Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The related tyrosine phosphatase-like proteins islet Ag (IA)-2 and IA-2beta are autoantigens of type 1 diabetes in humans. Autoantibodies are predominantly against IA-2, and IA-2-specific epitopes are major autoantibody targets. We used the close homology of IA-2 and IA-2beta to design chimeras and mutants to identify humoral IA-2-specific epitopes. Two major IA-2 epitopes that are absent from the related autoantigens IA-2beta and IA-2Delta 13 splice variant ICA512.bdc were found contiguous to each other within IA-2 juxtamembrane amino acids 611-620 (epitope JM1) and 621-630 (epitope JM2). JM1 and JM2 are recognized by sera from 67% of patients with IA-2 Abs, and relatives of patients with type 1 diabetes having Abs to either JM epitope had a >50% risk for developing type 1 diabetes within 6 years, even in the absence of diabetes-associated HLA genotypes. Remarkably, the presence of Abs to one of these two epitopes was mutually exclusive of the other; JM2 Abs and not JM1 Abs were found in relatives with HLA DR3/4, DR4/13, or DR1/4 genotypes; and the binding of autoantibodies to the JM2 epitope, but not the JM1 epitope, markedly affected proteolysis of IA-2. This is a unique demonstration of HLA-associated B cell responses to epitopes within a single autoantigen in humans and is consistent with modification of Ag processing by specific Ab-influencing peptide presentation by HLA molecules.
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PMID:Two distinctly HLA-associated contiguous linear epitopes uniquely expressed within the islet antigen 2 molecule are major autoantibody epitopes of the diabetes-specific tyrosine phosphatase-like protein autoantigens. 1193 81

IA-2 and IA-2beta are highly related proteins that are autoantigens in type 1 diabetes, and provide a model for developing reagents and assays that distinguish similar proteins with unique autoantibody epitopes. Monoclonal antibodies (mAb) to IA-2 and IA-2beta were prepared and tested for their ability to bind to the related proteins and their ability to compete for specific autoantibody epitope binding by sera from patients with type 1 diabetes. Monoclonal antibodies that specifically bound IA-2 (76F) or bound both IA-2 and IA-2beta (A9) were isolated and characterized. 76F mAb recognized IA-2 of human, rat and mouse origin in native and denatured forms and had an epitope specificity for residues 626-630 (FEYQD) which are found in the juxtamembrane (JM) region of human and mouse IA-2, but not IA-2beta. This region overlaps with the autoantibody epitope JM2. Binding to the 76F monoclonal antibody was specifically inhibited by sera with antibodies to the JM2 epitope but not with antibodies to the adjacent JM1 epitope, indicating that unique epitopes can be distinguished by this approach. 76F mAb has the unique property to distinguish between the two closely related autoantigens IA-2 and IA-2beta by targeting an IA-2 specific epitope of the juxtamembrane region. The findings define an approach to develop assays for specific antibody epitope measurements which may be relevant for disease prognosis and monitoring intervention therapies.
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PMID:Monoclonal antibody 76F distinguishes IA-2 from IA-2beta and overlaps an autoantibody epitope. 1650 16

Autoantibodies, a hallmark of autoimmune disease, are directed against diverse antigens and epitopes. This diversity aids in characterising disease progression and identifying disease-associated autoantibodies. Here we aimed to develop a sensitive assay to detect and quantify epitope-specific autoantibodies. We generated constructs to integrate known peptide epitopes into the TrxA protein, and used these to in vitro synthesize radio-labelled proteins for a radiobinding assay (RBA). This assay was first validated with an animal model using mice immunized with the MOG(40-55) peptide. Using type 1 diabetes-associated protein tyrosine phosphatase-like autoantigen IA-2 as a human model, we expressed IA-2(609-621), IA-2(619-631), or IA-2(609-631) peptide in the TrxA construct and used the RBA to test sera from 113 patients with type 1 diabetes and 87 controls. Antibodies were detected to the IA-2(609-631) epitope in 37 of 113 patient sera and one control; 17 sera were reactive to the IA-2(609-621) (JM1) epitope, and 16 to the IA-2(619-631) (JM2) epitope. Interestingly, a novel third epitope (JM3) was identified in 7 sera that reacted to IA-2(609-631) but not the JM1 and JM2 sub-specificities. An ELISA using IA-2(609-631) was less sensitive than the RBA, as it detected only some of the JM1 and JM3 antibody positive sera and none of the JM2. Mutagenesis of single IA-2(609-631) amino acids in combination with the RBA showed that antibodies to JM2 and JM3 were highly diverse in their specific residue requirements. Our strategy using in vitro synthesized antigens and the RBA was thus a highly sensitive and versatile method to identify epitopes and quantify epitope-specific antibodies.
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PMID:Radiobinding assay for detecting autoantibodies to single epitopes. 1850 77