Determination of the peptide binding motif and high-affinity ligands for HLA-DQ4 using synthetic peptide libraries

Volz, Thomas; Schwarz, Gerold; Fleckenstein, Burkhard; Schepp, Carsten P.; Haug, Markus; Roth, Johannes; Wiesmüller, Karl‐Heinz; Dannecker, Günther

doi:10.1016/j.humimm.2004.02.027

Cited by 9 publications

(12 citation statements)

References 30 publications

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“…This feature is also absent from the HLA-DQ4 peptide-binding motif. 29 An immortalized homozygous HLA-DR8 cell line carrying the T1D-associated HLA-DR8-DQ4 haplotype 6 was used for the analysis. There is little information about peptides binding DR8 and no concrete information about the peptide-binding motif.…”

Section: Discussionmentioning

confidence: 99%

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

et al. 2011

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The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1*0801-DQA1*0401/DQB1*0402 (DR8-DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-A g7 . Similar to HLA-DQ8 and H-2 I-A g7 , HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8-or I-A g7 ligands, and several diabetes-specific peptides associated with DQ8 or I-A g7 could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes.

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Section: Discussionmentioning

confidence: 99%

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

et al. 2011

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“…A technique involving synthetic peptide libraries has been used for the identification of a peptide-binding motif of HLA-DQ4 in juvenile idiopathic arthritis [34]. Furthermore, a differential peptide-binding motif for three juvenile arthritis-associated HLA-DQ molecules was deduced by a similar technique [35].…”

Section: Discussionmentioning

confidence: 99%

HLA-DR, -DQB Typing of Steroid-Sensitive Idiopathic Nephrotic Syndrome Children in Taiwan

Huang

Lin

et al. 2009

Nephron Clin Pract

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Background: The association between human leukocyte antigens (HLA) and idiopathic nephrotic syndrome (INS) in children has been discussed in various studies. Methods: In this study, 59 Chinese children with steroid-sensitive nephritic syndrome (SSNS) in Taiwan were enrolled, and 33 patients underwent renal biopsy. Results: The frequency of HLA-DR11 was found to be significantly higher and HLA-DR14 was lower in SSNS patients as compared with the healthy control group. In frequent relapsers, HLA-DR4 was more frequent, while HLA-DQB1*0602 was less frequent, as compared with infrequent relapsers. However, there was no significant difference between steroid-dependent and non-steroid-dependent patients. In patients who showed a response to levamisole, the HLA-DR9 and -DQB1*0303 alleles were more frequent, while HLA-DR13 was less frequent. In a comparison of HLA in different INS pathologies, HLA-DQB1*0401 was significantly frequent in IgM nephropathy. Even though we compared each group with the control group separately, the HLA distributions of both groups still differed from each other. Our data suggest that the immunogenic characteristics of children with SSNS in Taiwan are different from those of other populations. The common motif between different HLA alleles and the three-dimensional crystal structures may offer an explanation for the varying results from different populations. Conclusion: According to HLA typing, the results support the hypothesis that IgM nephropathy is a different entity from minimal change nephrotic syndrome.

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“…The amino acids within the antigenic peptide must interact with residues within the binding groove, and class II MHC molecules have a strong bias for amino acids presented at peptide positions P1, P4, P6, P7 and P9 from the N terminal anchor position [91,92]. By knowing the structure of the antigen binding groove, the ideal antigenic peptide to fit within the groove can be predicted [93][94][95][96].…”

Section: Autoantigen Selection and Presentationmentioning

confidence: 99%

Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

Czaja

2010

Dig Dis Sci

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Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block autoantigen expression, a dimeric recombinant human fusion protein of cytotoxic T lymphocyte antigen-4, monoclonal antibodies against tumor necrosis factor-alpha, recombinant interleukin 10, tolerization techniques for disease-triggering autoantigens, T regulatory cell transfer, vaccination against antigen-specific cytotoxic CD8+ T cells, and gene silencing methods using small inhibitory RNAs are feasible interventions to explore. Treatments directed at dampening immunocyte activation with soluble cytotoxic T lymphocyte antigen-4, inhibiting immunocyte differentiation with recombinant interleukin 10, and improving immunosuppressive activity with regulatory T cell modulation have the most immediate promise. Progress in the development of an animal model of autoimmune hepatitis and experiences in other immune-mediated diseases justify the evaluation of site-specific molecular and cellular interventions in this disease.

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Determination of the peptide binding motif and high-affinity ligands for HLA-DQ4 using synthetic peptide libraries

Cited by 9 publications

References 30 publications

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

HLA-DR, -DQB Typing of Steroid-Sensitive Idiopathic Nephrotic Syndrome Children in Taiwan

Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

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