Systemic autoinflammatory disease in adults

Betrains, Albrecht; Staels, Frederik; Schrijvers, R.; Meyts, Isabelle; Humblet-Baron, Stéphanie; Langhe, Ellen De; Wouters, Carine; Blockmans, Daniel Engelbert; Vanderschueren, Steven

doi:10.1016/j.autrev.2021.102774

Cited by 32 publications

(58 citation statements)

References 114 publications

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“…Some of these patients were given the diagnosis of Schnitzler disease prior to genetic diagnosis ( 147 ). Clinical presentation includes intermittent febrile episodes, fatigue, headache, neutrophilic urticaria, conjunctivitis, and arthralgia ( 173 ).…”

Section: Genetic Defects Associated With Adult-onset Ieimentioning

confidence: 99%

“…Adult-onset phenotypes are associated with low penetrance variants such as p.R92Q or p.P46L ( 150 ) but also somatic mosaicism has been described in two cases of adult-onset TRAPS ( 151 , 152 ). Clinical features may range from atypical images such as isolated recurrent pericarditis to more typical but adult-onset periodic fever syndromes with serositis, myalgia/arthralgia, erythematosus skin lesions, periorbital edema, and, in case of long-standing uncontrolled inflammation, amyloidosis ( 173 ).…”

Section: Genetic Defects Associated With Adult-onset Ieimentioning

confidence: 99%

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Monogenic Adult-Onset Inborn Errors of Immunity

et al. 2021

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Inborn errors of immunity (IEI) are a heterogenous group of disorders driven by genetic defects that functionally impact the development and/or function of the innate and/or adaptive immune system. The majority of these disorders are thought to have polygenic background. However, the use of next-generation sequencing in patients with IEI has led to an increasing identification of monogenic causes, unravelling the exact pathophysiology of the disease and allowing the development of more targeted treatments. Monogenic IEI are not only seen in a pediatric population but also in adulthood, either due to the lack of awareness preventing childhood diagnosis or due to a delayed onset where (epi)genetic or environmental factors can play a role. In this review, we discuss the mechanisms accounting for adult-onset presentations and provide an overview of monogenic causes associated with adult-onset IEI.

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Section: Genetic Defects Associated With Adult-onset Ieimentioning

confidence: 99%

Section: Genetic Defects Associated With Adult-onset Ieimentioning

confidence: 99%

Monogenic Adult-Onset Inborn Errors of Immunity

et al. 2021

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“…While features of vasculitis in DADA2 are well described, mechanisms underlying immunodeficiency have been less well explored. Initial descriptions noted B cell lymphopenia, progressive hypogammaglobulinemia occasionally mimicking agammaglobulinemia, increased numbers of naïve and CD21 lo B cells, but reductions in switched memory B cells and plasmablasts [1,15,16]. In vitro findings of decreased T-dependent Ig secretion and increased B cell apoptosis inferred that a B cell-intrinsic defect underlies humoral immunodeficiency in DADA2 [1,16].…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency

et al. 2021

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Purpose Deficiency of adenosine deaminase type 2 (ADA2) (DADA2) is a rare inborn error of immunity caused by deleterious biallelic mutations in ADA2. Clinical manifestations are diverse, ranging from severe vasculopathy with lacunar strokes to immunodeficiency with viral infections, hypogammaglobulinemia and bone marrow failure. Limited data are available on the phenotype and function of leukocytes from DADA2 patients. The aim of this study was to perform in-depth immunophenotyping and functional analysis of the impact of DADA2 on human lymphocytes. Methods In-depth immunophenotyping and functional analyses were performed on ten patients with confirmed DADA2 and compared to heterozygous carriers of pathogenic ADA2 mutations and normal healthy controls. Results The median age of the patients was 10 years (mean 20.7 years, range 1–44 years). Four out of ten patients were on treatment with steroids and/or etanercept or other immunosuppressives. We confirmed a defect in terminal B cell differentiation in DADA2 and reveal a block in B cell development in the bone marrow at the pro-B to pre-B cell stage. We also show impaired differentiation of CD4+ and CD8+ memory T cells, accelerated exhaustion/senescence, and impaired survival and granzyme production by ADA2 deficient CD8+ T cells. Unconventional T cells (i.e. iNKT, MAIT, Vδ2+ γδT) were diminished whereas pro-inflammatory monocytes and CD56bright immature NK cells were increased. Expression of the IFN-induced lectin SIGLEC1 was increased on all monocyte subsets in DADA2 patients compared to healthy donors. Interestingly, the phenotype and function of lymphocytes from healthy heterozygous carriers were often intermediate to that of healthy donors and ADA2-deficient patients. Conclusion Extended immunophenotyping in DADA2 patients shows a complex immunophenotype. Our findings provide insight into the cellular mechanisms underlying some of the complex and heterogenous clinical features of DADA2. More research is needed to design targeted therapy to prevent viral infections in these patients with excessive inflammation as the overarching phenotype.

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“…Interestingly, all of these manifestations improved, but did not normalize, with IL‐1 blockade. Overall, the clinical picture strongly suggested an uncharacterized late‐onset autoinflammatory disease, but the concrete features did not fit well with any of the monogenic autoinflammatory diseases (14). Despite the low probability of finding a genetic defect, the genetics study performed identified the p.Ser171Phe NLRC4 variant, with a mutant allele fraction compatible with that expected for postzygotic variants causing mosaicism (15).…”

Section: Discussionmentioning

confidence: 88%

First Description of Late‐Onset Autoinflammatory Disease Due to Somatic NLRC4 Mosaicism

Ionescu

Peñín‐Franch

Mensa‐Vilaró

et al. 2022

Arthritis & Rheumatology

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Objective Autoinflammatory diseases are inherited disorders of innate immunity that usually start during childhood. However, several recent reports have described an increasing number of patients with autoinflammatory disease starting in adulthood. This study was undertaken to investigate the underlying cause of a case of late‐onset uncharacterized autoinflammatory disease. Methods Genetics studies were performed using Sanger sequencing and next‐generation sequencing (NGS) methods. In silico, in vitro, and ex vivo analyses were performed to determine the functional consequences of the detected variant. Results We studied a 57‐year‐old woman who at the age of 47 years began to have recurrent episodes of fever, myalgias, arthralgias, diffuse abdominal pain, diarrhea, adenopathies, and systemic inflammation, which were relatively well controlled with anti–interleukin‐1 (anti‐IL‐1) drugs. NGS analyses did not detect germline variants in any of the known autoinflammatory disease–associated genes, but they identified the p.Ser171Phe NLRC4 variant in unfractionated blood, with an allele fraction (2–4%) compatible with gene mosaicism. Structural modeling analyses suggested that this missense variant might favor the open, active conformation of the NLRC4 protein, and in vitro and ex vivo analyses confirmed its propensity to oligomerize and activate the NLRC4 inflammasome, with subsequent overproduction of IL‐18. Conclusion Our findings indicate that the postzygotic p.Ser171Phe NLRC4 variant is a plausible cause of the disease in the enrolled patient. Functional and structural studies clearly support, for the first time, its gain‐of‐function behavior, consistent with previously reported NLRC4 pathogenic variants. These novel findings should be considered in the diagnostic evaluation of patients with adult‐onset uncharacterized autoinflammatory disease.

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Systemic autoinflammatory disease in adults

Cited by 32 publications

References 114 publications

Monogenic Adult-Onset Inborn Errors of Immunity

Monogenic Adult-Onset Inborn Errors of Immunity

Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency

First Description of Late‐Onset Autoinflammatory Disease Due to Somatic NLRC4 Mosaicism

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