Adenosine deaminase 2 regulates the activation of the toll-like receptor 9 in response to nucleic acids

Human cells contain two types of adenosine deaminases(ADA)each with unique properties:ADA1,which is present in all cells where it modulates intracellular functions and extracellular signaling,and ADA2,which is secreted by immune cells.The exact intracellular functions of ADA2 remain undetermined and less defined than those of ADA1.ADA2 has distinct characteristics,such as low adenosine affinity,heparin-binding ability,and putative lysosomal entry.Here,we confirm that ADA2 is a lysosomal protein that binds toll-like receptor 9(TLR9)agonists,specifically CpG oligodeoxynucleotides(CpG ODNs).We show that interferon-alpha(IFN-α)is secreted in response to TLR9 activation by CpG ODNs and natural DNA and markedly increases when ADA2 expression is downregulated in plasmacytoid dendritic cells(pDCs).Additionally,the pretreatment of pDCs with RNA further stimulates IFN-αsecretion by pDCs after activation with CpG ODNs.Our findings indicate that ADA2 regulates TLR9 responses to DNA in activated pDCs.In conclusion,decreasing ADA2 expression or blocking it with specific oligonucleotides can enhance IFN-αsecretion from pDCs,improving immune responses against intracellular infections and cancer.

Effect of genetic factors on the association between coronary artery disease and PTPN22 polymorphism

PTPN22 has been previously found associated with coronary artery disease(CAD). In the present note we have studied the effect of p53 codon 72,acid phosphatse locus 1(ACP1) and adenosine deaminase(ADA) genetic polymorphism on the strength of association between PTPN22 and CAD. We have studied 133 non diabetic subjects with CAD,122 non diabetic cardiovascular patients without CAD and 269 healthy blood donors. Informed written consent was obtained from all subjects and the study was approved by the Ethical Committee. A high significant association between PTPN22 and CAD is observed in carriers of *A allele of ACP1 with a higher proportion of *T allele carriers in non diabetic subjects with CAD as compared to controls and to non diabetic subjects with cardiovascular diseasewithout CAD. A similar pattern is observed in carriers of *Pro allele of p53 codon 72 with a higher proportion of *T allele carriers in non diabetic subjects with CAD as compared to other groups. A highly significant association between PTPN22 and CAD is observed in carriers of ADA2 *2 allele with higher proportion of *T allele carriers in non diabetic subjects with CAD as compared to other group. There is a high significant correlation between the number of factors that contributes to increase the strength of association between PTPN22 *T and CAD and the proportion of *T carriers in CAD. ACP1,p53 codon 72 and ADA are involved in immune reaction and give an important additive contribution to the strength of association between PTPN22 and CAD. This study stresses the importance of the simultaneous analysis of multiple genes functionally related to a specific disease: the approach may give important hints to understand multifactorial disorders.