Dominance of an alternative CLIP sequence in the celiac disease associated HLA-DQ2 molecule

Wiesner, Martina; Stepniak, Dariusz; Ru, Arnoud H. de; Moustakis, Antonis K.; Drijfhout, Jan W.; Papadopoulos, George K.; Veelen, Peter A. van; Koning, Frits

doi:10.1007/s00251-008-0310-6

Cited by 15 publications

(17 citation statements)

References 15 publications

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“…Our results demonstrate that CLIP2 associates with DQ molecules other than DQ2, including the T1D‐protective DQ6 and T1D‐neutral DQ1 molecules. It is also interesting to note that CLIP2 peptides were also present in samples from cells expressing DQ2+Ii+DM, consistent with prior findings indicating the CLIP2 register has a relatively high affinity for DQ2 .…”

Section: Resultssupporting

confidence: 87%

Type 1 diabetes associated HLA‐DQ2 and DQ8 molecules are relatively resistant to HLA‐DM mediated release of invariant chain‐derived CLIP peptides

et al. 2016

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Summary HLA-DM is essential for editing peptides bound to MHC class II, thus influencing the repertoire of peptides mediating selection and activation of CD4+ T cells. Individuals expressing HLA-DQ2 or DQ8, and DQ2/8 trans-dimers, have elevated risk for type 1 diabetes (T1D). Cells co-expressing DM with these DQ molecules were observed to express elevated levels of CLIP (Class II associated invariant chain peptide). Relative resistance to DM-mediated editing of CLIP was further confirmed by HPLC-MS/MS analysis of eluted peptides, which also demonstrated peptides from known T1D-associated autoantigens, including a shared epitope from ZnT8 that is presented by all four major T1D-susceptible DQ molecules. Assays with purified recombinant soluble proteins confirmed that DQ2-CLIP complexes are highly resistant to DM editing, whereas DQ8-CLIP is partially sensitive to DM, but with an apparent reduction in catalytic potency. DM sensitivity was enhanced in mutant DQ8 molecules with disruption of hydrogen bonds that stabilize DQ8 near the DM-binding region. Our findings show that T1D-susceptible DQ2 and DQ8 share significant resistance to DM editing, compared with control DQ molecules. The relative resistance of the T1D-susceptible DQ molecules to DM editing and preferential presentation of T1D-associated autoantigenic peptides may contribute to the pathogenesis of T1D.

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Section: Resultssupporting

confidence: 87%

Type 1 diabetes associated HLA‐DQ2 and DQ8 molecules are relatively resistant to HLA‐DM mediated release of invariant chain‐derived CLIP peptides

et al. 2016

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“…Most MHCII alleles bind CLIP in a single binding register (“CLIP1”), shown in the crystal structure of CLIP bound to DR3 and using Met91 (human Ii numbering) to occupy the P1 position of the groove (19). DQ2.5, however, is able to bind in a non-canonical “CLIP2” binding register, with Pro96 in P1 (78-79). In vitro , the rate of spontaneous CLIP release, in either register, from recombinant soluble DQ2.5 molecules is slower than CLIP release from DR3, and even slower than that of some gliadin peptides.…”

Section: Celiac Diseasementioning

confidence: 99%

On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

Busch

Riva

Hadjinicolaou

et al. 2012

Expert Rev. Mol. Med.

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This review discusses mechanisms that link allelic variants of MHC class II molecules (MHCII) to immune pathology. We focus on HLA-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (Ag7), in murine T1D. MHCII molecules bind peptides, and alleles vary in their peptide-binding specificity. Disease-associated alleles permit binding of disease-inducing peptides, such as gluten-derived, Glu-/Pro-rich gliadin peptides in CD and peptides from islet autoantigens, including insulin, in T1D. In addition, the CD-associated DQ2.5 and DQ8 alleles are unusual in their interactions with factors that regulate their peptide loading, invariant chain (Ii) and HLA-DM (DM). The same alleles, as well as other T1D DQ risk alleles (and Ag7) share nonpolar residues in place of Asp at β57 and prefer peptides that place acidic side chains in a pocket in the MHCII groove (P9). Antigen-presenting cells from T1D-susceptible mice and humans retain CLIP due to poor DM editing, although underlying mechanisms differ between species. We propose that these effects on peptide presentation make key contributions to CD and T1D pathogenesis.

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“…Recently, an alternative CLIP sequence was discovered with a twofold lower IC 50 for DQ2. 36 However, to be consistent and obtain comparable results, the original CLIP peptide has been used in the binding assays. Subsequently, 50 ml of the peptide sample was applied to the SPV-L3/HLA-DQ-coated wells.…”

Section: Cell-free Peptide-binding Assaysmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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Dominance of an alternative CLIP sequence in the celiac disease associated HLA-DQ2 molecule

Cited by 15 publications

References 15 publications

Type 1 diabetes associated HLA‐DQ2 and DQ8 molecules are relatively resistant to HLA‐DM mediated release of invariant chain‐derived CLIP peptides

Type 1 diabetes associated HLA‐DQ2 and DQ8 molecules are relatively resistant to HLA‐DM mediated release of invariant chain‐derived CLIP peptides

On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

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