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Plasma Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust Ontogeny Across the First Four Months of Human Life

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Plasma Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust Ontogeny Across the First Four Months of Human Life Thomas Jefferson University Jefferson Digital Commons Department of Pathology, Anatomy, and Cell Department of Pathology, Anatomy, and Cell Biology Faculty Papers Biology 5-27-2021 Plasma Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust Ontogeny Across the First Four Months of Human Life. Oludare A. Odumade Alec L. Plotkin Jensen Pak Olubukola T. Idoko Matthew A. Pettengill See next page for additional authors Follow this and additional works at: https://jdc.jefferson.edu/pacbfp Part of the Pediatrics Commons Let us know how access to this document benefits ouy This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Pathology, Anatomy, and Cell Biology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. Authors Oludare A. Odumade, Alec L. Plotkin, Jensen Pak, Olubukola T. Idoko, Matthew A. Pettengill, Tobias R. Kollmann, Al Ozonoff, Beate Kampmann, Ofer Levy, and Kinga K. Smolen ORIGINAL RESEARCH published: 27 May 2021 doi: 10.3389/fimmu.2021.578700 Plasma Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust Ontogeny Across the First Four Months of Human Life † † Oludare A. Odumade 1,2,3* , Alec L. Plotkin 1 , Jensen Pak 1, Olubukola T. Idoko 1,4,5, Matthew A. Pettengill 1,6, Tobias R. Kollmann 7, Al Ozonoff 1,2, Beate Kampmann 4,5, Ofer Levy 1,2,8 and Kinga K. Smolen 1,2* on behalf of the EPIC Consortium 1 Precision Vaccines Program, Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, United States, 2 Department of Pediatrics, Harvard Medical School, Boston, MA, United States, 3 Division of Medicine Critical Care, Boston Edited by: Children’s Hospital, Boston, MA, United States, 4 Vaccines & Immunity Theme, Medical Research Council Unit The Gambia Per T. Sangild, at the London School of Hygiene and Tropical Medicine, Banjul, Gambia, 5 The Vaccine Centre, Faculty of Infectious and University of Copenhagen, Denmark Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom, 6 Department of Pathology, 7 Reviewed by: Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, United States, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia, 8 Broad Institute of MIT & Harvard, Cambridge, MA, United States Raghavan Chinnadurai, Mercer University, United States Jason Michael Springer, Background: Human adenosine deaminases (ADAs) modulate the immune response: University of Kansas Medical Center fl Research Institute, United States ADA1 via metabolizing adenosine, a purine metabolite that inhibits pro-in ammatory and *Correspondence: Th1 cytokine production, and the multi-functional ADA2, by enhancing T-cell proliferation Kinga K. Smolen and monocyte differentiation. Newborns are relatively deficient in ADA1 resulting in [email protected] elevated plasma adenosine concentrations and a Th2/anti-inflammatory bias compared Oludare A. Odumade [email protected] to adults. Despite the growing recognition of the role of ADAs in immune regulation, little is †These authors share first authorship known about the ontogeny of ADA concentrations. Methods: In a subgroup of the EPIC002-study, clinical data and plasma samples were Specialty section: This article was submitted to collected from 540 Gambian infants at four time-points: day of birth; first week of life; one Vaccines and Molecular month of age; and four months of age. Concentrations of total extracellular ADA, ADA1, Therapeutics, a section of the journal and ADA2 were measured by chromogenic assay and evaluated in relation to clinical data. Frontiers in Immunology Plasma cytokines/chemokine were measured across the first week of life and correlated Received: 01 July 2020 to ADA concentrations. Accepted: 11 May 2021 fi Published: 27 May 2021 Results: ADA2 demonstrated a steady rise across the rst months of life, while ADA1 Citation: concentration significantly decreased 0.79-fold across the first week then increased 1.4- Odumade OA, Plotkin AL, fold by four months of life. Males demonstrated significantly higher concentrations of Pak J, Idoko OT, Pettengill MA, ADA2 (1.1-fold) than females at four months; newborns with early-term (37 to <39 weeks) Kollmann TR, Ozonoff A, Kampmann B, Levy O and and late-term (≥41 weeks) gestational age demonstrated significantly higher ADA1 at birth Smolen KK (2021) Plasma (1.1-fold), and those born to mothers with advanced maternal age (≥35 years) had lower Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust plasma concentrations of ADA2 at one month (0.93-fold). Plasma ADA1 concentrations Ontogeny Across the First Four were positively correlated with plasma CXCL8 during the first week of life, while ADA2 Months of Human Life. concentrations correlated positively with TNF , IFN and CXCL10, and negatively with Front. Immunol. 12:578700. a g doi: 10.3389/fimmu.2021.578700 IL-6 and CXCL8. Frontiers in Immunology | www.frontiersin.org 1 May 2021 | Volume 12 | Article 578700 Odumade et al. Ontogeny of Adenosine Deaminases in Early Life Conclusions: The ratio of plasma ADA2/ADA1 concentration increased during the first week of life, after which both ADA1 and ADA2 increased across the first four months of life suggesting a gradual development of Th1/Th2 balanced immunity. Furthermore, ADA1 and ADA2 were positively correlated with cytokines/chemokines during the first week of life. Overall, ADA isoforms demonstrate robust ontogeny in newborns and infants but further mechanistic studies are needed to clarify their roles in early life immune development and the correlations with sex, gestational age, and maternal age that were observed. Keywords: adenosine, adenosine deaminase, ontogeny, sex differences, cytokines, chemokines, biomarkers INTRODUCTION and dendritic cells (DCs) (8, 9). Independent of its enzymatic activity, ADA2 modulates immunity via binding cognate receptors on Early life demonstrates unique immunologic challenges and immune cells (14, 26, 27). ADA2 also induces monocyte adaptations related to the transition from an intra-uterine differentiation to macrophages in T-cell co-cultures (14). ADA2- environment and progressive responses to extra-uterine deficient cells are unable to differentiate into M2/pro-resolution environmental cues (1). This dynamic landscape necessitates macrophages (24, 28, 29) suggesting that ADA2 directs age-dependent changes in cellular and soluble factors that shape differentiation of macrophages towards an anti-inflammatory immunity and that have yet to be fully characterized (1–7). Given phenotype. First described in 2014 (30, 31), ADA2 deficiency that infancy is the time of receipt of most vaccines coupled with (DADA2) presents with heterogeneous manifestations of which the heavy burden of early life infection, and a period of profound vascular inflammation is predominant (32–52). Patients with changes in the immune system, a better understanding of ADA2 deficiency and vasculitis often have missense mutations with immune ontogeny in human newborns is essential. at least 3% residual activity, whereas complete loss of function was Among the soluble immunoregulatory proteins of human associated with pure red cells aplasia and bone marrow failure (39). plasma are adenosine deaminases (ADAs) -1 and -2. ADA1 ADA2 binds to neutrophils, monocytes, NK cells, and B cells (27), (41kDa) is encoded by the ADA gene on chromosome 20q13.12 and patients with ADA2 deficiency can present with inflammatory (OMIM 608958 or Entrez Gene ID 100) and is produced by all cells conditions and altered distribution of immune cell subsets and (8, 9). While the intracellular role of ADA1 has been established, immunoglobulin levels (32, 35, 39–41, 47, 50, 51). Overall, ADA2 this enzyme also has extracellular roles (10–13), including formation is a protein of relevance to the human immune system whose by ADA1 (or ecto-ADA) of a ternary complex with CD26 and A2a expression in early life has been incompletely characterized. receptors bridging two different cells as a co-stimulatory molecule We have previously demonstrated that adenosine inhibits that impacts T-cell proliferation (14, 15). ADA1 converts adenosine, TLR-induced production of TNFa but not IL-6 and that pre- an endogenous purine metabolite that acts via leukocyte purine incubation of cord blood mononuclear cells with recombinant receptors to suppress pro-inflammatory and Th1-polarizing ADA1 (rADA1) enhances TLR-mediated TNFa production responses, to inosine, which is immunologically inert (16–19). (16). Moreover, in a small cohort (n = 4-12 per group), ADA1 also has roles in enhancing T-helper 2 (Th2) immunity newborns exhibit lower plasma concentrations of extracellular via adenosine receptors (20). ADA1 deficiency impairs thymocyte ADA1 compared to adults, resulting in elevated newborn plasma development and B-lymphocyte immunoglobulin production (21) adenosine concentrations and a Th2/anti-inflammatory bias (3, resulting in severe
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