TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2)

Deuitch, Natalie; Yang, Dan; Lee, Pui Y.; Yu, Xiaomin; Moura, Natalia Sampaio; Schnappauf, Oskar; Ombrello, Amanda K.; Stone, Deborah L.; Rosenzweig, Sergio D.; Hoffmann, Patrycja; Cudrici, Cornelia; Levy, Deborah; Kessler, Elizabeth R.; Soep, Jennifer B.; Hay, Arielle; Dalrymple, A.; Sun, Li; Zhang, Qiuye; Tang, Xuemei; Wu, Yuan; Rao, Koneti; Li, Haibo; Luo, Hong; Zhang, Yao; Burnham, Jon M.; Boehm, Manfred; Barron, Karyl S.; Kastner, Daniel L.; Aksentijevich, Ivona; Zhou, Qing

doi:10.1016/j.jaci.2021.10.030

Cited by 28 publications

(25 citation statements)

References 21 publications

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“…CD169/SIGLEC1 is a cell adhesion protein induced by type I IFN-signaling and a potential myeloid cell-specific biomarker for an overt type I IFN response on monocytes ( 44 ). This finding is in line with reported evidence of upregulated type I IFN signaling in DADA2 with elevation of IFN score ( 12 , 37 , 43 – 48 ).…”

Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...supporting

confidence: 92%

“…This observation was in line with the identification of elevated plasma levels of IFNγ. Similar findings were reported in other studies profiling transcriptome and proteome analysis on whole blood samples or gene expression on DADA2 PBMCs ( 37 , 43 ). The authors suggested that elevated IFNγ may activate cell signaling, leading to monocytes differentiation into M1 macrophages and release of TNFα ( 39 ).…”

Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...supporting

confidence: 91%

“…Together with IFN type I, the latter study also identified a clear NFKB signature in the whole blood of untreated patients, with normalization of both findings after anti-TNF treatment ( 37 ).…”

Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...mentioning

confidence: 83%

“…In fact, DADA2 is an atypical autoinflammatory disease, in which the causative gene is not involved in the canonical inflammatory pathways, but rather affects purines metabolism and signaling ( 24 , 76 , 77 ). Monocytes/macrophages remain central actors in the pathogenesis of vasculitis-related phenotype ( 37 ), but other mechanisms have been recently shown to contribute to endothelial disruption, such as increased NETosis and NETs stimulatory effect on macrophages itself ( 62 ).…”

Section: Discussionmentioning

confidence: 99%

“…Zhou and colleagues ( 1 ) showed a skewed in vitro monocyte differentiation, with increased proinflammatory M1 macrophages and relatively decreased anti-inflammatory M2 macrophages subset in DADA2 patients. This monocyte/macrophage polarization is supposed to induce a release of proinflammatory cytokines, leading to downstream endothelial disruption ( 1 , 37 ). Notably, the lentiviral correction of defective ADA2 enzymatic activity with ADA2 reconstitution in patients macrophages is able to restrain inflammation ( 36 , 38 ).…”

Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...mentioning

confidence: 99%

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Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity

et al. 2022

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Deficiency of Adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder presenting with a broad spectrum of clinical manifestations, including immunodeficiency, vasculopathy and hematologic disease. Biallelic mutations in ADA2 gene have been associated with a decreased ADA2 activity, leading to reduction in deamination of adenosine and deoxyadenosine into inosine and deoxyinosine and subsequent accumulation of extracellular adenosine. In the early reports, the pivotal role of innate immunity in DADA2 pathogenic mechanism has been underlined, showing a skewed polarization from the M2 macrophage subtype to the proinflammatory M1 subtype, with an increased production of inflammatory cytokines such as TNF-α. Subsequently, a dysregulation of NETosis, triggered by the excess of extracellular Adenosine, has been implicated in the pathogenesis of DADA2. In the last few years, evidence is piling up that adaptive immunity is profoundly altered in DADA2 patients, encompassing both T and B branches, with a disrupted homeostasis in T-cell subsets and a B-cell skewing defect. Type I/type II IFN pathway upregulation has been proposed as a possible core signature in DADA2 T cells and monocytes but also an increased IFN-β secretion directly from endothelial cells has been described. So far, a unifying clear pathophysiological explanation for the coexistence of systemic inflammation, immunedysregulation and hematological defects is lacking. In this review, we will explore thoroughly the latest understanding regarding DADA2 pathophysiological process, with a particular focus on dysregulation of both innate and adaptive immunity and their interacting role in the development of the disease.

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Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...supporting

confidence: 92%

Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...supporting

confidence: 91%

Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...mentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: The Impact Of Ada2 Deficiency On the Cross Talk Between Inna...mentioning

confidence: 99%

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Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity

et al. 2022

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A new CECR1 mutation associated with severe hematological involvement in ADA2 deficiency

Nicoară,

Niță,

Stanilă

et al. 2023

Immunity Inflam & Disease

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BackgroundThe deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease resulting from loss‐of‐function mutations in ADA2, formerly named CECR1 (cat eye syndrome chromosome region, candidate 1) gene. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic; however, most patients presented with significant overlap between these three phenotype groups.Case PresentationWe present a case of DADA2 deficiency with disease onset at 3 years old, not recognized till the age of 18 with severe gastrointestinal vasculitis and recurrent episodes of neutropenia associated with a new CECR1 mutation.

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Mechanisms of vascular inflammation in deficiency of adenosine deaminase 2 (DADA2)

2022

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TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2)

Cited by 28 publications

References 21 publications

Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity

Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity

A new CECR1 mutation associated with severe hematological involvement in ADA2 deficiency

Mechanisms of vascular inflammation in deficiency of adenosine deaminase 2 (DADA2)

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