PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 7903260

Major histocompatibility complex-encoded antigen processing gene polymorphism in IDDM.

P M van Endert·R S Liblau·S D Patel·L Fugger·T Lopez·F Pociot·J Nerup·H O McDevitt
View original source ↗Export metadata ↓

Abstract

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is greatly influenced by polymorphisms in the genes of the class II region of the human leukocyte antigen (HLA) complex. The complexity of this genetic association and the lack of a direct proof of involvement of HLA class II genes in human IDDM have continued to support speculation on a possible role of genes encoded in the close vicinity of these loci in IDDM. Because the recently discovered transporter associated with antigen processing (TAP) and large multifunctional protease (LMP) genes are encoded in the HLA class II region and are implicated in the processing of antigenic proteins for presentation by HLA class I molecules, they are additional candidates for a role in IDDM pathogenesis. We have analyzed genomic and coding sequence polymorphisms in the LMP2, TAP1, and TAP2 genes of 77 Danish IDDM patients and 102 control subjects. Although patients and control subjects did not differ in TAP1 and LMP2 alleles, we found a striking absence of the TAP2 allele B (long form) in IDDM patients. An analysis of the TAP2 alleles in individual DR types, however, revealed that this phenomenon is likely to be caused by linkage disequilibrium between the two loci. Thus, polymorphisms in the TAP and LMP genes are unlikely to be associated with IDDM.

Explore related subjects

ATP Binding Cassette Transporter, Subfamily B, Member 2ATP Binding Cassette Transporter, Subfamily B, Member 3ATP-Binding Cassette TransportersAdultAllelesAmino Acid SequenceBase SequenceCarrier ProteinsCodonCysteine EndopeptidasesDNA PrimersDNA ProbesDiabetes Mellitus, Type 1FemaleGenes, MHC Class IGenes, MHC Class IIHistocompatibility Antigens Class IIHumansMajor Histocompatibility ComplexMaleMolecular Sequence DataPolymerase Chain ReactionPolymorphism, Restriction Fragment LengthProteinsReference ValuesRestriction MappingJournal ArticleResearch Support, Non-U.S. Gov't

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

P M van Endert, R S Liblau, S D Patel, L Fugger, T Lopez, F Pociot, J Nerup, H O McDevitt. 1994. Major histocompatibility complex-encoded antigen processing gene polymorphism in IDDM.. https://doi.org/10.2337/diab.43.1.110

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed1997

Prominence of beta 2-microglobulin, class I heavy chain conformation, and tapasin in the interactions of class I heavy chain with calreticulin and the transporter associated with antigen processing.

Newly synthesized class I heavy (H) chain/beta 2m heterodimers awaiting peptides in the endoplasmic reticulum are associated with the transporter associated with Ag processing (TAP). We present evidence here that calreticulin, but not calnexin, displays steady state association with class I/TAP complexes. To separate the ability of beta 2m to bind with TAP and calreticulin from that of H chain, we studied human cell lines that lack expression of beta 2m or H chain. Little if any H chain was detected in association with TAP and calreticulin in the beta 2m- cell line Daudi. By contrast, high levels of beta 2m are found with TAP and calreticulin in the H chain-deficient cell line LCL 721.221, even after preclearance of the trace amount of class IB protein expressed by this cell line. Thus, beta 2m appears to bind TAP in the absence of H chain, providing an elegant mechanism to retain beta 2m in the endoplasmic reticulum at the site of peptide loading. To investigate whether other molecules participate in the binding of beta 2m and H chain to TAP and calreticulin, we analyzed the deletion mutant cell line LCL 721.220, which lacks tapasin. In 721.220, TAP and calreticulin are not associated with each other. Also, in these cells, H chain/beta 2m are not associated with TAP, but H chain and a low level of beta 2m are associated with calreticulin. These results suggest that tapasin is an obligatory mediator of the assemblage of calreticulin/H chain/beta 2m with TAP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Novel peptide-binding proteins and peptide transport in normal and TAP-deficient microsomes.

Most major histocompatibility complex (MHC) class I-binding peptides are translocated by TAP heterodimers, but some enter the ER lumen by alternative pathways. To further define mechanisms of peptide handling, we developed a system for the analysis of peptide-binding components in the ER membrane and lumen using iodinated cross-linkable peptide derivatives. Here we demonstrate that at least three proteins bind peptides in the ER lumen. Peptide cross-linking to these lumenal proteins can be used as an alternative method to monitor peptide transport. TAP and one other protein bind peptides on the cytoplasmic face of the ER. The presence of multiple peptide-binding proteins necessitates caution in interpreting traditional peptide-binding and transport assays. Finally, we demonstrate sequence-specific peptide transport in TAP-deficient cells transfected with only rat TAP1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Are transporter associated with antigen processing (TAP) and tapasin class I MHC chaperones?

Class I MHC heavy chains associate with many proteins in the endoplasmic reticulum, including TAP, calnexin, calreticulin, and the newly defined tapasin molecule. Recent studies have begun to resolve the nature of how these proteins interact with class I as well as the functional significance of each of these interactions. We propose here that TAP and tapasin are leading candidates to be highly specific chaperones for the class I molecule.

ATP Binding Cassette Transporter, Subfamily B, Mem↗