiles among uni and bilateral MD patients (42). They suggested an immune-mediated etiology in the subgroup that exhibited elevated interleucin-1β plasma levels as well as mold-induced TNF-α secretion.…”

Section: Discussionmentioning

confidence: 99%

Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct

et al. 2019

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Two histopathological subtypes of Meniere's disease (MD) were recently described in a human post-mortem pathology study. The first subtype demonstrated a degenerating distal endolymphatic sac (ES) in the affected inner ear (subtype MD-dg); the second subtype (MD-hp) demonstrated an ES that was developmentally hypoplastic. The two subtypes were associated with different clinical disease features (phenotypes), suggesting that distinct endotype-phenotype patterns exist among MD patients. Therefore, clinical endotyping based on ES pathology may reveal clinically meaningful MD patient subgroups. Here, we retrospectively determined the ES pathologies of clinical MD patients (n = 72) who underwent intravenous delayed gadolinium-enhanced inner ear magnetic resonance imaging using previously established indirect radiographic markers for both ES pathologies. Phenotypic subgroup differences were evidenced; for example, the MD-dg group presented a higher average of vertigo attacks (ratio of vertigo patterns daily/weekly/other vs. monthly, MD-dg: 6.87: 1; MD-hp: 1.43: 1; p = 0.048) and more severely reduced vestibular function upon caloric testing (average caloric asymmetry ratio, MD-dg: 30.2% ± 30.4%; MD-hp: 13.5% ± 15.2%; p = 0.009), while the MD-hp group presented a predominantly male sex ratio (MD-hp: 0.06:1 [f/m]; MD-dg: 1.2:1 [f/m]; p = 0.0004), higher frequencies of bilateral clinical affection (MD-hp: 29.4%; MD-dg: 5.5%; p = 0.015), a positive family history for hearing loss/vertigo/MD (MD-hp: 41.2%; MD-dg: 15.7%; p = 0.028), and radiographic signs of concomitant temporal bone abnormalities, i.e., semicircular canal dehiscence (MD-hp: 29.4%; MD-dg: 3.6%; p = 0.007). In conclusion, this new endotyping approach may potentially improve the diagnosis, prognosis and clinical decision-making for individual MD patients.

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Section: Discussionmentioning

confidence: 99%

Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct

et al. 2019

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“…Since these patients did not show any comorbid autoimmune condition, they could be considered within the spectrum of auto-inflammatory disorders. Moreover, extracts from Aspergillus and Penicillium molds triggered a release of TNFα in these patients with high basal levels, which was not observed in the control experiments, suggesting that these molds may contribute to the exacerbation of innate-mediated inflammation in MD 54 .…”

Section: Evidence For An Auto-inflammatory Variant Of Ménière’s Diseamentioning

confidence: 58%

“…Several mechanisms have been demonstrated in auto-inflammatory diseases, including (a) IL-1β-mediated auto-inflammation which may involve the NLRP3 inflammasome and its responses to IL-1β blockade 51 , (b) IL-18-mediated auto-inflammation with mutations in the NLRC4 gene and macrophage activation syndrome 52 , and (c) A20 haploinsufficiency with mutations in the TNFAIP3 gene associated with an increase of pro-inflammatory cytokines such as IL-1β, TNFα, IL-6, IL-18, and IL-17 and NF-κB-mediated inflammation 53 . Although the evidence to support an auto-inflammatory process is still limited in MD, a case control study has shown that pro-inflammatory cytokines such as IL-1β, IL-1RA, TNFα, and IL-6 were elevated in 21% of MD patients in the supernatant from patient-derived peripheral blood mononuclear cells 54 . Since these patients did not show any comorbid autoimmune condition, they could be considered within the spectrum of auto-inflammatory disorders.…”

Section: Evidence For An Auto-inflammatory Variant Of Ménière’s Diseamentioning

confidence: 99%

Towards personalized medicine in Ménière’s disease

2018

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Ménière’s disease (MD) represents a heterogeneous group of relatively rare disorders with three core symptoms: episodic vertigo, tinnitus, and sensorineural hearing loss involving 125 to 2,000 Hz frequencies. The majority of cases are considered sporadic, although familial aggregation has been recognized in European and Korean populations, and the search for familial MD genes has been elusive until the last few years. Detailed phenotyping and cluster analyses have found several clinical predictors for different subgroups of patients, which may indicate different mechanisms, including genetic and immune factors. The genes associated with familial MD are COCH, FAM136A, DTNA, PRKCB, SEMA3D, and DPT. At least two mechanisms have been involved in MD: (a) a pro-inflammatory immune response mediated by interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNFα), and IL-6, and (b) a nuclear factor-kappa B (NF-κB)-mediated inflammation in the carriers of the single-nucleotide variant rs4947296. It is conceivable that microbial antigens trigger inflammation with release of pro-inflammatory cytokines at different sites within the cochlea, such as the endolymphatic sac, the stria vascularis, or the spiral ligament, leading to fluid imbalance with an accumulation of endolymph. Computational integration of clinical and “omics” data eventually should transform the management of MD from “one pill fits all” to precise patient stratification and a personalized approach. This article lays out a proposal for an algorithm for the genetic diagnosis of MD. This approach will facilitate the identification of new molecular targets for individualized treatment, including immunosuppressant and gene therapy, in the near future.

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“…There have been growing evidences on the role of autoimmunity and immunological mechanisms in the development of MD as follows: (1) The increased prevalence of autoimmune disease among MD patients, (2) The elevated levels of autoantibodies and immunocomplexes in MD patients, (3) The association of MD with HLA-types and genetic polymorphisms, and (4) The positive response to steroid (52)(53)(54). Recent studies have found that basal levels of proinflammatory cytokines were increased in some patients with MD (55,56). Gene expression study using mRNA also demonstrated that immune-related genes such as GSTM1, TMEM176A, and TMEM176B were highly expressed in MD patients compared to normal controls (57).…”

Section: Discussionmentioning

confidence: 99%

Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

Shin

Kim

et al. 2020

Front. Neurol.

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Objectives: The cause of Meniere's disease (MD) is unclear but likely involves genetic and environmental factors. The aim of this study was to investigate the genetic basis underlying MD by screening putative candidate genes for MD. Methods: Sixty-eight patients who met the diagnostic criteria for MD of the Barany Society were included. We performed targeted gene sequencing using next generation sequencing (NGS) panel composed of 45 MD-associated genes. We identified the rare variants causing non-synonymous amino acid changes, stop codons, and insertions/deletions in the coding regions, and excluded the common variants with minor allele frequency >0.01 in public databases. The pathogenicity of the identified variants was analyzed by various predictive tools and protein structural modeling. Results: The average read depth for the targeted regions was 1446.3-fold, and 99.4% of the targeted regions were covered by 20 or more reads, achieving the high quality of the sequencing. After variant filtering, annotation, and interpretation, we identified a total of 15 rare heterozygous variants in 12 (17.6%) sporadic patients. Among them, four variants were detected in familial MD genes (DTNA, FAM136A, DPT), and the remaining 11 in MD-associated genes (PTPN22, NFKB1, CXCL10, TLR2, MTHFR, SLC44A2, NOS3, NOTCH2). Three patients had the variants in two or more genes. All variants were not detected in our healthy controls (n = 100). No significant differences were observed between patients with and without a genetic variant in terms of sex, mean age of onset, bilaterality, the type of MD, and hearing threshold at diagnosis. Conclusions: Our study identified rare variants of putative candidate genes in some of MD patients. The genes were related to the formation of inner ear structures, the immune-associated process, or systemic hemostasis derangement, suggesting the multiple genetic predispositions in the development of MD.

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Proinflammatory cytokines and response to molds in mononuclear cells of patients with Meniere disease

Cited by 65 publications

References 36 publications

Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct

Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct

Towards personalized medicine in Ménière’s disease

Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

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