A. r., Maurizi

A., Crino

A., Lauria

A., Palermo

Barchetta, Ilaria

Bizzarri, C.

Buzzetti, Raffaella

C., Guglielmi

C., Moretti

C., Suraci

C., Tubili

Cavallo, Maria Gisella

D., Benevento

D., Maggi

D., Pitocco

D., Tuccinardi

E., Astorri

E., Cipponeri

E., Di Stasio

E., Fioriti

E., Maddaloni

F., Costantino

G., Beretta Anguissola

G., Defeudis

G., Ghirlanda

G., Giannone

L., Cipolloni

L., Morviducci

L., Valente

Leslie, Dr

M. r., Cappa

M., Altomare

M., Capizzi

M., Cappa

M., Hawa

M., Khazrai Yeganeh

N., Napoli

N., Visalli

P., Patera

P., Pozzilli

R. m., Pinto

R., Portuesi

R., Schiaffini

R., Scrocca

R., Strollo

S., Fallucca

S., Kyanvash

S., Manfrini

S., Spera

Diabetes Care

C. Bizzarri

R. m. Pinto

D. Pitocco

E. Astorri

M. Cappa

M. Hawa

G. Giannone

A. Palermo

E. Maddaloni

Leslie Dr

P. Pozzilli

M. Altomare

BARCHETTA, ILARIA

D. Benevento

G. Beretta Anguissola

BUZZETTI, Raffaella

M. Capizzi

M. r. Cappa

CAVALLO, Maria Gisella

L. Cipolloni

E. Cipponeri

F. Costantino

A. Crino

G. Defeudis

E. Di Stasio

S. Fallucca

E. Fioriti

G. Ghirlanda

C. Guglielmi

M. Khazrai Yeganeh

S. Kyanvash

A. Lauria

D. Maggi

S. Manfrini

A. r. Maurizi

C. Moretti

L. Morviducci

N. Napoli

P. Patera

R. Portuesi

R. Schiaffini

R. Scrocca

S. Spera

R. Strollo

C. Suraci

C. Tubili

D. Tuccinardi

L. Valente

N. Visalli

Archivio della ricerca- Università di Roma La Sapienza

Diabetes-related autoantibodies in children with acute lymphoblastic leukemia

Bizzarri, C

Pinto, RM

Pitocco, D

Astorri, E

Cappa, M

Hawa, M

Giannone, G

Palermo, A

Maddaloni, E

Leslie, DRG

Pozzilli, P

Grp, IMDIAB

Queen Mary Research Online

Diabetes-related autoantibodies in children with acute lymphoblasticleukemia.Bizzarri, C; Pinto, RM; Pitocco, D; Astorri, E; Cappa, M; Hawa, M; Giannone, G; Palermo, A;Maddaloni, E; Leslie, DR; Pozzilli, P; IMDIAB Group     © 2012 by the American Diabetes AssociationCC-BY-NC-ND  For additional information about this publication click this link.http://qmro.qmul.ac.uk/xmlui/handle/123456789/19616   Information about this research object was correct at the time of download; we occasionallymake corrections to records, please therefore check the published record when citing. Formore information contact scholarlycommunications@qmul.ac.ukOBSERVATIONSDiabetes-RelatedAutoantibodies inChildrenWith AcuteLymphoblasticLeukemiaAcute lymphoblastic leukemia (ALL)is the most common subtype of leu-kemia in children. Although ALL andtype 1 diabetes appear to be biologicallyunrelated, there are common threads inboth epidemiology and etiology. Risingincidence rates of both ALL (1) and type 1diabetes (2) observed over recent decadesin many Western countries seem to sup-port common etiological factors (3).In the current study, we report ondiabetes-related autoantibodies (Abs) ina group of patients with ALL. Thirty-fourconsecutive children (19 males and 15 fe-males, mean age 6.2 6 4.6 years) were re-ferred to our institution in 2004 for newlydiagnosedALL. Patientswere tested for Absto islet and thyroid antigens. After the ini-tial investigation and treatment, 31/34(91%) patients (3 died in the mean time)were followedup for 6 years to evaluatethe evolution of the autoimmune markersand progression toward type 1 diabetes.Glutamic acid decarboxylase (GAD)Abs by direct radioligand assay (Centak,Medipan, Germany), insulin Abs (IAA) bya semiquantitative radioimmunoassay (AIA2100; DIAsource, Nivelles, Belgium), IA2Abs by a direct radioligand assay (Centak,Medipan, Germany), and thyroperoxidaseAbs (TPOAbs) by an ultrasensitive chemi-luminescent enzyme immunoassays byAdvia Centaur (Bayer HealthCare LLCDivi-sion, Tarrytown, NY) were measured twiceat diagnosis and after 6 years. Our labora-tory participated in the latest 2010 Diabe-tes Antibody Standardization Program.Seven children (20.5%) showed atleast one diabetes-related Ab; two chil-dren (5.9%) were found positive for allthree Abs (GAD, IAA, and IA2) with one ofthe two also showing TPOAbs positivity;isolated IAA positivity was found in ﬁve(14.7%) children. Autoantibodies retestedin the 31 surviving children 6 years laterwere found to be negative in all patients.Also, none of the children who were Absnegative at ALL diagnosis became Abs pos-itive at follow-up. No patient manifestedhyperglycemia during ALL therapy, andnone developed type 1 diabetes and/orautoimmune thyroiditis during follow-up.Finally, in Abs-positive ALL patientsHLA typewas not typical of type 1 diabetes,and indeed, only one patient showed amod-erate risk HLA genotype for type 1 diabetes.Our data suggest that the activation ofthe immune system against self-antigensin childhood ALL is nonspeciﬁc and self-limiting, even though chemotherapy maycontribute to suppress autoimmunity dur-ing follow-up. The dysregulation of the im-mune response in ALL is probably related tothe profound functional derangement of theimmune response during malignancy. Therelatively low Ab titer in ALL children sup-ports the hypothesis that the autoimmuneprocess in ALL is not an aggressive one.Genome-wide association studiesidentiﬁed an ALL susceptibility locusnear the IKZF1 gene (4). Recently, one ofthese single nucleotide polymorphisms(rs10272724) conferring susceptibility toALL was found to be protective againsttype 1 diabetes in a large population ofpatients of European ancestry (5). Verylikely genetic susceptibility to type 1 diabe-tes and ALL is regulated by distinct genes.In conclusion, the autoimmune humoralresponse may start in ALL children as aconsequence of the disease, but it shouldbe considered as an epiphenomenon re-lated to the general immune dysregulation.CARLA BIZZARRI, MD1RITA M. PINTO, MD2DARIO PITOCCO, MD3ELISA ASTORRI, MD, PHD4MARCO CAPPA, MD1MOHAMMED HAWA, MD4GERMANA GIANNONE, MD5ANDREA PALERMO, MD6ERNESTO MADDALONI, MD6DAVID R.G. LESLIE, MD4PAOLO POZZILLI, MD4,6ON BEHALF OF THE IMDIAB GROUP*From the 1Department of Endocrinology and Di-abetes, Bambino Gesù Children’s Hospital, Rome,Italy; the 2Department of Hematology and On-cology, Bambino Gesù Children’s Hospital,Rome, Italy; the 3Department of Diabetology,Catholic University, Rome, Italy; the 4Centre ofDiabetes, St. Bartholomews & The LondonSchool of Medicine, Queen Mary, Universityof London, London, U.K.; the 5Department ofChemistry, Bambino Gesù Children’s Hospital,Rome, Italy; and the 6Department of Endocri-nology and Diabetes, University Campus Bio-Medico, Rome, Italy.Corresponding author: Paolo Pozzilli, p.pozzilli@unicampus.it.DOI: 10.2337/dc11-1946*A complete list of the members of the IMDIABStudy Group can be found in the APPENDIX.© 2012 by the American Diabetes Association. Readersmay use this article as long as the work is properlycited, the use is educational and not for proﬁt, andthe work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.Acknowledgments—No potential conﬂicts ofinterest relevant to this article were reported.C.B. and R.M.P. performed research, analyzeddata, and wrote the manuscript. D.P., E.A., M.H.,and G.G. performed research and contributed tothe manuscript. M.C. analyzed data and criticallyrevised themanuscript. A.P. andE.M. contributedto the discussion and critically reviewed the man-uscript. D.R.G.L. and P.P. designed research, ana-lyzed data, and critically reviewed and edited themanuscript.All authors approved theﬁnal versionof the manuscript. C.B. is the guarantor of thiswork and, as such, had full access to all the data inthe study and takes responsibility for the integrityof the data and the accuracy of the data analysis.APPENDIX—Members of the IMDIABGroup: Altomare M, Astorri E, Barchetta I,Benevento D, Beretta Anguissola G, BizzarriC, Buzzetti R, Capizzi M, Cappa M, CassoneFaldetta M.R., Cavallo M.G., Cipolloni L,Cipponeri E, Costantino F, Crinò A,Defeudis G, Di Stasio E, Fallucca S, Fioriti E,Ghirlanda G, Guglielmi C, KhazraiYeganeh M, Kyanvash S, Lauria A,Maddaloni E, Maggi D,Manfrini S, MauriziA.R., Moretti C, Morviducci L, Napoli N,Palermo A, Patera P, Pitocco D, Portuesi R,Pozzilli P, Schiafﬁni R, Scrocca R, Spera S,Strollo R, Suraci C, Tubili C, Tuccinardi D,Valente L, and Visalli N.c c c c c c c c c c c c c c c c c c c c c c c cReferences1. Pui CH. Recent advances in acute lympho-blastic leukemia. Oncology (WillistonPark) 2011;25:341, 346–3472. Patterson CC, Dahlquist GG, Gyürüs E,Green A, Soltész G; EURODIAB StudyGroup. Incidence trends for childhoodtype 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20:a multicentre prospective registrationstudy. Lancet 2009;373:2027–20333. Feltbower RG, McKinney PA, Greaves MF,Parslow RC, Bodansky HJ. Internationalparallels in leukaemia and diabetes epide-miology. Arch Dis Child 2004;89:54–564. Papaemmanuil E, Hosking FJ, VijayakrishnanJ, et al. Loci on 7p12.2, 10q21.2 and14q11.2are associated with risk of childhood acutelymphoblastic leukemia.NatGenet 2009;41:1006–10105. Swafford AD, Howson JM, Davison LJ, et al.An allele of IKZF1 (Ikaros) conferring sus-ceptibility to childhood acute lymphoblas-tic leukemia protects against type 1 diabetes.Diabetes 2011;60:1041–1044care.diabetesjournals.org DIABETES CARE, VOLUME 35, MARCH 2012 e23O N L I N E L E T T E R S

Diabetes-Related Autoantibodies in Children With Acute Lymphoblastic Leukemia

Carla Bizzarri

Rita M. Pinto

Dario Pitocco

Elisa Astorri

Marco Cappa

Mohammed Hawa

Germana Giannone

Andrea Palermo

Ernesto Maddaloni

David R.G. Leslie

Paolo Pozzilli

null null

Crossref

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/19616/Bizzarri%20Diabetes-related%20autoantibodies%20in%20children%20with%20acute%20lymphoblastic%20leukemia%202012%20Published.pdf?sequence=1

Diabetes-Related Autoantibodies in Children With Acute Lymphoblastic Leukemia

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