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Monogenic polyarteritis: the lesson of ADA2 deficiency

View Article: PubMed Central - PubMed

ABSTRACT

The deficiency of Adenosine Deaminase 2 (DADA2) is a new autoinflammatory disease characterised by an early onset vasculopathy with livedoid skin rash associated with systemic manifestations, CNS involvement and mild immunodeficiency.

This condition is secondary to autosomal recessive mutations of CECR1 (Cat Eye Syndrome Chromosome Region 1) gene, mapped to chromosome 22q11.1, that encodes for the enzymatic protein adenosine deaminase 2 (ADA2). By now 19 different mutations in CECR1 gene have been detected.

The pathogenetic mechanism of DADA2 is still unclear. ADA2 in a secreted protein mainly expressed by cells of the myeloid lineage; its enzymatic activity is higher in conditions of hypoxia, inflammation and oncogenesis. Moreover ADA2 is able to induce macrophages proliferation and differentiation; it’s deficiency is in fact associated with a reduction of anti-inflammatory macrophages (M2). The deficiency of ADA2 is also associated with an up-regulation of neutrophils-expressed genes and an increased secretion of pro-inflammatory cytokines. The mild immunodeficiency detected in many DADA2 patients suggests a role of this protein in the adaptive immune response; an increased mortality of B cells and a reduction in the number of memory B cells, terminally differentiated B cells and plasmacells has been described in many patients. The lack of the protein is associated with endothelium damage; however the function of this protein in the endothelial homeostasis is still unknown.

From the clinical point of view, this disease is characterized by a wide spectrum of severity. Chronic or recurrent systemic inflammation with fever, elevation of acute phase reactants and skin manifestations (mainly represented by livedo reticularis) is the typical clinical picture. While in some patients the disease is mild and skin-limited, others present a severe, even lethal, disease with multi-organ involvement; the CNS involvement is rather common with ischemic or hemorrhagic strokes. In many patients not only the clinical picture but also the histopathologic features are undistinguishable from those of systemic polyarteritis nodosa (PAN). Of note, patients with an unusual phenotype, mainly dominated by clinical manifestations suggestive for an immune-disrective condition, have been described.

Due to its rarity, the response to treatment of DADA2 is still anecdotal. While steroids can control the disease’s manifestations at high dosage, none of the common immunosuppressive drugs turned out to be effective. Biologic drugs have been used only in few patients, without a clear effectiveness; anti-TNF drugs are those associated to a better clinical response. Hematopoietic stem cells transplantation was effective in patients with a severe phenotype.

No MeSH data available.


Related in: MedlinePlus

Production and physiological role of Adenosine Deaminase 2 (ADA2). ADA2 is produced and secreted by cells of myeloid lineage; it exerts its enzymatic activity in the extracellular space, especially in the presence of a low pH or high temperature. On monocytes (a) ADA2 acts as growth-factor with an autocrine activity: it induces monocytes’ proliferation and promote the differentiation of M2 anti-inflammatory macrophages. On neutrophils (b) ADA2 induces the gene of expression of some pro-inflammatory proteins, such as myeloperoxidase (MPO) and neutrophils’ activations, leading to the secretion of pro-inflammatory cytokines. There are indirect evidences of a possible role of ADA2 as growth-factor for endothelial cells (c)
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Fig2: Production and physiological role of Adenosine Deaminase 2 (ADA2). ADA2 is produced and secreted by cells of myeloid lineage; it exerts its enzymatic activity in the extracellular space, especially in the presence of a low pH or high temperature. On monocytes (a) ADA2 acts as growth-factor with an autocrine activity: it induces monocytes’ proliferation and promote the differentiation of M2 anti-inflammatory macrophages. On neutrophils (b) ADA2 induces the gene of expression of some pro-inflammatory proteins, such as myeloperoxidase (MPO) and neutrophils’ activations, leading to the secretion of pro-inflammatory cytokines. There are indirect evidences of a possible role of ADA2 as growth-factor for endothelial cells (c)

Mentions: ADA2 is more stable at high temperatures and the optimum pH for its activity is generally acid (about 6.5), which suggests a specialized role of this enzyme in conditions of hypoxia, inflammation and oncogenesis; in these conditions its deaminase activity is higher [17] (Fig. 2).Fig. 2


Monogenic polyarteritis: the lesson of ADA2 deficiency
Production and physiological role of Adenosine Deaminase 2 (ADA2). ADA2 is produced and secreted by cells of myeloid lineage; it exerts its enzymatic activity in the extracellular space, especially in the presence of a low pH or high temperature. On monocytes (a) ADA2 acts as growth-factor with an autocrine activity: it induces monocytes’ proliferation and promote the differentiation of M2 anti-inflammatory macrophages. On neutrophils (b) ADA2 induces the gene of expression of some pro-inflammatory proteins, such as myeloperoxidase (MPO) and neutrophils’ activations, leading to the secretion of pro-inflammatory cytokines. There are indirect evidences of a possible role of ADA2 as growth-factor for endothelial cells (c)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5015262&req=5

Fig2: Production and physiological role of Adenosine Deaminase 2 (ADA2). ADA2 is produced and secreted by cells of myeloid lineage; it exerts its enzymatic activity in the extracellular space, especially in the presence of a low pH or high temperature. On monocytes (a) ADA2 acts as growth-factor with an autocrine activity: it induces monocytes’ proliferation and promote the differentiation of M2 anti-inflammatory macrophages. On neutrophils (b) ADA2 induces the gene of expression of some pro-inflammatory proteins, such as myeloperoxidase (MPO) and neutrophils’ activations, leading to the secretion of pro-inflammatory cytokines. There are indirect evidences of a possible role of ADA2 as growth-factor for endothelial cells (c)
Mentions: ADA2 is more stable at high temperatures and the optimum pH for its activity is generally acid (about 6.5), which suggests a specialized role of this enzyme in conditions of hypoxia, inflammation and oncogenesis; in these conditions its deaminase activity is higher [17] (Fig. 2).Fig. 2

View Article: PubMed Central - PubMed

ABSTRACT

The deficiency of Adenosine Deaminase 2 (DADA2) is a new autoinflammatory disease characterised by an early onset vasculopathy with livedoid skin rash associated with systemic manifestations, CNS involvement and mild immunodeficiency.

This condition is secondary to autosomal recessive mutations of CECR1 (Cat Eye Syndrome Chromosome Region 1) gene, mapped to chromosome 22q11.1, that encodes for the enzymatic protein adenosine deaminase 2 (ADA2). By now 19 different mutations in CECR1 gene have been detected.

The pathogenetic mechanism of DADA2 is still unclear. ADA2 in a secreted protein mainly expressed by cells of the myeloid lineage; its enzymatic activity is higher in conditions of hypoxia, inflammation and oncogenesis. Moreover ADA2 is able to induce macrophages proliferation and differentiation; it’s deficiency is in fact associated with a reduction of anti-inflammatory macrophages (M2). The deficiency of ADA2 is also associated with an up-regulation of neutrophils-expressed genes and an increased secretion of pro-inflammatory cytokines. The mild immunodeficiency detected in many DADA2 patients suggests a role of this protein in the adaptive immune response; an increased mortality of B cells and a reduction in the number of memory B cells, terminally differentiated B cells and plasmacells has been described in many patients. The lack of the protein is associated with endothelium damage; however the function of this protein in the endothelial homeostasis is still unknown.

From the clinical point of view, this disease is characterized by a wide spectrum of severity. Chronic or recurrent systemic inflammation with fever, elevation of acute phase reactants and skin manifestations (mainly represented by livedo reticularis) is the typical clinical picture. While in some patients the disease is mild and skin-limited, others present a severe, even lethal, disease with multi-organ involvement; the CNS involvement is rather common with ischemic or hemorrhagic strokes. In many patients not only the clinical picture but also the histopathologic features are undistinguishable from those of systemic polyarteritis nodosa (PAN). Of note, patients with an unusual phenotype, mainly dominated by clinical manifestations suggestive for an immune-disrective condition, have been described.

Due to its rarity, the response to treatment of DADA2 is still anecdotal. While steroids can control the disease’s manifestations at high dosage, none of the common immunosuppressive drugs turned out to be effective. Biologic drugs have been used only in few patients, without a clear effectiveness; anti-TNF drugs are those associated to a better clinical response. Hematopoietic stem cells transplantation was effective in patients with a severe phenotype.

No MeSH data available.


Related in: MedlinePlus