Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

1. Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18(8):832–42.https://doi.org/10.1038/ni.3777.

   Article CAS PubMed  Google Scholar 

2. •• Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370(10):911–20.https://doi.org/10.1056/NEJMoa1307361.The first report of DADA2 as a cause of early-onset stroke. Provides experimental evidence supporting causalityof ADA2 deficiency and evidence implicating M1 macrophage polarization in pathogenesis

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3. •• Navon Elkan P, Pierce SB, Segel R, Walsh T, Barash J, Padeh S, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921–31.https://doi.org/10.1056/NEJMoa1307362.The first report of DADA2 as a cause of familial and sporadic PAN. Provides evidence of the efficacy of anti-TNF therapy in controlling autoinflammation

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4. Schrader WP, Pollara B, Meuwissen HJ. Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency. Proc Natl Acad Sci U S A. 1978;75(1):446–50.

   Article CAS PubMed PubMed Central  Google Scholar 

5. Iwaki-Egawa S, Yamamoto T, Watanabe Y. Human plasma adenosine deaminase 2 is secreted by activated monocytes. Biol Chem. 2006;387(3):319–21.https://doi.org/10.1515/BC.2006.042.

   Article CAS PubMed  Google Scholar 

6. Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G. Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J Leukoc Biol. 2010;88(2):279–90.https://doi.org/10.1189/jlb.1109764.

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7. Zavialov AV, Engstrom A. Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity. Biochem J. 2005;391(Pt 1):51–7.https://doi.org/10.1042/BJ20050683.

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8. Zavialov AV, Yu X, Spillmann D, Lauvau G, Zavialov AV. Structural basis for the growth factor activity of human adenosine deaminase ADA2. J Biol Chem. 2010;285(16):12367–77.https://doi.org/10.1074/jbc.M109.083527.

   Article CAS PubMed PubMed Central  Google Scholar 

9. Poursharifi P, Saghiri R, Ebrahimi-Rad M, Nazem H, Pourpak Z, Moin M, et al. Adenosine deaminase in patients with primary immunodeficiency syndromes: the analysis of serum ADA1 and ADA2 activities. Clin Biochem. 2009;42(13–14):1438–43.https://doi.org/10.1016/j.clinbiochem.2008.10.019.

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10. Caorsi R, Penco F, Schena F, Gattorno M. Monogenic polyarteritis: the lesson of ADA2 deficiency. Pediatr Rheumatol Online J. 2016;14(1):51.https://doi.org/10.1186/s12969-016-0111-7.

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11. Berkun Y, Segel R, Navon-Elkan P. Adenosine deaminase 2 deficiency: more than monogenic vasculitis. Isr Med Assoc J. 2017;19(7):435–7.

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12. • Ozen S. The changing face of polyarteritis nodosa and necrotizing vasculitis. Nat Rev Rheumatol. 2017;13(6):381–6.https://doi.org/10.1038/nrrheum.2017.68.A thoughtful and informative recent review of PAN

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13. Garg N, Kasapcopur O, Foster J 2nd, Barut K, Tekin A, Kizilkilic O, et al. Novel adenosine deaminase 2 mutations in a child with a fatal vasculopathy. Eur J Pediatr. 2014;173(6):827–30.https://doi.org/10.1007/s00431-014-2320-8.

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14. • van Montfrans J, Zavialov A, Zhou Q. Mutant ADA2 in vasculopathies. N Engl J Med. 2014;371(5):478.https://doi.org/10.1056/NEJMc1405506#SA1.HSCT from a matched allogeneic donor was performed for PRCA in a patient later discovered to have DADA2. Serum ADA2 and clinical status were normal 11 years post transplant

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15. • Van Eyck L Jr, Hershfield MS, Pombal D, Kelly SJ, Ganson NJ, Moens L, et al. Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency. J Allergy Clin Immunol. 2015;135(1):283–7 e5.https://doi.org/10.1016/j.jaci.2014.10.010.Describes the complicated course and successful HSCT in one of two siblings with DADA2, and documents elevated IL-6 in both siblings

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16. Van Eyck L, Liston A, Meyts I. Mutant ADA2 in vasculopathies. N Engl J Med. 2014;371(5):478–9.https://doi.org/10.1056/NEJMc1405506#SA2.

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17. • Van Eyck L, Liston A, Wouters C. Mutant ADA2 in vasculopathies. N Engl J Med. 2014;371(5):480.https://doi.org/10.1056/NEJMc1405506#SA4.DADA2 as a cause of HHV8-negativer Castleman disease, effectively treated with anti-IL6

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18. • Bras J, Guerreiro R, Santo GC. Mutant ADA2 in vasculopathies. N Engl J Med. 2014;371(5):478–80.https://doi.org/10.1056/NEJMc1405506#SA3.DADA2 as a cause of familial Sneddon syndrome (onset of livedo racemosa and stroke in the second decade of life)

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19. •• Belot A, Wassmer E, Twilt M, Lega JC, Zeef LA, Oojageer A, et al. Mutations in CECR1 associated with a neutrophil signature in peripheral blood. Pediatr Rheumatol Online J. 2014;12:44.https://doi.org/10.1186/1546-0096-12-44.Disconvery of interfereon signature and overexpression of neutrophil genes in two patients with DADA2. Suggests inflammatory features and PAN may result from chronic neutophil activation

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20. Gonzalez Santiago TM, Zavialov A, Saarela J, Seppanen M, Reed AM, Abraham RS, et al. Dermatologic features of ADA2 deficiency in cutaneous polyarteritis nodosa. JAMA Dermatol. 2015;151(11):1230–4.https://doi.org/10.1001/jamadermatol.2015.1635.

    Article PubMed  Google Scholar 

21. Abraham RS, Gibson LE. Error in complementary DNA nomenclature in “Dermatologic Features of ADA2 Deficiency in Cutaneous Polyarteritis Nodosa”. JAMA Dermatol. 2016;152(9):1065.https://doi.org/10.1001/jamadermatol.2016.2595.

    Article PubMed  Google Scholar 

22. Westendorp WF, Nederkoorn PJ, Aksentijevich I, Hak AE, Lichtenbelt KD, Braun KP. Unexplained early-onset lacunar stroke and inflammatory skin lesions: consider ADA2 deficiency. Neurology. 2015;84(20):2092–3.https://doi.org/10.1212/WNL.0000000000001581.

    Article PubMed PubMed Central  Google Scholar 

23. • Batu ED, Karadag O, Taskiran EZ, Kalyoncu U, Aksentijevich I, Alikasifoglu M, et al. A case series of adenosine deaminase 2-deficient patients emphasizing treatment and genotype-phenotype correlations. J Rheumatol. 2015;42(8):1532–4.https://doi.org/10.3899/jrheum.150024.Highlights weak correlation between genotype and phenotype

    Article CAS PubMed  Google Scholar 

24. Fellmann F, Angelini F, Wassenberg J, Perreau M, Arenas Ramirez N, Simon G, et al. IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation. J Allergy Clin Immunol. 2016;137(4):1189–96 e1-2.https://doi.org/10.1016/j.jaci.2015.07.053.

    Article CAS PubMed  Google Scholar 

25. Keer N, Hershfield M, Caskey T, Unizony S. Novel compound heterozygous variants in CECR1 gene associated with childhood onset polyarteritis nodosa and deficiency of ADA2. Rheumatology (Oxford). 2016;55(6):1145–7.https://doi.org/10.1093/rheumatology/kew050.

    Article  Google Scholar 

26. • Nanthapisal S, Murphy C, Omoyinmi E, Hong Y, Standing A, Berg S, et al. Deficiency of adenosine deaminase type 2: a description of phenotype and genotype in fifteen cases. Arthritis Rheumatol. 2016;68(9):2314–22.https://doi.org/10.1002/art.39699.Highlights phenotypic heterogeneity in related patients homozygous for the same CECR1 mutation

    Article CAS PubMed  Google Scholar 

27. Uettwiller F, Sarrabay G, Rodero MP, Rice GI, Lagrue E, Marot Y, et al. ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters. RMD Open. 2016;2(1):e000236.https://doi.org/10.1136/rmdopen-2015-000236.

    Article CAS PubMed PubMed Central  Google Scholar 

28. • Ben-Ami T, Revel-Vilk S, Brooks R, Shaag A, Hershfield MS, Kelly SJ, et al. Extending the clinical phenotype of adenosine deaminase 2 deficiency. J Pediatr. 2016;177:316–20.https://doi.org/10.1016/j.jpeds.2016.06.058.Highlights PRCA and other hematologic disorders in patients with DADA2 from several Arab families

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29. • Van Montfrans JM, Hartman EA, Braun KP, Hennekam EA, Hak EA, Nederkoorn PJ, et al. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford). 2016;55(5):902–10.https://doi.org/10.1093/rheumatology/kev439.Highlights phenotypic heterogeneity in related patients homozygous for the same CECR1 mutation

    Article  Google Scholar 

30. Schepp J, Bulashevska A, Mannhardt-Laakmann W, Cao H, Yang F, Seidl M, et al. Deficiency of adenosine deaminase 2 causes antibody deficiency. J Clin Immunol. 2016;36(3):179–86.https://doi.org/10.1007/s10875-016-0245-x.

    Article CAS PubMed  Google Scholar 

31. • Hsu AP, West RR, Calvo KR, Cuellar-Rodriguez J, Parta M, Kelly SJ, et al. Adenosine deaminase type 2 deficiency masquerading as GATA2 deficiency: successful hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2016;138(2):628–30 e2.https://doi.org/10.1016/j.jaci.2016.03.016.DADA2 as a cause of MonoMAC syndrome, successfully treated by HSCT

    Article CAS PubMed PubMed Central  Google Scholar 

32. Poswar Fde O, da Fonseca RM, de Albuquerque LC, Zhou Q, Jardim LB, Monte TL, et al. Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis. J Neurol. 2016;263(4):818–20.https://doi.org/10.1007/s00415-016-8070-y.

    Article PubMed  Google Scholar 

33. Elbracht M, Mull M, Wagner N, Kuhl C, Abicht A, Kurth I, et al. Stroke as initial manifestation of adenosine deaminase 2 deficiency. Neuropediatrics. 2017;48(2):111–4.https://doi.org/10.1055/s-0036-1597611.

    CAS PubMed  Google Scholar 

34. • Hashem H, Egler R, Dalal J. Refractory pure red cell aplasia manifesting as deficiency of adenosine deaminase 2. J Pediatr Hematol Oncol. 2017;https://doi.org/10.1097/MPH.0000000000000805.Successful HSCT for PRCA following diagnosis of DADA2

35. • Hashem H, Vatsayan A, Gupta A, Nagle K, Hershfield M, Dalal J. Successful reduced intensity hematopoietic cell transplant in a patient with deficiency of adenosine deaminase 2. Bone Marrow Transplant. 2017;https://doi.org/10.1038/bmt.2017.173.

36. Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. 2017;https://doi.org/10.1136/annrheumdis-2016-210802.

37. •• Schepp J, Proietti M, Frede N, Buchta M, Hubscher K, Rojas Restrepo J, et al. Screening of 181 patients with antibody deficiency for deficiency of adenosine deaminase 2 sheds new light on the disease in adulthood. Arthritis Rheumatol. 2017;69(8):1689–700.https://doi.org/10.1002/art.40147.Screening idenitfied DADA2 in 11 (6%) of 181 patients with antibody deficiency (CVID)

    Article CAS PubMed  Google Scholar 

38. Skrabl-Baumgartner A, Plecko B, Konig N, Hershfield M, Gruber-Sedlmayr U, Lee-Kirsch MA. Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. Pediatr Rheumatol. 2017;15(1):67.https://doi.org/10.1186/s12969-017-0193-x.

39. Ombrello A, Stone D, Hoffmann P, Jones A, Barham B, Barron K et al. The deficiency of adenosine deaminase type 2—results of therapeutic intervention. Pediatric Rheumatology. 2015;13 (Suppl 1). doi:https://doi.org/10.1186/1546-0096-13-S1-O40.

40. •• Hashem H, R A, Kumar AR, Müller I, Babor F, Bredius R et al. Hematopoietic stem cell transplantation rescues the hematological, immunological and vascular phenotype in DADA2. Blood. 2017, in Press.Reviews the experience with HSCT performed in 14 patients with DADA2.

41. Azzari C, la Marca G, Resti M. Neonatal screening for severe combined immunodeficiency caused by an adenosine deaminase defect: a reliable and inexpensive method using tandem mass spectrometry. J Allergy Clin Immunol. 2011;127(6):1394–9.https://doi.org/10.1016/j.jaci.2011.03.040.

    Article CAS PubMed  Google Scholar 

42. Richard E, Arredondo-Vega FX, Santisteban I, Kelly SJ, Patel DD, Hershfield MS. The binding site of human adenosine deaminase for CD26/dipeptidyl peptidase IV: the Arg142Gln mutation impairs binding to cd26 but does not cause immune deficiency. J Exp Med. 2000;192(9):1223–36.

    Article CAS PubMed PubMed Central  Google Scholar 

43. Homma K, Matsushita T, Natori S. Purification, characterization, and cDNA cloning of a novel growth factor from the conditioned medium of NIH-Sape-4, an embryonic cell line of Sarcophaga peregrina (flesh fly). J Biol Chem. 1996;271(23):13770–5.

    Article CAS PubMed  Google Scholar 

44. Homma KJ, Tanaka Y, Matsushita T, Yokoyama K, Matsui H, Natori S. Adenosine deaminase activity of insect-derived growth factor is essential for its growth factor activity. J Biol Chem. 2001;276(47):43761–6.https://doi.org/10.1074/jbc.M105088200.

    Article CAS PubMed  Google Scholar 

45. Zurovec M, Dolezal T, Gazi M, Pavlova E, Bryant PJ. Adenosine deaminase-related growth factors stimulate cell proliferation in Drosophila by depleting extracellular adenosine. Proc Natl Acad Sci U S A. 2002;99(7):4403–8.https://doi.org/10.1073/pnas.062059699.

    Article CAS PubMed PubMed Central  Google Scholar 

46. Riazi MA, Brinkman-Mills P, Nguyen T, Pan H, Phan S, Ying F, et al. The human homolog of insect-derived growth factor, CECR1, is a candidate gene for features of cat eye syndrome. Genomics. 2000;64(3):277–85.https://doi.org/10.1006/geno.1999.6099.

    Article CAS PubMed  Google Scholar 

47. Charlab R, Valenzuela JG, Andersen J, Ribeiro JM. The invertebrate growth factor/CECR1 subfamily of adenosine deaminase proteins. Gene. 2001;267(1):13–22.

    Article CAS PubMed  Google Scholar 

48. Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, et al. Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cell Mol Life Sci. 2017;74(3):555–70.https://doi.org/10.1007/s00018-016-2357-0.

    Article CAS PubMed  Google Scholar 

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