Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations

Saettini, Francesco; Fazio, Grazia; Cortí, Paola; Quadri, Manuel; Bugarin, Cristina; Gaipa, Giuseppe; Penco, Federica; Moratto, Daniele; Chiarini, Marcho; Baronio, Manuela; Gazzurelli, Luisa; Paghera, Simone; Giliani, Silvia; Cazzaniga, Giovanni; Plebani, Alessandro; Badolato, Raffaele; Lougaris, Vassilios; Gattorno, Marco; Biondi, Andrea

doi:10.1016/j.clim.2020.108525

Cited by 15 publications

(9 citation statements)

References 11 publications

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“…These findings are reminiscent of our previous analysis of the CD8 + T cell compartment in individuals with pathogenic bi-allelic inactivating variants in DOCK8 [40,66,67] or gain-of-function variants in PIK3CD [39] who are also susceptible to recurrent infections with herpes viruses and have an abundance of dysfunctional exhausted-type CD8 + T cells. The defect in ADA2-deficient cytotoxic lymphocytes may also explain why some DADA2 patients present with hemophagocytic lymphohistiocytosis (unpublished observation) or CD3 + CD8 + large granular lymphocytes [68,69].…”

Section: Discussionmentioning

confidence: 90%

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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Section: Discussionmentioning

confidence: 90%

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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“…It has been reported that the amounts of residual Ada2 activity, rather than mutant genotype, may be more predictive of the resulting phenotype [ 12 ]. Recently, cases of lymphoproliferative disease with resemblance to large granular lymphocyte leukemia have been described in a Finnish cohort of DADA2 patients [ 13 ] and a lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbation have been reported in two siblings exhibiting novel ADA2 variants, including the P311L variant (proline to leucine substitution) [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype

Vai

Marin

Cosso

et al. 2021

IJMS

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Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up.

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“…An increased proportion of CD4-CD8-aß+ TCR+ cells is also reported in several patients (18)(19)(20)71), consistently with an ALPS-like phenotype (3,11,71,72).…”

Section: Neutrophils and Interplay With Innate Immune Cellsmentioning

confidence: 59%

“…The polymorphic DADA2 clinical presentation reflects the ADA2 defect’s deep impact on different immune response branches ( Figure 1 ), even if the possible presence of different clinical manifestations in patients with the same mutation ( 3 , 8 , 19 , 20 ) advocates for further factors influencing the clinical phenotype. Recently a pivotal work unraveled in DADA2 an association of partial loss of ADA2 activity with the vasculitic phenotype and predominant missense mutations, whereas complete absent activity was observed in hematologic disease ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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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Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations

Cited by 15 publications

References 11 publications

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

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

A Novel Germline Mutation of ADA2 Gene in Two “Discordant” Homozygous Female Twins Affected by Adenosine Deaminase 2 Deficiency: Description of the Bone-Related Phenotype

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

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