Monogenic polyarteritis: the lesson of ADA2 deficiency

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.

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

“…Eighteen mutations of CECR1 have been detected so far 3. The p.G47R mutation has been detected in homozygous state in most patients of Georgian Jewish and Turkish ancestries 1 2.…”

Expanding the clinical features of autoinflammation and phospholipase Cγ2‐associated antibody deficiency and immune dysregulation by description of a novel patient

“…3,11 It is not clear whether sensorineural deafness could be related to the ototoxic drugs as antibiotics, methotrexate or vinblastine administered to the only patient with deafness reported to date. 4 Vasculitis as a feature of other AIDs has been described in familial Mediterranean fever, stimulator of interferon gene associated vasculopathy of infancy, 15 adenosine deaminase-2 deficiency, 16,17 tumour necrosis factor receptor-associated periodic syndrome, among others; 18 however, CNSV has not been previously described in APLAID. As the number of reported patients with APLAID is very small, it is possible that the overall spectrum of clinical manifestations of this disease has not been completely elucidated; and consequently, we suggest that CNSV might be an occasional, but severe feature of this disease.…”

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis

“…ADA2 is predominantly expressed in monocytes/macrophages and is released to the extracellular environment . ADA2 plays a role in purine metabolism through its enzymatic activity, induces monocytes differentiation to macrophages, stimulates proliferation of macrophages and CD4 + T cells, and also belongs to ADA‐related growth factors that act like growth factor particularly in endothelial cells …”