Abstract |
Pancreatic duodenal homeobox 1 (Pdx1) protein is a key transcription factor involved in the regulation of insulin gene expression that is expressed at high levels in the beta-cells of the pancreatic islets. We asked whether Pdx1 is a target of anti-islet autoimmunity in type I diabetes (T1D). Pdx1 autoantibodies (PAAs) were detected in non-obese diabetic (NOD) mice using ELISA, western blotting, and radioimmunoprecipitation of [(35)S]-labeled insulinoma cell line-derived Pdx1 protein. PAAs were detected as early as at 5 weeks of age, and generally peaked before the onset of clinically overt diabetes in diabetes-prone female NOD mice. Levels declined substantially after the onset of diabetes. PAAs were not detected in the sera of NOD-scid, C57BL/6, or BALB/c mice. The titers of PAAs in NOD mouse sera were as high as 1/93 750 by ELISA. The fine specificity of PAAs was determined by western blotting using a series of truncated recombinant Pdx1 proteins. The immunodominant epitopes were located to the C-terminus of the Pdx1 (p200-283) in NOD mice. PAAs also were detected in sera from human T1D patients, but the major epitopes were localized to amino acids 159-200 as well as the same region (p200-283) recognized by PAAs from NOD mice. Using [(3)H] thymidine incorporation, the p83 fragment of Pdx1 specifically stimulated proliferation of splenic T cells from recent-onset diabetic NOD mice. The presence of PAAs in prediabetic NOD mice and human T1D patients, and Pdx1-specific T-cell proliferation in NOD mice provide a strong rationale for further investigation of the pathogenic role of immune responses against Pdx1 in T1D.
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Authors | Shi-Wu Li, Vijay Koya, Yi Li, William Donelan, Peng Lin, Westley H Reeves, Li-Jun Yang |
Journal | Laboratory investigation; a journal of technical methods and pathology
(Lab Invest)
Vol. 90
Issue 1
Pg. 31-9
(Jan 2010)
ISSN: 1530-0307 [Electronic] United States |
PMID | 19901909
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Autoantibodies
- Autoantigens
- Homeodomain Proteins
- Immunodominant Epitopes
- Mutant Proteins
- Peptide Fragments
- Recombinant Proteins
- Trans-Activators
- pancreatic and duodenal homeobox 1 protein
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Topics |
- Animals
- Antibody Specificity
- Autoantibodies
(blood, immunology)
- Autoantigens
(blood, immunology)
- Autoimmunity
- Cell Line, Tumor
- Cell Proliferation
- Diabetes Mellitus, Type 1
(blood, immunology, pathology)
- Female
- Homeodomain Proteins
(genetics, immunology, pharmacology)
- Humans
- Immunodominant Epitopes
(blood)
- Insulin-Secreting Cells
(immunology)
- Insulinoma
(immunology)
- Mice
- Mice, Congenic
- Mice, Inbred NOD
- Mice, Inbred Strains
- Mice, SCID
- Mutant Proteins
(pharmacology)
- Pancreatic Neoplasms
(immunology)
- Peptide Fragments
(immunology, pharmacology)
- Prediabetic State
(immunology)
- Rats
- Recombinant Proteins
(pharmacology)
- Spleen
(pathology)
- T-Lymphocytes
(pathology)
- Trans-Activators
(genetics, immunology, pharmacology)
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