Intrinsic Defects in B Cell Development and Differentiation, T Cell Exhaustion and Altered Unconventional T Cell Generation Characterize Human Adenosine Deaminase Type 2 Deficiency.
Adenosine Deaminase
/ blood
Adolescent
Adult
Agammaglobulinemia
/ blood
Aged
B-Lymphocytes
/ immunology
Cell Differentiation
Child
Child, Preschool
Dendritic Cells
/ immunology
Humans
Infant
Intercellular Signaling Peptides and Proteins
/ blood
Killer Cells, Natural
/ immunology
Middle Aged
Severe Combined Immunodeficiency
/ blood
T-Lymphocytes
/ immunology
Young Adult
ADA2 deficiency
DADA2
Humoral immunodeficiency
Monocytes
SIGLEC-1
T cell exhaustion
Type I IFN signature
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
01
06
2021
accepted:
22
07
2021
pubmed:
18
10
2021
medline:
19
2
2022
entrez:
17
10
2021
Statut:
ppublish
Résumé
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. 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. 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 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.
Identifiants
pubmed: 34657246
doi: 10.1007/s10875-021-01141-0
pii: 10.1007/s10875-021-01141-0
pmc: PMC8604888
doi:
Substances chimiques
Intercellular Signaling Peptides and Proteins
0
ADA2 protein, human
EC 3.5.4.4
Adenosine Deaminase
EC 3.5.4.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1915-1935Informations de copyright
© 2021. The Author(s).
Références
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.
pubmed: 24552284
pmcid: 4193683
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.
pubmed: 24552285
Meyts I, Aksentijevich I. Deficiency of adenosine deaminase 2 (DADA2): updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol. 2018;38(5):569–78.
pubmed: 29951947
pmcid: 6061100
Hashem H, Egler R, Dalal J. Refractory pure red cell aplasia manifesting as deficiency of adenosine deaminase 2. J Pediatr Hematol Oncol. 2017;39(5):e293–6.
pubmed: 28230570
Alabbas F, Elyamany G, Alsharif O, Hershfield M, Meyts I. Childhood Hodgkin Lymphoma: Think DADA2. J Clin Immunol. 2019;39(1):26–9.
pubmed: 30644014
Ombrello AK, Qin J, Hoffmann PM, Kumar P, Stone D, Jones A, et al. Treatment strategies for deficiency of adenosine deaminase 2. N Engl J Med. 2019;380(16):1582–4.
pubmed: 30995379
pmcid: 7372950
Cooray S, Omyinmi E, Hong Y, Papadopoulou C, Harper L, Al-Abadi E, et al. Anti-tumour necrosis factor treatment for the prevention of ischaemic events in patients with deficiency of adenosine deaminase 2 (DADA2). Rheumatology (Oxford). 2021.
Lee PY, Kellner ES, Huang Y, Furutani E, Huang Z, Bainter W, et al. Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol. 2020;145(6):1664-72 e10.
pubmed: 31945408
pmcid: 7282972
Hashem H, Kumar AR, Muller I, Babor F, Bredius R, Dalal J, et al. Hematopoietic stem cell transplantation rescues the hematological, immunological, and vascular phenotype in DADA2. Blood. 2017;130(24):2682–8.
pubmed: 28974505
pmcid: 5731089
Hashem H, Bucciol G, Ozen S, Unal S, Bozkaya IO, Akarsu N, et al. Hematopoietic cell transplantation cures adenosine deaminase 2 deficiency: report on 30 patients. J Clin Immunol. 2021;41(7):1633–47. https://doi.org/10.1007/s10875-021-01098-0 .
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.
pubmed: 26922074
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.
pubmed: 28493328
Van Eyck Jr L, 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.
pubmed: 25457153
pmcid: 4282724
Arts K, Bergerson JRE, Ombrello AK, Similuk M, Oler AJ, Agharahimi A, et al. Warts and DADA2: a Mere Coincidence? J Clin Immunol. 2018;38(8):836–43.
pubmed: 30386947
Betrains A, Staels F, Schrijvers R, Meyts I, Humblet-Baron S, De Langhe E, et al. Systemic autoinflammatory disease in adults. Autoimmun Rev. 2021;102774.
Schena F, Penco F, Volpi S, Pastorino C, Caorsi R, Kalli F, et al. Dysregulation in B-cell responses and T follicular helper cell function in ADA2 deficiency patients. Eur J Immunol. 2020;51(1):206–19.
pubmed: 32707604
Tangye SG, Ma CS. Regulation of the germinal center and humoral immunity by interleukin-21. J Exp Med. 2020;217(1).
Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M. Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis. Pediatr Blood Cancer. 2017;65(4).
Barzaghi F, Minniti F, Mauro M, Bortoli M, Balter R, Bonetti E, et al. ALPS-like phenotype caused by ADA2 deficiency rescued by allogeneic hematopoietic stem cell transplantation. Front Immunol. 2018;9:2767.
pubmed: 30692987
Payne K, Li W, Salomon R, Ma CS. OMIP-063: 28-color flow cytometry panel for broad human immunophenotyping. Cytometry A. 2020;97(8):777–81.
pubmed: 32298042
Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J Allergy Clin Immunol. 2015;136(4):993-1006 e1.
pubmed: 26162572
pmcid: 5042203
Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–21.
pubmed: 21215658
pmcid: 3046815
Abeles RD, McPhail MJ, Sowter D, Antoniades CG, Vergis N, Vijay GK, et al. CD14, CD16 and HLA-DR reliably identifies human monocytes and their subsets in the context of pathologically reduced HLA-DR expression by CD14(hi) /CD16(neg) monocytes: Expansion of CD14(hi) /CD16(pos) and contraction of CD14(lo) /CD16(pos) monocytes in acute liver failure. Cytometry A. 2012;81(10):823–34.
pubmed: 22837127
Avery DT, Kane A, Nguyen T, Lau A, Nguyen A, Lenthall H, et al. Germline-activating mutations in PIK3CD compromise B cell development and function. J Exp Med. 2018;215(8):2073–95.
pubmed: 30018075
pmcid: 6080914
van Zelm MC, van der Burg M, de Ridder D, Barendregt BH, de Haas EF, Reinders MJ, et al. Ig gene rearrangement steps are initiated in early human precursor B cell subsets and correlate with specific transcription factor expression. J Immunol. 2005;175(9):5912–22.
pubmed: 16237084
Uckun FM. Regulation of human B-cell ontogeny. Blood. 1990;76(10):1908–23.
pubmed: 2242419
Ma CS, Wong N, Rao G, Nguyen A, Avery DT, Payne K, et al. Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets. J Exp Med. 2016;213(8):1589–608.
pubmed: 27401342
pmcid: 4986526
Avery DT, Deenick EK, Ma CS, Suryani S, Simpson N, Chew GY, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med. 2010;207(1):155–71.
pubmed: 20048285
pmcid: 2812540
Bier J, Rao G, Payne K, Brigden H, French E, Pelham SJ, et al. Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4(+) T cells. J Allergy Clin Immunol. 2019;144(1):236–53.
pubmed: 30738173
pmcid: 6612302
Schnappauf O, Sampaio Moura N, Aksentijevich I, Stoffels M, Ombrello AK, Hoffmann P, et al. Sequence-based screening of patients with idiopathic polyarteritis nodosa, granulomatosis with polyangiitis, and microscopic polyangiitis for deleterious genetic variants in ADA2. Arthritis Rheumatol. 2021;73(3):512–9.
pubmed: 33021335
Muraoka T, Katsuramaki T, Shiraishi H, Yokoyama MM. Automated enzymatic measurement of adenosine deaminase isoenzyme activities in serum. Anal Biochem. 1990;187(2):268–72.
pubmed: 2382828
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.
pubmed: 27514238
Rice GI, Melki I, Fremond ML, Briggs TA, Rodero MP, Kitabayashi N, et al. Assessment of type I interferon signaling in pediatric inflammatory disease. J Clin Immunol. 2017;37(2):123–32.
pubmed: 27943079
Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Moller R, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell. 2020;181(5):1036-45 e9.
pubmed: 32416070
pmcid: 7227586
Garcia-Prat M, Alvarez-Sierra D, Aguilo-Cucurull A, Salgado-Perandres S, Briongos-Sebastian S, Franco-Jarava C, et al. Extended immunophenotyping reference values in a healthy pediatric population. Cytometry B Clin Cytom. 2019;96(3):223–33.
pubmed: 30334372
Ma CS, Pittaluga S, Avery DT, Hare NJ, Maric I, Klion AD, et al. Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease. J Clin Investig. 2006;116(2):322–33.
pubmed: 16424938
pmcid: 1332028
Cuss AK, Avery DT, Cannons JL, Yu LJ, Nichols KE, Shaw PJ, et al. Expansion of functionally immature transitional B cells is associated with human-immunodeficient states characterized by impaired humoral immunity. J Immunol. 2006;176(3):1506–16.
pubmed: 16424179
Suryani S, Fulcher DA, Santner-Nanan B, Nanan R, Wong M, Shaw PJ, et al. Differential expression of CD21 identifies developmentally and functionally distinct subsets of human transitional B cells. Blood. 2010;115(3):519–29.
pubmed: 19965666
Moens L, Tangye SG. Cytokine-mediated regulation of plasma cell generation: IL-21 takes center stage. Front Immunol. 2014;5:65.
pubmed: 24600453
pmcid: 3927127
Aoki K, Shimada S, Simantini DS, Tun MM, Buerano CC, Morita K, et al. Type-I interferon response affects an inoculation dose-independent mortality in mice following Japanese encephalitis virus infection. Virol J. 2014;11:105.
pubmed: 24903089
pmcid: 4074870
Edwards ESJ, Bier J, Cole TS, Wong M, Hsu P, Berglund LJ, et al. Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. J Allergy Clin Immunol. 2019;143(1):276-91 e6.
pubmed: 29800648
Randall KL, Chan SS, Ma CS, Fung I, Mei Y, Yabas M, et al. DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice. J Exp Med. 2011;208(11):2305–20.
pubmed: 22006977
pmcid: 3201196
Ives ML, Ma CS, Palendira U, Chan A, Bustamante J, Boisson-Dupuis S, et al. Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function. J Allergy Clin Immunol. 2013;132(2):400-11 e9.
pubmed: 23830147
pmcid: 3785237
Bjorkstrom NK, Riese P, Heuts F, Andersson S, Fauriat C, Ivarsson MA, et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood. 2010;116(19):3853–64.
pubmed: 20696944
Della Chiesa M, Pesce S, Muccio L, Carlomagno S, Sivori S, Moretta A, et al. Features of memory-like and PD-1(+) human NK cell subsets. Front Immunol. 2016;7:351.
pubmed: 27683578
pmcid: 5021715
Meyts I, Aksentijevich I. Deficiency of adenosine deaminase 2 (DADA2): updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol. 2018;38(5):569–78.
pubmed: 29951947
pmcid: 6061100
Villar J, Segura E. The more, the merrier: DC3s join the human dendritic cell family. Immunity. 2020;53(2):233–5.
pubmed: 32814019
Rhodes JW, Tong O, Harman AN, Turville SG. Human dendritic cell subsets, ontogeny, and impact on HIV infection. Front Immunol. 2019;10:1088.
pubmed: 31156637
pmcid: 6532592
Skrabl-Baumgartner A, Plecko B, Schmidt WM, Konig N, Hershfield M, Gruber-Sedlmayr U, et al. Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation. Pediatr Rheumatol Online J. 2017;15(1):67.
pubmed: 28830446
pmcid: 5568374
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.
pubmed: 25278816
pmcid: 4181355
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.
pubmed: 27252897
pmcid: 4879337
Insalaco A, Moneta GM, Pardeo M, Caiello I, Messia V, Bracaglia C, et al. Variable clinical phenotypes and relation of interferon signature with disease activity in ADA2 deficiency. J Rheumatol. 2019;46(5):523–6.
pubmed: 30647181
Biesen R, Demir C, Barkhudarova F, Grun JR, Steinbrich-Zollner M, Backhaus M, et al. Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum. 2008;58(4):1136–45.
pubmed: 18383365
Van Eyck L, Hershfield MS, Pombal D, Kelly SJ, Ganson NJ, Moens L, Frans G, Schaballie H, De Hertogh G, Dooley J, Bossuyt X, Wouters C, Liston A, Meyts I. 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.
pubmed: 25457153
pmcid: 4282724
Cook MC, Korner H, Riminton DS, Lemckert FA, Hasbold J, Amesbury M, et al. Generation of splenic follicular structure and B cell movement in tumor necrosis factor-deficient mice. J Exp Med. 1998;188(8):1503–10.
pubmed: 9782127
pmcid: 2213402
Anolik JH, Ravikumar R, Barnard J, Owen T, Almudevar A, Milner EC, et al. Cutting edge: anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effects on lymphoid germinal centers and follicular dendritic cell networks. J Immunol. 2008;180(2):688–92.
pubmed: 18178805
Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood. 2003;101(7):2711–20.
pubmed: 12433688
Liu C, Emami SN, Pettersson J, Ranford-Cartwright L, Faye I, Parmryd I. Vgamma9Vdelta2 T cells proliferate in response to phosphoantigens released from erythrocytes infected with asexual and gametocyte stage Plasmodium falciparum. Cell Immunol. 2018;334:11–9.
pubmed: 30177348
Vavassori S, Kumar A, Wan GS, Ramanjaneyulu GS, Cavallari M, El Daker S, et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gammadelta T cells. Nat Immunol. 2013;14(9):908–16.
pubmed: 23872678
Liu J, Bian Z, Wang X, Xu LP, Fu Q, Wang C, et al. Inverse correlation of Vdelta2(+) T-cell recovery with EBV reactivation after haematopoietic stem cell transplantation. BJH. 2018;180(2):276–85.
pubmed: 29270985
De Rosa SC, Mitra DK, Watanabe N, Herzenberg LA, Herzenberg LA, Roederer M. Vdelta1 and Vdelta2 gammadelta T cells express distinct surface markers and might be developmentally distinct lineages. J Leukoc Biol. 2001;70(4):518–26.
pubmed: 11590187
Le Voyer T, Boutboul D, Ledoux-Pilon A, de Fontbrune FS, Boursier G, Latour S, et al. Late-Onset EBV Susceptibility and Refractory Pure Red Cell Aplasia Revealing DADA2. J Clin Immunol. 2020;40(6):948–53.
pubmed: 32643137
Staples E, Simeoni I, Stephens JC, Allen HL, BioResource N, Wright P, et al. ADA2 deficiency complicated by EBV-driven lymphoproliferative disease. Clin Immunol. 2020;215:108443.
pubmed: 32353633
pmcid: 7306156
Brooks JP, Rice AJ, Ji W, Lanahan SM, Konstantino M, Dara J, et al. Uncontrolled Epstein-Barr Virus as an atypical presentation of deficiency in ADA2 (DADA2). J Clin Immunol. 2021;41(3):680–3.
pubmed: 33394316
Cekic C, Linden J. Purinergic regulation of the immune system. Nat Rev Immunol. 2016;16(3):177–92.
pubmed: 26922909
Pillay BA, Avery DT, Smart JM, Cole T, Choo S, Chan D, et al. Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients. JCI Insight. 2019;5(11):e127527.
Pillay BA, Fusaro M, Gray PE, Statham AL, Burnett L, Bezrodnik L, et al. Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency. JCI. 2021;131(3).
Trotta L, Martelius T, Siitonen T, Hautala T, Hamalainen S, Juntti H, et al. ADA2 deficiency: Clonal lymphoproliferation in a subset of patients. The J Allergy clin Immunol. 2018;141(4):1534–7.
pubmed: 29391253
Saettini F, Fazio G, Corti P, Quadri M, Bugarin C, Gaipa G, et al. Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations. Clin Immunol. 2020;218:108525.
pubmed: 32659374
Belge KU, Dayyani F, Horelt A, Siedlar M, Frankenberger M, Frankenberger B, et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol. 2002;168(7):3536–42.
pubmed: 11907116
Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, et al. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010;116(16):e74-80.
pubmed: 20628149
Mukherjee R, Kanti Barman P, Kumar Thatoi P, Tripathy R, Kumar Das B, Ravindran B. Non-classical monocytes display inflammatory features: validation in sepsis and systemic lupus erythematous. Sci Rep. 2015;5:13886.
pubmed: 26358827
pmcid: 4566081
Perez-Zsolt D, Martinez-Picado J, Izquierdo-Useros N. When dendritic cells go viral: the role of Siglec-1 in host defense and dissemination of enveloped viruses. Viruses. 2019;12(1).
Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O’Neil LJ, Liu Y, et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood. 2019;134(4):395–406.
pubmed: 31015188
pmcid: 6659253
Watanabe N, Gao S, Wu Z, Batchu S, Kajigaya S, Diamond C, et al. Analysis of deficiency of adenosine deaminase 2 pathogenesis based on single-cell RNA sequencing of monocytes. J Leukoc Biol. 2021.
Ehlers L, Meyts I. What a difference ADA2 makes: Insights into the pathophysiology of ADA2 deficiency from single-cell RNA sequencing of monocytes. J Leukoc Biol. 2021.