Acta Diabetologica

, Volume 51, Issue 4, pp 577–585 | Cite as

Recognition of zinc transporter 8 and MAP3865c homologous epitopes by new-onset type 1 diabetes children from continental Italy

  • Speranza Masala
  • Davide Cossu
  • Simona Piccinini
  • Novella Rapini
  • Arianna Massimi
  • Ottavia Porzio
  • Silvia Pietrosanti
  • Roberta Lidano
  • Maria Luisa Manca Bitti
  • Leonardo Antonio SechiEmail author
Original Article


There are several pieces of evidence indicating that Mycobacterium avium subspecies paratuberculosis (MAP) infection is linked to type 1 diabetes (T1D) in Sardinian patients. An association between MAP and T1D was recently observed in an Italian cohort of pediatric T1D individuals, characterized by a different genetic background. It is interesting to confirm the prevalence of anti-MAP antibodies (Abs) in another pediatric population from continental Italy, looking at several markers of MAP presence. New-onset T1D children, compared to age-matched healthy controls (HCs), were tested by indirect enzyme-linked immunosorbent assay for the presence of Abs toward the immunodominant MAP3865c/ZnT8 homologues epitopes, the recently identified C-terminal MAP3865c281–287 epitope and MAP-specific protein MptD. Abs against MAP and ZnT8 epitopes were more prevalent in the sera of new-onset T1D children compared to HCs. These findings support the view that MAP3865c/ZnT8 cross-reactivity is involved in the pathogenesis of T1D, and addition of Abs against these peptides to the panel of existing T1D biomarkers should be considered. It is important now to investigate the timing of MAP infection during prospective follow-up in at-risk children to elucidate whether Ab-titers against these MAP/ZnT8 epitopes are present before T1D onset and if so if they wane after diagnosis.


Mycobacterium avium subsp. paratuberculosis New-onset type 1 diabetes Pediatrics Zinc transporter 8 



This research was supported by the Sardinian Region L.R.7 2009 and 2010 Progetti di ricerca di base, PRIN MIUR Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale < Bando PRIN 2009 > Protocollo: 2009ZYECWZ and Italian Minister of Health, “Finalized Research” Protocollo: RF-2009-1545765, to LAS. LAS is the guarantor. The present publication was produced as part of the RAS research Project Number 10 selection code 06/A3-10 developed at Sassari University by Speranza Masala and supported by P.O.R. Sardinia F.S.E. 2007–2013, Axis IV human capitals, Line of Business l.3.1.

Conflict of interest

No conflicts of interest related to the manuscript to declare.

Human and Animal Rights

All procedures followed were in accordance with the ethical standards of the institutional committee on human experimentation.

Informed Consent

Informed consent procedure does not apply as IHDR data are non identifiable.


  1. 1.
    La Torre D (2012) Immunobiology of beta-cell destruction. Adv Exp Med Biol 771:194–218PubMedGoogle Scholar
  2. 2.
    Banin P, Rimondi F, De Togni A, Cantoni S, Chiari G, Iughetti L, Salardi S, Zucchini S, Marsciani A, Suprani T, Tarchini L, Tozzola A, Xella R, Marsella M, De Sanctis V (2010) Type 1 diabetes (T1DM) in children and adolescents of immigrated families in Emilia-Romagna (Italy). Acta Biomed 81(1):35–39PubMedGoogle Scholar
  3. 3.
    Arvan P, Pietropaolo M, Ostrov D, Rhodes CJ (2012) Islet autoantigens: structure, function, localization, and regulation. Cold Spring Harb Perspect Med 2(8):1–20Google Scholar
  4. 4.
    Andersson C, Larsson K, Vaziri-Sani F, Lynch K, Carlsson A, Cedervall E, Jönsson B, Neiderud J, Månsson M, Nilsson A, Lernmark A, Elding Larsson H, Ivarsson SA (2011) The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes. Autoimmunity 44(5):394–405PubMedCrossRefGoogle Scholar
  5. 5.
    Masala S, Paccagnini D, Cossu D, Brezar V, Pacifico A, Ahmed N, Mallone R, Sechi LA (2011) Antibodies recognizing Mycobacterium avium paratuberculosis epitopes cross-react with the beta-cell antigen ZnT8 in Sardinian type 1 diabetic patients. PLoS ONE 6(10):e26931PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Masala S, Zedda MA, Cossu D, Ripoli C, Palermo M, Sechi LA (2013) Zinc transporter 8 and MAP3865c homologous epitopes are recognized at T1D onset in Sardinian children. PLoS ONE 8(5):e63371PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Masala S, Cossu D, Pacifico A, Molicotti P, Sechi LA (2012) Sardinian type 1 diabetes patients, Transthyretin and Mycobacterium avium subspecies paratuberculosis infection. Gut Pathog 274(1):24CrossRefGoogle Scholar
  8. 8.
    Cossu D, Masala S, Sechi LA (2013) A Sardinian map for multiple sclerosis. Future Microbiol 8:223–232PubMedCrossRefGoogle Scholar
  9. 9.
    Cossu D, Masala S, Cocco E, Paccagnini D, Frau J, Marrosu MG, Sechi LA (2012) Are Mycobacterium avium subsp. paratuberculosis and Epstein–Barr virus triggers of multiple sclerosis in Sardinia? Mult Scler 18(8):1181–1184PubMedCrossRefGoogle Scholar
  10. 10.
    Bitti ML, Masala S, Capasso F, Rapini N, Piccinini S, Angelini F, Pierantozzi A, Lidano R, Pietrosanti S, Paccagnini D, Sechi LA (2012) Mycobacterium avium subsp. paratuberculosis in an Italian cohort of type 1 diabetes pediatric patients. Clin Dev Immunol 2012:785262. doi: 10.1155/2012/785262
  11. 11.
    Sechi LA, Rosu V, Pacifico A, Fadda G, Ahmed N, Zanetti S (2008) Humoral immune responses of type 1 diabetes patients to Mycobacterium avium subsp. paratuberculosis lend support to the infectious trigger hypothesis. Clin Vaccine Immunol 15:320–326PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Lampasona V, Petrone A, Tiberti C, Capizzi M, Spoletini M, di Pietro S, Songini M, Bonicchio S, Giorgino F, Bonifacio E, Bosi E, Buzzetti R (2010) Non insulin requiring autoimmune diabetes (NIRAD) study group. Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4. Diabetes Care 33(1):104–108PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    American Diabetes Association (2011) Diagnosis and classification of diabetes mellitus. Diabetes Care 34(1):S62–S69PubMedCentralCrossRefGoogle Scholar
  14. 14.
    Cossu A, Rosu V, Paccagnini D, Cossu D, Pacifico A, Sechi LA (2011) MAP3738c and MptD are specific tags of Mycobacterium avium subsp. paratuberculosis infection in type I diabetes mellitus. Clin Immunol 141(1):49–57PubMedCrossRefGoogle Scholar
  15. 15.
    Capasso F, Rapini N, Di Matteo G, Testi M, Arcano S, Lidano R, Petrelli A, Rossi P, Piccinini S, Manca Bitti ML, Angelini F (2013) A variable degree of autoimmunity in the pedigree of a patient with type 1 diabetes homozygous for the PTPN22 1858T variant. Pediatr Diabetes 14(4):304–310PubMedCrossRefGoogle Scholar
  16. 16.
    Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci USA 104:17040–17045PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Wenzlau JM, Liu Y, Yu L, Moua O, Fowler KT, Rangasamy S, Walters J, Eisenbarth GS, Davidson HW, Hutton JC (2008) A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. Diabetes 57(10):2693–2697PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Vaziri-Sani F, Delli AJ, Elding-Larsson H, Lindblad B, Carlsson A, Forsander G, Ivarsson SA, Ludvigsson J, Marcus C, Lernmark Å (2011) A novel triple mix radiobinding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants in children with newly diagnosed diabetes. J Immunol Methods 371:25–37PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Paccagnini D, Sieswerda L, Rosu V, Masala S, Pacifico A, Gazouli M, Ikonomopoulos J, Ahmed N, Zanetti S, Sechi LA (2009) Linking chronic infection and autoimmune diseases: Mycobacterium avium subspecies paratuberculosis, SLC11A1 polymorphisms and type-1 diabetes mellitus. PLoS One 4(9):e7109PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Sechi LA, Paccagnini D, Salza S, Pacifico A, Ahmed N, Zanetti S (2008) Mycobacterium avium subspecies paratuberculosis bacteremia in type 1 diabetes mellitus: an infectious trigger? Clin Infect Dis 46:148–149PubMedCrossRefGoogle Scholar
  21. 21.
    Boitard C (2012) Pancreatic islet autoimmunity. Presse Med 41(2):e636–e650PubMedCrossRefGoogle Scholar
  22. 22.
    Sechi LA, Scanu AM, Molicotti P, Cannas S, Mura M, Dettori G, Fadda G, Zanetti S (2005) Detection and Isolation of Mycobacterium avium subspecies paratuberculosis from intestinal mucosal biopsies of patients with and without Crohn’s disease in Sardinia. Am J Gastroenterol 100(7):1529–1536PubMedCrossRefGoogle Scholar
  23. 23.
    Cossu D, Masala S, Cocco E, Paccagnini D, Tranquilli S, Frau J, Marrosu MG, Sechi LA (2013) Association of Mycobacterium avium subsp. paratuberculosis and SLC11A1 polymorphisms in Sardinian multiple sclerosis patients. J Infect Dev Ctries 7(3):203–207PubMedCrossRefGoogle Scholar
  24. 24.
    Frau J, Cossu D, Coghe G, Lorefice L, Fenu G, Melis M, Paccagnini D, Sardu C, Murru M, Tranquilli S, Marrosu M, Sechi L, Cocco E (2013) Mycobacterium avium subsp. paratuberculosis and multiple sclerosis in Sardinian patients: epidemiology and clinical features. Mult Scler 19(11):1432–1437CrossRefGoogle Scholar
  25. 25.
    Scotto M, Afonso G, Larger E, Raverdy C, Lemonnier FA, Carel JC, Dubois-Laforgue D, Baz B, Levy D, Gautier JF, Launay O, Bruno G, Boitard C, Sechi LA, Hutton JC, Davidson HW, Mallone R (2012) Zinc transporter (ZnT)8(186–194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients. Diabetologia 55(7):2026–2031PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2014

Authors and Affiliations

  • Speranza Masala
    • 1
  • Davide Cossu
    • 1
  • Simona Piccinini
    • 2
  • Novella Rapini
    • 2
  • Arianna Massimi
    • 3
  • Ottavia Porzio
    • 3
  • Silvia Pietrosanti
    • 2
  • Roberta Lidano
    • 2
  • Maria Luisa Manca Bitti
    • 2
  • Leonardo Antonio Sechi
    • 1
    Email author
  1. 1.Sezione di Microbiologia e Virologia, Dipartimento di Scienze BiomedicheUniversità degli Studi di SassariSassariItaly
  2. 2.Pediatric Diabetology Unit, Policlinico di Tor VergataUniversity of Rome Tor VergataRomeItaly
  3. 3.Department of Experimental Medicine and SurgeryUniversity of Rome Tor VergataRomeItaly

Personalised recommendations