A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus

Duan, Ruonan; Liu, Qi; Li, Jiangxia; Bian, Xianli; Yuan, Qianqian; Li, Yan; Long, Feng; Gao, Shang; Wei, Shijun; Li, Pengyu; Gao, Fei; Sun, Wei; Li, Xi; Liu, Qiji

doi:10.1007/s10875-019-00695-4

Cited by 17 publications

(8 citation statements)

References 32 publications

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“…By contrast, A20 haploinsufficiency in humans was associated with the development of an early-onset autoimmune disorder, of which at least one patient was diagnosed with a condition resembling SLE ( Zhou et al., 2015 ). The recent identification of a frameshift mutation in TNFAIP3 in a patient with NPSLE ( Duan et al., 2019 ) provides further support for the validity of our model.…”

Section: Discussionsupporting

confidence: 65%

“…TNFAIP3 (tumor necrosis factor alpha induced protein 3) is a well-known susceptibility locus for SLE and recently, a mutation was discovered in a patient with NPSLE ( Duan et al., 2019 ; Ma and Malynn, 2012 ). TNFAIP3 encodes the ubiquitin-editing enzyme A20, a strong negative regulator of the family of nuclear factor-kappa B (NF-κB) transcription factors and a prominent cytoprotective protein ( Adrianto et al., 2011 ; Graham et al., 2008 ; Musone et al., 2008 ; S. Wang et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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A20/TNFAIP3 heterozygosity predisposes to behavioral symptoms in a mouse model for neuropsychiatric lupus

Daems

Sekulić

Vulsteke

et al. 2020

Brain, Behavior, & Immunity - Health

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Background Neuropsychiatric lupus (NPSLE) refers to the neurological and psychiatric manifestations that are commonly observed in patients with systemic lupus erythematosus (SLE). An important question regarding the pathogenesis of NPSLE is whether the symptoms are caused primarily by CNS-intrinsic mechanisms or develop as a consequence of systemic autoimmunity. Currently used spontaneous mouse models for SLE have already contributed significantly to unraveling how systemic immunity affects the CNS. However, they are less suited when interested in CNS primary mechanisms. In addition, none of these models are based on genes that are associated with SLE. In this study, we evaluate the influence of A20, a well-known susceptibility locus for SLE, on behavior and CNS-associated changes in inflammatory markers. Furthermore, given the importance of environmental triggers for disease onset and progression, the influence of an acute immunological challenge was evaluated. Methods Female and male A20 heterozygous mice (A20 +/− ) and wildtype littermates were tested in an extensive behavioral battery. This was done at the age of 10±2weeks and 24 ± 2 weeks to evaluate the impact of aging. To investigate the contribution of an acute immunological challenge, LPS was injected intracerebroventricularly at the age of 10±2weeks followed by behavioral analysis. Underlying molecular mechanisms were evaluated in gene expression assays on hippocampus and cortex. White blood cell count and blood-brain barrier permeability were analyzed to determine whether peripheral inflammation is a relevant factor. Results A20 heterozygosity predisposes to cognitive symptoms that were observed at the age of 10 ± 2 weeks and 24 ± 2 weeks. Young A20 +/− males and females showed a subtle cognitive phenotype (10±2weeks) with distinct neuroinflammatory phenotypes. Aging was associated with clear neuroinflammation in female A20 +/− mice only. The genetic predisposition in combination with an environmental stimulus exacerbates the behavioral impairments related to anxiety, cognitive dysfunction and sensorimotor gating. This was predominantly observed in females. Furthermore, signs of neuroinflammation were solely observed in female A20 +/− mice. All above observations were made in the absence of peripheral inflammation and of changes in blood-brain barrier permeability, thus consistent with the CNS-primary hypothesis. Conclusions We show that A20 heterozygosity is a predisposing factor for NPSLE. Further mechanistic insight and possible therapeutic interventions can be studied in this mouse model that recapitulates several key hallmarks of the disease.

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Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

A20/TNFAIP3 heterozygosity predisposes to behavioral symptoms in a mouse model for neuropsychiatric lupus

Daems

Sekulić

Vulsteke

et al. 2020

Brain, Behavior, & Immunity - Health

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“…Total RNA extraction and real-time PCR assays were performed as previously described [ 30 ]. The expression of GAPDH was used as an internal control.…”

Section: Methodsmentioning

confidence: 99%

Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway

Duan

Yang

et al. 2021

J Neuroinflammation

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Background Experimental autoimmune encephalomyelitis (EAE) is an animal disease model of multiple sclerosis (MS) that involves the immune system and central nervous system (CNS). However, it is unclear how genetic predispositions promote neuroinflammation in MS and EAE. Here, we investigated how partial loss-of-function of suppressor of MEK1 (SMEK1), a regulatory subunit of protein phosphatase 4, facilitates the onset of MS and EAE. Methods C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) to establish the EAE model. Clinical signs were recorded and pathogenesis was investigated after immunization. CNS tissues were analyzed by immunostaining, quantitative polymerase chain reaction (qPCR), western blot analysis, and enzyme-linked immunosorbent assay (ELISA). Single-cell analysis was carried out in the cortices and hippocampus. Splenic and lymph node cells were evaluated with flow cytometry, qPCR, and western blot analysis. Results Here, we showed that partial Smek1 deficiency caused more severe symptoms in the EAE model than in controls by activating myeloid cells and that Smek1 was required for maintaining immunosuppressive function by modulating the indoleamine 2,3-dioxygenase (IDO1)-aryl hydrocarbon receptor (AhR) pathway. Single-cell sequencing and an in vitro study showed that Smek1-deficient microglia and macrophages were preactivated at steady state. After MOG35-55 immunization, microglia and macrophages underwent hyperactivation and produced increased IL-1β in Smek1-/+ mice at the peak stage. Moreover, dysfunction of the IDO1-AhR pathway resulted from the reduction of interferon γ (IFN-γ), enhanced antigen presentation ability, and inhibition of anti-inflammatory processes in Smek1-/+ EAE mice. Conclusions The present study suggests a protective role of Smek1 in autoimmune demyelination pathogenesis via immune suppression and inflammation regulation in both the immune system and the central nervous system. Our findings provide an instructive basis for the roles of Smek1 in EAE and broaden the understanding of the genetic factors involved in the pathogenesis of autoimmune demyelination.

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“…Sporadic reports exist of A20 haploinsufficiency with neurological symptoms, such as aseptic meningitis, and CNS vasculitis ( 23 , 24 ). Furthermore, a frameshift variant in TNFAIP3 has been reported as the cause of neuropsychiatric SLE manifested as headache, seizures, cognitive impairment, ptosis, and difficulty with upward gaze ( 22 ). The pathogenesis may involve an influence on blood brain barrier (BBB) permeability from the disease associated variant ( 22 ).…”

Section: Autoinflammatory Disordersmentioning

confidence: 99%

“…Furthermore, a frameshift variant in TNFAIP3 has been reported as the cause of neuropsychiatric SLE manifested as headache, seizures, cognitive impairment, ptosis, and difficulty with upward gaze ( 22 ). The pathogenesis may involve an influence on blood brain barrier (BBB) permeability from the disease associated variant ( 22 ). Although Tnfaip3 -/- mice are prone to fulminant neuroinflammation involving the NLRP3 inflammasome ( 90 ), the neurological spectrum in human TNFAIP3 haploinsufficiency suggests that species differences exist or that one TNFAIP3 allele is sufficient to restrain inflammation in the CNS.…”

Section: Autoinflammatory Disordersmentioning

confidence: 99%

Neuroinflammation Associated With Inborn Errors of Immunity

Lindahl

Bryceson

2022

Front. Immunol.

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The advent of high-throughput sequencing has facilitated genotype-phenotype correlations in congenital diseases. This has provided molecular diagnosis and benefited patient management but has also revealed substantial phenotypic heterogeneity. Although distinct neuroinflammatory diseases are scarce among the several thousands of established congenital diseases, elements of neuroinflammation are increasingly recognized in a substantial proportion of inborn errors of immunity, where it may even dominate the clinical picture at initial presentation. Although each disease entity is rare, they collectively can constitute a significant proportion of neuropediatric patients in tertiary care and may occasionally also explain adult neurology patients. We focus this review on the signs and symptoms of neuroinflammation that have been reported in association with established pathogenic variants in immune genes and suggest the following subdivision based on proposed underlying mechanisms: autoinflammatory disorders, tolerance defects, and immunodeficiency disorders. The large group of autoinflammatory disorders is further subdivided into IL-1β-mediated disorders, NF-κB dysregulation, type I interferonopathies, and hemophagocytic syndromes. We delineate emerging pathogenic themes underlying neuroinflammation in monogenic diseases and describe the breadth of the clinical spectrum to support decisions to screen for a genetic diagnosis and encourage further research on a neglected phenomenon.

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A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus

Cited by 17 publications

References 32 publications

A20/TNFAIP3 heterozygosity predisposes to behavioral symptoms in a mouse model for neuropsychiatric lupus

A20/TNFAIP3 heterozygosity predisposes to behavioral symptoms in a mouse model for neuropsychiatric lupus

Smek1 deficiency exacerbates experimental autoimmune encephalomyelitis by activating proinflammatory microglia and suppressing the IDO1-AhR pathway

Neuroinflammation Associated With Inborn Errors of Immunity

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