Humoral autoimmunity against the extracellular domain of the neuroendocrine autoantigen IA-2 heightens the risk of type 1 diabetes.
The objective of this study was to determine whether antigenic determinants localized within the extracellular domain of the neuroendocrine autoantigen tyrosine phosphatase-like protein IA-2 are targets of humoral responses in type 1 diabetes (T1DM). Previous studies indicated that the immunodominant region of IA-2 is localized within its intracellular domain (IA-2ic; amino acids 601-979). We analyzed 333 subjects from the Children's Hospital of Pittsburgh study, 102 of whom progressed to insulin-requiring diabetes (prediabetics). Autoantibodies from these individuals were initially assayed for ICA512bdc (Barbara Davis Center amino acids 257-556; 630-979), IA-2ic (amino acids 601-979), and IA-2 full-length (amino acids 1-979) in addition to islet cell antibody (ICA), glutamic acid decarboxylase, 65-kDa isoform, and insulin autoantibodies. We identified an autoantibody response reactive with the extracellular domain of IA-2 that is associated with very high risk of T1DM progression. Relatives with no detectable autoantibodies against ICA512bdc (or IA-2ic) exhibited antibody responses against the IA-2 full-length peptide (log rank, P = 0.008). This effect was also observed in first-degree relatives who were positive for glutamic acid decarboxylase, 65-kDa isoform (log rank, P = 0.026) or at least two islet autoantibodies but were negative for ICA512bdc (log rank, P = 0.022). Competitive binding experiments and immunoprecipitation of the IA-2 extracellular domain (amino acid residues 26-577) further lend support for the presence of autoantibodies reactive with new antigenic determinants within the extracellular domain of IA-2. In summary, the addition of measurements of autoantibodies reactive with the IA-2 extracellular domain to assays geared to assess the progression of autoimmunity to clinical T1DM may more accurately characterize this risk. This has considerable implications not only for stratifying high diabetes risk but also facilitating the search for pathogenic epitopes to enable the design of peptide-based immunotherapies that may prevent the progression to overt T1DM at its preclinical stages.
Morran
Michael P
MP
Laboratory of Immunogenetics, The Brehm Center for Diabetes Research, 1000 Wall Street, Ann Arbor, Michigan 48105. maxtp@umich.edu.
Casu
Anna
A
Arena
Vincent C
VC
Pietropaolo
Susan
S
Zhang
Ying-Jian
YJ
Satin
Leslie S
LS
Nelson
Patrick
P
Omenn
Gilbert S
GS
Trucco
Massimo
M
Becker
Dorothy J
DJ
Pietropaolo
Massimo
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D047468:Immunoprecipitation; D007223:Infant; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
D001323:Autoantibodies; D001324:Autoantigens; C096322:ICA512 autoantibody; D011994:Recombinant Proteins
Diabetes. 1996 Jul;45(7):926-33
8666144
Ann N Y Acad Sci. 2008 Dec;1150:245-7
19120304
Clin Exp Immunol. 1980 Dec;42(3):463-9
7214741
Diabetes. 2008 May;57(5):1276-83
18332100
DNA Cell Biol. 1994 May;13(5):505-14
8024693
Am J Epidemiol. 1981 Sep;114(3):379-84
7304573
Diabetes. 1997 Jan;46(1):40-3
8971079
N Engl J Med. 1979 Feb 22;300(8):413-9
366414
Diabetes Care. 1985 Sep-Oct;8 Suppl 1:101-7
4053948
Nature. 1990 Sep 13;347(6289):151-6
1697648
Diabetologia. 2008 Aug;51(8):1444-8
18504544
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):674-9
18178618
Muscle Nerve. 2008 Apr;37(4):537-43
18061937
J Immunol. 1994 Mar 15;152(6):3183-8
8144912
Nat Cell Biol. 2006 May;8(5):435-45
16622421
Diabetes. 1996 Oct;45(10):1344-9
8826969
J Immunol. 2005 Dec 1;175(11):7755-62
16301686
J Clin Invest. 1999 Nov;104(10):1449-57
10562307
Math Biosci Eng. 2009 Oct;6(4):753-78
19835428
Transplant Proc. 1995 Dec;27(6):3377
8540003
Diabetes. 1982 Feb;31(2):136-44
6759229
J Autoimmun. 1998 Feb;11(1):1-10
9480718
Diabetes. 2004 Feb;53(2):384-92
14747289
J Biol Chem. 2008 Nov 28;283(48):33719-29
18824546
Diabetologia. 2002 Jan;45(1):66-76
11845225
Endocrinology. 2009 Feb;150(2):607-15
18818288
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8704-9
15939893
Immunol Ser. 1993;59:119-29
7681695
Lancet. 2001 Jul 21;358(9277):221-9
11476858
Pediatr Diabetes. 2005 Dec;6(4):184-92
16390386
Science. 1983 Dec 23;222(4630):1337-9
6362005
J Endocrinol. 2008 Mar;196(3):573-81
18310453
Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17040-5
17942684
J Clin Endocrinol Metab. 1997 Feb;82(2):375-80
9024221
J Biol Chem. 1996 Jul 26;271(30):18161-70
8663434
Diabetologia. 1983 Aug;25(2):82-5
6605267