Analysis of Pancreas Tissue in a Child Positive for Islet Cell Antibodies

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2008 Aug 13

PMID 18696046

Citations 42

Authors

M Oikarinen

S Tauriainen

T Honkanen

K Vuori

P Karhunen

C Vasama-Nolvi

S Oikarinen

C Verbeke

G E Blair

I Rantala

J Ilonen

O Simell

M Knip

H Hyoty

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: Type 1 diabetes is caused by an immune-mediated process, reflected by the appearance of autoantibodies against pancreatic islets in the peripheral circulation. Detection of multiple autoantibodies predicts the development of diabetes, while positivity for a single autoantibody is a poor prognostic marker. The present study assesses whether positivity for a single autoantibody correlates with pathological changes in the pancreas.

Methods: We studied post mortem pancreatic tissue of a child who repeatedly tested positive for islet cell antibodies (ICA) in serial measurements. Paraffin sections were stained with antibodies specific for insulin, glucagon, somatostatin, interferon alpha, CD3, CD68, cyclooxygenase-2 (COX-2), beta-2-microglobulin, coxsackie B and adenovirus receptor (CAR), natural killer and dendritic cells. Apoptosis was detected using Fas-specific antibody and TUNEL assay. Enterovirus was searched for using immunohistochemistry and in situ hybridisation, as well as enterovirus-specific RT-PCR from serum samples.

Results: The structure of the pancreas did not differ from normal. The number of beta cells was not reduced and no signs of insulitis were observed. Beta-2-microglobulin and CAR were strongly produced in the islets, but not in the exocrine pancreas. Enterovirus protein was detected selectively in the islets by two enterovirus-specific antibodies, but viral RNA was not found.

Conclusions/interpretation: These observations suggest that positivity for ICA alone, even when lasting for more than 1 year, is not associated with inflammatory changes in the islets. However, it is most likely that the pancreatic islets were infected by an enterovirus in this child.

Citing Articles

Charting Peptide Shared Sequences Between 'Diabetes-Viruses' and Human Pancreatic Proteins, Their Structural and Autoimmune Implications.

James S, Joshua I Bioinform Biol Insights. 2024; 18:11779322241289936.

PMID: 39502449 PMC: 11536397. DOI: 10.1177/11779322241289936.

Viral Protein VP1 Virus-like Particles (VLP) of CVB4 Induces Protective Immunity against Lethal Challenges with Diabetogenic E2 and Wild Type JBV Strains in Mice Model.

Gharbi J, Hadj Hassine I, Hassine M, Al-Malki M, Al-Yami A, Al-Bachir A Viruses. 2023; 15(4).

PMID: 37112858 PMC: 10145976. DOI: 10.3390/v15040878.

Persistent coxsackievirus B infection and pathogenesis of type 1 diabetes mellitus.

Nekoua M, Alidjinou E, Hober D Nat Rev Endocrinol. 2022; 18(8):503-516.

PMID: 35650334 PMC: 9157043. DOI: 10.1038/s41574-022-00688-1.

Primary Site of Coxsackievirus B Replication in the Small Intestines: No Proof of Peyer's Patches Involvement.

Bopegamage S, Berakova K, Gomocak P, Baksova R, Galama J, Hyoty H Microorganisms. 2021; 9(12).

PMID: 34946201 PMC: 8709031. DOI: 10.3390/microorganisms9122600.

Insulitis in the pancreas of non-diabetic organ donors under age 25 years with multiple circulating autoantibodies against islet cell antigens.

Smeets S, De Paep D, Stange G, Verhaeghen K, Van der Auwera B, Keymeulen B Virchows Arch. 2021; 479(2):295-304.

PMID: 33594586 PMC: 8364522. DOI: 10.1007/s00428-021-03055-z.

References

Sayama K, Imagawa A, Okita K, Uno S, Moriwaki M, Kozawa J . Pancreatic beta and alpha cells are both decreased in patients with fulminant type 1 diabetes: a morphometrical assessment. Diabetologia. 2005; 48(8):1560-4. DOI: 10.1007/s00125-005-1829-9. View

Kukko M, Kimpimaki T, Korhonen S, Kupila A, Simell S, Veijola R . Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population. J Clin Endocrinol Metab. 2005; 90(5):2712-7. DOI: 10.1210/jc.2004-1371. View

Mrena S, Savola K, Kulmala P, Akerblom H, Knip M . Natural course of preclinical type 1 diabetes in siblings of affected children. Acta Paediatr. 2004; 92(12):1403-10. DOI: 10.1111/j.1651-2227.2003.tb00823.x. View

Bottazzo G, Florin-Christensen A, Doniach D . Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974; 2(7892):1279-83. DOI: 10.1016/s0140-6736(74)90140-8. View

Foulis A, McGill M, Farquharson M, Hilton D . A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM. Diabetologia. 1997; 40(1):53-61. DOI: 10.1007/s001250050642. View

Int Veld P, Lievens D, De Grijse J, Ling Z, Van der Auwera B, Pipeleers-Marichal M . Screening for insulitis in adult autoantibody-positive organ donors. Diabetes. 2007; 56(9):2400-4. DOI: 10.2337/db07-0416. View

Yousef G, BROWN I, Mowbray J . Derivation and biochemical characterization of an enterovirus group-specific monoclonal antibody. Intervirology. 1987; 28(3):163-70. DOI: 10.1159/000150012. View

McDonald D, Stockwin L, Matzow T, Blair Zajdel M, Blair G . Coxsackie and adenovirus receptor (CAR)-dependent and major histocompatibility complex (MHC) class I-independent uptake of recombinant adenoviruses into human tumour cells. Gene Ther. 1999; 6(9):1512-9. DOI: 10.1038/sj.gt.3301006. View

Bourlet T, Gharbi J, Omar S, Aouni M, Pozzetto B . Comparison of a rapid culture method combining an immunoperoxidase test and a group specific anti-VP1 monoclonal antibody with conventional virus isolation techniques for routine detection of enteroviruses in stools. J Med Virol. 1998; 54(3):204-9. DOI: 10.1002/(sici)1096-9071(199803)54:3<204::aid-jmv11>3.0.co;2-h. View

10.

Lernmark A, Molenaar J, van Beers W, Yamaguchi Y, Nagataki S, Ludvigsson J . The Fourth International Serum Exchange Workshop to standardize cytoplasmic islet cell antibodies. The Immunology and Diabetes Workshops and Participating Laboratories. Diabetologia. 1991; 34(7):534-5. DOI: 10.1007/BF00403293. View

11.

Yoon J, Austin M, Onodera T, Notkins A . Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med. 1979; 300(21):1173-9. DOI: 10.1056/NEJM197905243002102. View

12.

Dotta F, Censini S, van Halteren A, Marselli L, Masini M, Dionisi S . Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A. 2007; 104(12):5115-20. PMC: 1829272. DOI: 10.1073/pnas.0700442104. View

13.

Hyoty H . Enterovirus infections and type 1 diabetes. Ann Med. 2002; 34(3):138-47. View

14.

Conaldi P, Serra C, Mossa A, Falcone V, Basolo F, Camussi G . Persistent infection of human vascular endothelial cells by group B coxsackieviruses. J Infect Dis. 1997; 175(3):693-6. DOI: 10.1093/infdis/175.3.693. View

15.

Ylipaasto P, Klingel K, Lindberg A, Otonkoski T, Kandolf R, Hovi T . Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia. 2004; 47(2):225-39. DOI: 10.1007/s00125-003-1297-z. View

16.

Harkonen T, Puolakkainen M, Sarvas M, Airaksinen U, Hovi T, Roivainen M . Picornavirus proteins share antigenic determinants with heat shock proteins 60/65. J Med Virol. 2000; 62(3):383-91. DOI: 10.1002/1096-9071(200011)62:3<383::aid-jmv11>3.0.co;2-#. View

17.

Mena I, Fischer C, Gebhard J, Perry C, Harkins S, Whitton J . Coxsackievirus infection of the pancreas: evaluation of receptor expression, pathogenesis, and immunopathology. Virology. 2000; 271(2):276-88. DOI: 10.1006/viro.2000.0332. View

18.

Meier J, Butler A, Saisho Y, Monchamp T, Galasso R, Bhushan A . Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes. 2008; 57(6):1584-94. PMC: 3697779. DOI: 10.2337/db07-1369. View

19.

Lonnrot M, Sjoroos M, Salminen K, Maaronen M, Hyypia T, Hyoty H . Diagnosis of enterovirus and rhinovirus infections by RT-PCR and time-resolved fluorometry with lanthanide chelate labeled probes. J Med Virol. 1999; 59(3):378-84. View

20.

Oikarinen M, Tauriainen S, Honkanen T, Oikarinen S, Vuori K, Kaukinen K . Detection of enteroviruses in the intestine of type 1 diabetic patients. Clin Exp Immunol. 2007; 151(1):71-5. PMC: 2276929. DOI: 10.1111/j.1365-2249.2007.03529.x. View