Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders

Kadowaki, Toru; Ohnishi, Hiroyuki; Kawamoto, Norio; Hori, Tomohiro; Nishimura, Kenichi; Kobayashi, Chie; Shigemura, Tomonari; Ogata, Shohei; Inoue, Yuzaburo; Kawai, Tomoki; Hiejima, Eitaro; Takagi, Motoki; Imai, Kohsuke; Nishikomori, Ryuta; Ito, Shuichi; Heike, Toshio; Ohara, Osamu; Morio, Tomohiro; Fukao, Toshiyuki; Kanegane, Hirokazu

doi:10.1016/j.jaci.2017.10.039

Cited by 96 publications

(120 citation statements)

References 15 publications

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“…1,6,7,12,13 In patients with PIDs, mosaicism has been recognized since the early 1990s, although its contribution to disease pathogenesis has not yet been evaluated systematically. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] The paucity of reports of families with mosaicism might be mainly explained from a technical point of view because most genetic studies were performed in the past using the Sanger method of DNA sequencing as the gold standard technique. The intrinsic chemical characteristics of this technique and automated systems of analyses make it difficult to detect postzygotic variants with MAFs of less than 10%, which are often misinterpreted as background noise, and with MAFs of greater than 30%, which are often misinterpreted as germline variants.…”

Section: Discussionmentioning

confidence: 99%

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Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

Mensa‐Vilaró

García-Morato

Calle-Martin

et al. 2019

Journal of Allergy and Clinical Immunology

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Background: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. Objective: We sought to investigate the incidence of gene mosaicism in patients with PIDs. Methods: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n 5 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n 5 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n 5 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. Results: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderateto-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. Conclusion: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.

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Section: Discussionmentioning

confidence: 99%

“…[8][9][10][11][12][13] In the group of primary immunodeficiency diseases (PIDs), mosaicism has been occasionally reported since the early 1990s, often as isolated case reports. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] However, its precise incidence has not been systemically addressed and is currently poorly understood.…”

mentioning

confidence: 99%

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

Mensa‐Vilaró

García-Morato

Calle-Martin

et al. 2019

Journal of Allergy and Clinical Immunology

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“…Genome-wide association studies identified TNFAIP3/A20 as a susceptibility locus for psoriasis (Haase et al, 2015;Indhumathi et al, 2015;Li et al, 2014;Nair et al, 2009;and Zhang et al, 2015), and its role as a negative regulator in Th2-associated lung inflammation, in particular through its expression by dendritic cells, has been well characterized (Schuijs et al, 2015;Vroman et al, 2018). On the other hand, some cases of A20 haploinsufficiency yield distinct autoinflammatory and/or autoimmune skin pathology, possibly with skin ulcerations and pustular abscesses (Kadowaki et al, 2017;Takagi et al, 2017;Zhou et al, 2016). In addition, TNFAIP3/A20 single nucleotide polymorphisms correlate with response to TNF blockade in psoriasis patients (Tejasvi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Keratinocyte Expression of A20/TNFAIP3 Controls Skin Inflammation Associated with Atopic Dermatitis and Psoriasis

Devos

Mogilenko

Fleury

et al. 2019

Journal of Investigative Dermatology

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Keratinocytes are key players in chronic inflammatory skin diseases. A20 regulates NF-κB-dependent expression of proinflammatory genes and cell death, but the impact of its expression in keratinocytes on systemic inflammation and skin disorders has not been determined. Comparative transcriptomic analysis of microdissected epidermis showed that A20 is down-regulated in involved epidermis, but not in dermis, of psoriasis and atopic dermatitis patients, suggesting that loss of A20 expression in keratinocytes increases the vulnerability for psoriasis/atopic dermatitis induction. We have previously shown that epidermis-specific A20 knockout mice (A20) develop mild epidermal hyperplasia but no macroscopic skin inflammation. We now show that various cytokines and chemokines are up-regulated in A20 mouse skin. A20 mice also display systemic proinflammatory changes, even in the absence of skin immune cell infiltration, and an exacerbated disease severity upon induction of experimental psoriasis, atopic dermatitis, or skin barrier disruption. Keratinocytes showed increased proinflammatory gene expression in the absence of A20 in unstimulated and IL-17A-stimulated conditions, in part resulting from uncontrolled MyD88-dependent signaling. Our findings indicate that absence of A20 in keratinocytes leads to systemic inflammation at homeostatic conditions and is sufficient to exacerbate inflammatory skin disorders associated with different immune profiles by increasing cytokine and chemokine expression.

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“…HA20 is a recently described familial autoinfl ammatory disease originally reported to manifest as an early-onset Behçet-like disease 11 , yet the range of known clinical manifestations is rapidly expanding [16][17][18][19][20][21] . Here we studied patients with HA20 caused by a novel heterozygous TNFAIP3 p.(Lys91*) mutation resulting in severe truncation and production of an N-terminal protein fragment with highly limited functional capacity.…”

Section: Discussionmentioning

confidence: 99%

“…Similar to Tnfaip3 defi ciency in mice [12][13][14][15] , human HA20 led to exaggerated NF-κB responses and increased secretion of NLR family pyrin domain containing 3 (NLRP3) infl ammasome target cytokines 11 . Additional reports from these 16 and further identifi ed patients [17][18][19][20][21] have expanded the clinical spectrum of HA20 to comprise diseases such as autoimmune lymphoproliferative syndrome, systemic juvenile arthritis, psoriatic arthritis, Crohn's disease, and Hashimoto's thyroiditis. The increasing number of diseases associated with A20 have emphasized its role in infl ammatory diseases and in autoimmunity and raised the possibility that mutations in TNFAIP3 may be an unexpectedly common underlying factor in the pathogenesis of rheumatic and other autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation

Rajamäki

Keskitalo

Seppänen

et al. 2018

Preprint

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Objectives: TNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-κB), the major transcription factor coordinating infl ammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of infl ammatory and autoimmune diseases and recently, loss-of-function mutations in A20 were found to cause a novel infl ammatory disease 'haploinsuffi ciency of A20' (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-κB and the related infl ammasome pathway. Methods: NF-κB activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein-protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analyzed using mass spectrometry. NF-κB -dependent transcription, cytokine secretion, and infl ammasome activation were compared in immune cells of the HA20 patients and control subjects. Results: The protein-protein interactome of p.(Lys91*) mutant A20 was severely impaired, including interactions with proteins regulating NF-κB activation, DNA repair responses, and the NLR family pyrin domain containing 3 (NLRP3) infl ammasome. The p.(Lys91*) mutant A20 failed to suppress NF-κB signaling, which led to increased NF-κB -dependent proinfl ammatory cytokine transcription. Functional experiments in the HA20 patients' immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 infl ammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1β and -18. Conclusions: The current fi ndings signifi cantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.

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Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders

Cited by 96 publications

References 15 publications

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases

Keratinocyte Expression of A20/TNFAIP3 Controls Skin Inflammation Associated with Atopic Dermatitis and Psoriasis

Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation

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