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Rare Immunodeficiency Unanticipated Adenosine Deaminase Deficiency: Unanticipated Benefits from the Study of a Rare Immunodeficiency This information is current as Michael R. Blackburn and Linda F. Thompson of October 4, 2021. J Immunol 2012; 188:933-935; ; doi: 10.4049/jimmunol.1103519 http://www.jimmunol.org/content/188/3/933 Downloaded from References This article cites 24 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/188/3/933.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 4, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Adenosine Deaminase Deficiency: Unanticipated Benefits from the Study of a Rare Immunodeficiency Michael R. Blackburn* and Linda F. Thompson† he serendipitous discovery of adenosine deaminase ciated gouty arthritis (2), but this pathway was not thought (ADA) deficiency in two patients with cellular im- to be important for the immune system. Giblett and col- T munodeficiency in 1972 by Dr. Eloise Giblett and leagues proposed that the two patients might have rare mutant colleagues (1) ushered in a new era in the investigation of the alleles for the ADA gene. Alternatively, it was speculated that molecular mechanisms underlying primary immunodeficiency they might have a short chromosomal deletion encompassing disorders. This finding led to the eventual development of the ADA gene and a nearby critical immune response gene. novel therapies not only for ADA deficiency but also for other In either case, Giblett et al. concluded the following: “Since Downloaded from immunodeficiency disorders and certain leukemias. ADA anenzymia and the inherited diseases of cellular im- In the early 1970s, several primary immunodeficiency dis- munity are extremely rare, their coexistence in two unrelated eases, including SCID, X-linked agammaglobulinemia, and patients seems very unlikely to be fortuitous.” Wiskott-Aldrich syndrome, were well known to pediatric im- Measurements of purine metabolites in the body fluids of munologists and presumed to be caused by single gene defects ADA-deficient patients showed elevated levels of adenosine based on patterns of inheritance. However, the gene defects (3), one of the two substrates for ADA. Investigators quickly http://www.jimmunol.org/ responsible for these devastating disorders were unknown. showed that adenosine could slow the growth of lymphoid In those days, the only “cure” for severe immunodeficiency cell lines and the mitogen-induced proliferation of primary diseases was bone marrow transplantation (BMT) from a his- lymphocytes (3). In 1975, Giblett and colleagues (4) reported tocompatible donor. In the case of one of two patients de- a patient with an isolated T cell immunodeficiency who scribed by Giblett et al., routine HLA typing of family lacked activity of purine nucleoside phosphorylase, an enzyme members failed to identify suitable donors. Thus, the patient’s situated between ADA and HPRT in the purine salvage path- physicians sent blood samples to Dr. Giblett at the King way, providing convincing evidence of the critical importance County Central Blood Bank. It was hoped that she could shed of normal purine metabolism for a functioning immune sys- light on the relationships among the family members of the tem. Although it was originally reported that ATP was ele- by guest on October 4, 2021 patient by examining isozyme patterns for the enzyme ADA. vated in the RBCs of ADA-deficient patients (5), more sen- Much to her surprise, starch gel electrophoresis indicated that sitive HPLC separation schemes in the laboratories of Drs. the RBCs of the patient were completely devoid of ADA Mary Sue Coleman and Amos Cohen (6, 7) revealed that 29- enzyme activity! The parents showed detectable, but reduced, deoxyadenosine 59-triphosphate (dATP) levels were elevated ADA activity, suggesting an autosomal recessive mode of in- as well. This finding confirmed an earlier speculation by Dr. heritance. Subsequently, a second patient with severe cellular Dennis Carson et al. (8) that deoxyadenosine, the other sub- immunodeficiency was studied and also found to be ADA strate of ADA, rather than adenosine, was the toxic metabolite deficient. These were completely unexpected findings, as no in this disease. Subsequent experimentation showed that precedent existed for ADA deficiency in humans or for ADA’s deoxyadenosine is converted first to 29-deoxyadenosine 59- role in either the development or the function of the immune monophosphate and finally to dATP by the high levels of system. deoxynucleoside kinases in the thymus. A likely pathogenic ADA is part of the purine salvage pathway that includes mechanism is dATP-triggered cytochrome c release from mi- the enzyme hypoxanthine-guanine phosphoribosyltransferase tochondria, which triggers an apoptotic cascade, leading (HPRT). Mutations in the HPRT gene were known to cause to failure of T cell development (9). Interestingly, an under- the neurologic disorder Lesch-Nyhan syndrome and its asso- standing of this pathway led to the development of novel and successful chemotherapeutic approaches for treating hairy cell leukemia (10). *Department of Biochemistry and Molecular Biology, The University of Texas Med- Both ADA and purine nucleoside phosphorylase are ex- ical School at Houston, Houston, TX 77030; and †Immunobiology and Cancer Pro- pressed in virtually every cell in the body and had been con- gram, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104 sidered “housekeeping” genes. Thus, an immediate question Address correspondence and reprint requests to Dr. Linda F. Thompson, Immunobi- ology and Cancer Program, Oklahoma Medical Research Foundation, 825 NE 13th was why the effects of ADA deficiency were focused upon the Street, Oklahoma City, OK 73104. E-mail address: [email protected] immune system. This question led to a systematic evaluation Abbreviations used in this article: ADA, adenosine deaminase; BMT, bone marrow of the expression of purine-metabolizing enzymes in various transplantation; dATP, 29-deoxyadenosine 59-triphosphate; HPRT, hypoxanthine-gua- human tissues and to the discovery that ADA was found at nine phosphoribosyltransferase; PEG, polyethylene glycol. very high levels in the thymus, suggesting that this organ had Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 evolved a mechanism to prevent the buildup of ADA sub- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1103519 934 PILLARS OF IMMUNOLOGY strates. ADA is needed because the high rate of cell death in during fetal development and became ADA deficient only af- the thymus following T cell selection events provides a source ter birth. Surprisingly, they had normal liver function, show- of DNA that is degraded to deoxyadenosine. This, coupled ing that ADA was needed in the liver during fetal develop- with high levels of deoxynucleoside kinases, explains why the ment, but not thereafter. Equally surprising, these mice died thymi of ADA-deficient patients accumulate such high levels of respiratory failure at z3 wk of age (20). However, they of dATP (8). could be maintained on PEG-ADA indefinitely. When ADA In addition to the normal supportive therapy given to was suboptimal, they developed immunodeficiency, as ex- patients with SCID, ADA-deficient patients were initially pected (21). These mice have proved useful for examining the treated with packed RBC transfusions as a sort of “enzyme- mechanisms of ADA-deficient SCID (9). In addition, owing replacement” therapy (5). Many patients showed significant to the accumulation of adenosine, these animals have served as improvement in immune function as a result, especially those a biological screen for disorders associated with aberrant aden- with residual ADA enzyme activity. The breakthrough in the osine receptor signaling (22). In the past 20 y, it has become treatment of these patients came with the development of increasingly apparent that adenosine regulates many impor- polyethylene glycol (PEG)-modified bovine ADA by the bio- tant aspects of physiology through binding to four distinct, technology company Enzon. PEG-ADA (Adagen) was the seven-transmembrane–spanning G protein-coupled adenosine first FDA-approved PEG-modified protein drug. Its use as a receptors (23). Although adenosine is usually immunosup- therapy for ADA-deficient patients was championed by Dr. pressive and anti-inflammatory, work in ADA-deficient mice Michael Hershfield at Duke (11). Many patients who do not helped uncover novel roles for adenosine in promoting the have suitable bone marrow donors have been able to lead rea- progression of chronic diseases, including asthma, chronic ob- Downloaded from sonably normal lives as a result of treatment with PEG-ADA. structive pulmonary disease, and pulmonary fibrosis (22).
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