The Importance of DR4Dw4 β Chain Residues 70, 71, and 86 in Peptide Binding and T Cell Recognition

Signorelli, Kathy; Watts, Lynnetta M.; Lambert, Laurie E.

doi:10.1006/cimm.1995.1072

Cited by 14 publications

(7 citation statements)

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“…Consistent with our T-cell allorecognition data, mutations at position 71 of HLA-DRP, corresponding to DP position 69 of HLA-DPP, completely abolish recognition by several DR-allospecific Tcell clones (18,19), as well as the DR-restricted recognition of a pertussis toxin peptide (42) and influenza hemagglutinin peptides (16).…”

Section: U Tsupporting

confidence: 88%

“…Using site-directed mutagenesis on HLA-DR molecules, studies by Signorelli et al (16) and Zeliszewski et al (17) evaluated the role of the DR7 and DRll 71 residues in peptide binding and antigenspecific T-cell recognition. They demonstrated that the change in charge at this position, despite being crucial for T-cell recognition, has relatively little impact on quantitative peptide binding.…”

Section: U Tmentioning

confidence: 99%

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HLA‐DPp residue 69 plays a crucial role in allorecognition

et al. 1998

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To investigate the contribution to allorecognition of the individual polymorphic positions Glu 69 and Val 36 from the DPB1*02012 allele, DPB1*02012 cDNA was subjected to site-directed mutagenesis and alleles expressing Lys at 69 and Ala at 36 were generated. The lymphoblastoid cell line (LCL) 45.EM1, a previously generated mutant B-LCL which expresses normal levels of DPA mRNA but is not able to transcribe DPB, was transfected with wild-type or mutant DPB1*02012 cDNAs. The ability of two HLA-DPw2 alloreactive CD4+ cytotoxic T-lymphocyte (CTL) clones to lyse the panel of DPB1*02012 wild-type and site-directed mutant B-cell lines was tested. Both CTL clones (8.3 and 8.9) lysed the B-LCL 45.1, which is haploid for HLA and expresses wild-type DPB1*02012, and transfectants expressing Ala at 36 instead of Val, indicating that this polymorphic residue is not critical for T-cell recognition. However, the change of Glu to Lys at 69 prevented recognition by clones 8.3 and 8.9. These data demonstrate that the residue at peptide-binding position 69 is crucial for T-cell receptor recognition and suggest the requirement for a negatively charged residue at this position for allostimulation of these T-cell clones. The side chain of DPbeta-69 is predicted to point into the peptide-binding groove, and the existence of positive(Lys) or negative (Glu) residues probably leads to substantial differences in the allo- or auto-DP-bound peptides or to differences in the conformation of the peptide-MHC complex, which would therefore be responsible for specific DPw2 allorecognition. The binding of a panel of monomorphic and polymorphic anti-HLA-DP monoclonal antibodies (mAbs) to these transfectants was also tested by flow cytometry. The changes at Glu 69 and Val 36 did not affect recognition by any of the monomorphic antibodies tested. However, the binding pattern of some of the polymorphic mAbs was clearly modified. Therefore, even though it is not crucial for T-cell allorecognition, polymorphic residue 36 must be involved in epitopes recognized by some polymorphic anti-DP antibodies, while residue 69 of the DPB molecule is crucial both for T-cell allorecognition and recognition by some mAbs.

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Section: U Tsupporting

confidence: 88%

Section: U Tmentioning

confidence: 99%

HLA‐DPp residue 69 plays a crucial role in allorecognition

et al. 1998

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“…Functional studies of DR and DQ molecules have suggested that residues β70 and β71 may be crucial contact points for T cell recognition of the HLA-peptide complex, and that residues β57 and β30 may also influence T cell activation. [85][86][87] "The unique combination of amino acid residues that characterises the antigen binding cleft of a particular HLA molecule will determine which T cell populations can respond to peptides presented by that molecule"…”

Section: T Cell Interactionmentioning

confidence: 99%

Molecular aspects of type 1 diabetes

Kelly

Ml²,

Mijovic³

et al. 2003

Molecular Pathology

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“…In the predicted three-dimensional structure of the HLA class II fl chain [27], the sequence NYGVV at position 82-86 is located in the vicinity of the sequence QRRAA at position 70-74. Signorelli et al [107] reported the importance of DR4Dw4 fi chain residues 70, 71 and 86 in peptide binding and T cell recognition. In Japanese patients, a particular amino acid sequence QRRAA located in the third hypervariable region of the DRfi -1 chain (HLA-DRB 1"0101, 0404 and 0405) showed a strong association with RA [108].…”

Section: Etiology and Pathogenesis Of Ramentioning

confidence: 99%

Rheumatoid arthritis and enteric bacteria

Aoki

1999

Japanese Journal of Rheumatology

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Factors in the etiopathogenesis of rheumatoid arthritis (RA) include the genetic background, environmental factors and perpetuation of the inflammatory process. This review focuses on enteric bacteria as initiating or perpetuating factors in the etiopathogenesis of RA. Based on the hypothesis that entrobacterial antigens that originated from intestinal flora induce rheumatoid inflammation in the joints, animal models of arthritis due to Enterobacteriaceae, studies on humoral and cellular responses to entrobacterial antigens in RA, etiology of RA involving both genetic and environmental factors, pathogenesis of rheumatoid inflammation accompanied by joint destruction, and clinical trials with basic therapeutic considerations are reviewed. The results of immunological studies on RA suggest that some patients with RA are sensitized to antigens common among Enterobacteriaceae (bacterial outer membrane proteins of 35 and 38 kDa). A bacterial outer membrane protein of 38 kDa was identified as OmpC having amino acid homology (NYGVV) with HLA-DR4. This OmpC peptide elicited peripheral blood T cell proliferative responses in patients with RA. The presentation of this enterobacterial peptide by the RA-associated DR motif to CD4 + T cells could lead to initiation of disease. We now consider that in some patients, RA may be based on autoimmunity from molecular mimicry by entrobacterial antigens of HLA-DR4.

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The Importance of DR4Dw4 β Chain Residues 70, 71, and 86 in Peptide Binding and T Cell Recognition

Cited by 14 publications

References 0 publications

HLA‐DPp residue 69 plays a crucial role in allorecognition

HLA‐DPp residue 69 plays a crucial role in allorecognition

Molecular aspects of type 1 diabetes

Rheumatoid arthritis and enteric bacteria

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