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Diagnosis of gluten-induced autoimmune diseases

An autoimmune, gluten-based technology, applied in disease diagnosis, anti-enzyme immunoglobulin, measuring devices, etc., can solve the problem of not considering genes, deletions, etc.

Inactive Publication Date: 2012-12-19
UNIVERSITY OF DEBRECEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these studies did not take into account the three-dimensional structure of proteins that might be severely disrupted by total gene deletions, especially those affecting the core domain or the catalytic triad

Method used

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  • Diagnosis of gluten-induced autoimmune diseases
  • Diagnosis of gluten-induced autoimmune diseases
  • Diagnosis of gluten-induced autoimmune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0301] Example 1: Materials and methods

[0302] 1.1 Molecular Modeling

[0303] In human TG2 (PDB code: 1KV3)[ Liu S et al, Proc Natl Acad Sci U S A. 2002；99(5)：2743-7.]Residues 1-14, 44-45 and 123-132 are missing from the crystal structure, however, in the TG3 structure (PDB code: 1VJJ) [Ahvazi B et al., EMBO J. 2002; 21(9) :2055-67.], the corresponding region is visible and, therefore, used for modeling of full-length TG2. Homology models were constructed using the multiple template option of the Modeller [Sali A, Blundell TL, J Mol Biol. 1993;234(3):779-815.] program. Graphical analysis was performed on a Silicon Graphics Fuel workstation using the Sybyl program package (Tripos, St. Louis, MO), a study was performed to find amino acids that were located close enough to each other but belonged to different domains. In particular the interface of the core domain and the N-terminal (I) domain, and the interface of the core domain and the C-terminal (IV) domain were s...

Embodiment 2

[0359] Example 2: Pre-experiment for positioning celiac disease antigen epitope

[0360] Binding of celiac antibodies is associated with the calcium-binding site of TG2

[0361] In the detection of Ca2 + In the process of binding to human TG2, we found two negatively charged surface sheets on the core domain, which are adjacent to each other and can serve as Ca2 + binding site. Multiple mutations of acidic glutamic acid and aspartic acid residues to neutral glutamine and asparagine at position 4 (151DSEEERQE158 → 151NSQQQRQQ158) or position 5 (434DERED438 → 434NQRQN438), resulting in each TG Molecularly bound Ca 2+ The number of ions was reduced from 6 to 3, and was either largely (11.6±-8.5% bound by residues at site 4 compared to wild-type TG2) or moderately (11.6 ± -8.5% at site 5) in an enzyme-linked immunoassay (ELISA). , 51.3±16.0%) weakened the binding of celiac disease patient serum samples. These ELISA assays used serum samples taken from 62 celiac disease pa...

Embodiment 3

[0371] Example 3: Effect of mutations in putative celiac epitopes and associated surface regions

[0372] Based on preliminary results and computational analysis, within a large group of amino acids, six amino acids (R19, D151, E153, E154, E155, M659) were identified that are on or adjacent to the surface of TG2 associated with position 4, and are sufficiently close to each other that it is possible to form complex epitopes. These residues were changed either individually (single mutants) or together (double and triple mutants) by site-directed mutagenesis to serine, or in the case of acidic residues, to its neutral homologue.

[0373] We made the following point mutant TG2 molecules: E153S(E), R19S(R), M659S(M) or combinations of the respective mutations (D151N / E154Q / E155Q, RE, EM, RM, REM, E154K / R19S / M659S[RKM ]), and a large set of serial patient serum samples (n=76) were used to detect the protein. The relative amount of bound antibody can be calculated by comparison w...

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Abstract

The invention relates to selective diagnosis of gluten-induced autoimmune diseases by binding assays utilizing the main celiac epitope present on proteins of the transglutaminase family.

Description

field of invention [0001] The present invention relates to the selective diagnosis of gluten-induced autoimmune diseases by using binding assays for the main celiac epitope present on proteins of the transglutaminase family. Background technique [0002] Celiac disease (also known as celiac disease, nontropical sprue, or gluten-sensitive enteropathy) is a unique autoimmune disorder for which environmental triggers are known. The disorder occurs in genetically predisposed individuals with a human leukocyte antigen (HLA) DQ2 or DQ8 background and is characterized by chronic intestinal inflammation, malabsorption, and autoantibody production due to gluten ingestion. In addition to enteropathy, gluten can also cause itchy and blistering rashes, in which case the condition is called dermatitis herpetiformis. The disease can be successfully treated by removing gluten from the patient's diet, but for a sustained response the treatment should be followed for life. [0003] Ingesti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/573C07K16/40
CPCG01N2800/24G01N33/573
Inventor I·科尔波瑙伊-绍博L·费许什P·鲍戈斯E·彻斯R·基拉伊Z·西蒙-韦切伊M·马基
Owner UNIVERSITY OF DEBRECEN
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