Impact of Peptides on the Recognition of HLA Class I Molecules by Human HLA Antibodies

Mulder, Arend; Eijsink, Chantal; Kester, Michel G.D.; Franke, Marry E.I.; Kardol, M. J.; Heemskerk, Mirjam H.M.; Kooten, Cees van; Verreck, Frank A. W.; Drijfhout, Jan W.; Koning, Frits; Doxiadis, Ilias I.N.; Claas, Frans H.J.

doi:10.4049/jimmunol.175.9.5950

Cited by 46 publications

(24 citation statements)

References 28 publications

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“…In contrast the allo-determinants recognized by anti-Class I monoclonal antibodies have mapped predominantly to the polymorphic first and/or second external domains of the MHC Class I molecule (14, 38, 39). While alloantibodies and the corresponding BCR can discriminate between peptide-MHC Class I complexes (40, 41) the contribution of the peptide to the ability of the antibody to bind to the peptide Class I complex is relatively subtle. In these studies we used K d tetramers bound to the Plasmodium berghei circumsporozoite peptide 252-260 (SYIPSAEKI) as a proof of principle of the technique; however, it remains to be confirmed experimentally whether and to what degree K d tetramers bound to self-peptides would alter the absolute numbers of K d –specific B cells identified.…”

Section: Discussionmentioning

confidence: 99%

Reversing Endogenous Alloreactive B Cell GC Responses With Anti-CD154 or CTLA-4Ig

Chen

Yin

et al. 2013

American Journal of Transplantation

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Alloantibodies mediate acute antibody-mediated rejection as well as chronic allograft rejection in clinical transplantation. To better understand the cellular dynamics driving antibody production, we focused on the activation and differentiation of alloreactive B cells in the draining lymph nodes and spleen following sensitization to allogeneic cells or hearts. We used a modified staining approach with a single MHC Class I tetramer (Kd) bound to two different fluorochromes to discriminate between the Class I-binding and fluorochrome-streptavidin-binding B cells with a high degree of specificity and binding efficiency. By day 7-8 post-sensitization, there was a 1.5-3.2-fold increase in the total numbers of Kd-binding B cells. Within this Kd-binding B cell population, approximately half were IgDlow, MHC Class IIhigh and CD86+, 30-45 % expressed a germinal center (Fas+GL7+) phenotype, and 3-12 % were IRF4hi plasma cells. Remarkably, blockade with anti-CD40 or CTLA-4Ig, starting on day 7 post-immunization for 1 or 4 weeks, completely dissolved established GCs and halted further development of the alloantibody response. Thus MHC Class I tetramers can specifically track the in vivo fate of endogenous, Class I-specific B cells, and was used to demonstrate the ability of delayed treatment with anti-CD154 and CTLA-4Ig to halt established allo-B cell responses.

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Section: Discussionmentioning

confidence: 99%

Reversing Endogenous Alloreactive B Cell GC Responses With Anti-CD154 or CTLA-4Ig

Chen

Yin

et al. 2013

American Journal of Transplantation

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“…The structural epitope of 69AA has also contact residues on the HLA‐bound peptide (Figure ). Arend Mulder and colleagues have first demonstrated that certain human monoclonal HLA antibodies are peptide dependent (Mulder et al ., ). One can expect that the alleles of the immunizer and the Luminex panel have different peptide repertoires and that the binding of some antibodies will require contact with certain critical residues on the peptide.…”

Section: Description Of the Hla Epitope Registry Websitementioning

confidence: 97%

16th IHIW: A Website for Antibody‐Defined HLA Epitope Registry

Duquesnoy

Marrari

Sousa

et al. 2012

Int J Immunogenetics

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The concept that HLA antibodies are specific for epitopes rather than HLA antigens is important not only for the determination of mismatch acceptability for sensitized patients but also for a better understanding of the antibody response to an HLA mismatch. Numerous publications describe epitope-specific antibodies, but there is no standardized information about the repertoire of clinically relevant HLA epitopes. Under auspices of the 16th IHIW, we have developed a website-based registry of antibody-verified HLA epitopes. Epitope notations are based on HLA molecular modelling of amino acid residues in polymorphic sequence positions. Informative epitope-specific antibodies had been induced by a transplant, transfusion or pregnancy and were monoclonal antibodies or eluates of sera absorbed with single HLA alleles. Antibody reactivity was determined in binding assays with single-allele panels. Antibody producer/immunizer HLA types enhanced the characterization of specific epitopes. The Registry also includes epitopes described in original research publications. Based on the extent of antibody reactivity information, we assigned epitope status as confirmed (well documented) or provisional (more data are needed). At present, the Registry has 69 HLA-ABC, 53 DRB1/3/4/5, 17 DQ, 8 DP and 22 MICA antibody-verified epitopes and will be updated on a quarterly basis. Laboratories worldwide continue to submit data about previously unreported antibody-specific epitopes. For each epitope, the website shows its amino acid composition and HLA alleles that share the epitope. Links show antibody reactivity patterns, sensitization information and references. Other links show molecular modelling of corresponding structural epitopes and polymorphic residue information for epitope-carrying alleles. The website will also have a link to epitope frequency information in different populations. Search functions will list mismatched epitopes on mismatched alleles for selected HLA types. The HLA Epitope Registry will become a valuable resource for researchers interested in HLA compatibility at the epitope level and investigating antibody responses to HLA mismatches.

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“…Peptide residues P5, P6, P8, and P9 were identified as influencing the mAb recognition of HLA-B27 and -A11 molecules (5,13,14), whereas the P1 residue was described as being critical for the binding of 4D12 mAb to HLA-B35/-B51 (15). A more recent study with human mAbs revealed the impact of different peptides on the HLA-A2/peptide complexes and its mAb recognition (16).…”

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confidence: 99%

Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation

Racapé

Connan

Hoebeke

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The binding of peptides to MHC class I molecules induces MHC/ peptide complexes that have specific conformational features. Little is known about the molecular and structural bases required for an optimal MHC/peptide association able to induce a dominant T cell response. We sought to characterize the interaction between purified HLA-A3 molecules and four well known CD8 epitopes from HIV-1 proteins. To define the characteristics of HLA-peptide complex formation and to identify potential structural changes, we used biochemical assays that detect well formed complexes. We tested the amplitude, stability, and kinetic parameters of the interaction between HLA-A3, peptides, and anti-HLA mAbs. Our results show that the four epitopes Nef73-82, Pol325-333, Env37-46, and Gag20 -28 bind strongly to HLA-A3 molecules and form very stable complexes that are detected with differential patterns of mAb reactivity. The most striking result is the nonrecognition of the HLA-A3/Gag20 -28 complex by the A11.1M mAb specific to HLA-A3/-A11 alleles. To explain this observation, from the data published on HLA-A11 crystallographic structure, we propose molecular models of the HLA-A3 molecule complexed with Nef73-82, Pol325-333, and Gag20 -28 epitopes. In the HLA-A3/Gag20 -28 complex, we suggest that Arg at position P1 of the peptide may push the ␣2 helix residue Trp-167 of HLA-A3 and affect mAb recognition. Such observations may have great implications for T cell antigen receptor recognition and the immunogenicity of HLA/ peptide complexes. C rystallographic structure analysis of a series of class I MHC/peptide complexes revealed that peptides carrying specific MHC anchor residues bind in a large-solvent-exposed groove of the heavy chain. This binding groove consists of two long helices, ␣1 and ␣2, mounted on a floor of eight antiparallel ␤-strands. Polymorphic residues in the groove determine distinct binding pockets from A to F. Bound peptides adopt extended conformations that stretch from the N-to the C-terminal end of the groove, and their anchor residues, generally at positions P2 and P9/10, interact with pockets B and F, respectively (1-4). In most MHC complexes, peptides are partly buried in the binding site, and only a few side chains of the peptide pointing away from the groove toward the solvent are accessible for CD8 T cell recognition (1, 5).The impact of peptide binding on heavy-chain MHC conformation can be detected serologically by the observation of differential anti-MHC mAbs reactivities. This effect has been mainly documented with murine anti-H2-K b , -K d , and -L d mAbs by testing the expression on mutant cells of class I MHC molecules loaded with synthetic peptides or by performing selective immunoprecipitation of complexes containing different sets of peptide. In those studies, specific residues of the bound peptide essential for mAb recognition were identified, and the impact of exposed, but also buried, peptide residues on ␣1 and ␣2 MHC conformation was demonstrated (6-12). The same effect of peptides on mAb recogn...

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Impact of Peptides on the Recognition of HLA Class I Molecules by Human HLA Antibodies

Cited by 46 publications

References 28 publications

Reversing Endogenous Alloreactive B Cell GC Responses With Anti-CD154 or CTLA-4Ig

Reversing Endogenous Alloreactive B Cell GC Responses With Anti-CD154 or CTLA-4Ig

16th IHIW: A Website for Antibody‐Defined HLA Epitope Registry

Influence of dominant HIV-1 epitopes on HLA-A3/peptide complex formation

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