Promiscuous and allele-specific anchors in HLA-DR-binding peptides

Hammer, Juergen; Valsasnini, P.; Tolba, Khaled A.; Bolin, David; Higelin, Jacqueline; Takács, B.; Sinigaglia, Francesco

doi:10.1016/0092-8674(93)90306-b

Cited by 370 publications

(291 citation statements)

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“…As for the algorithms reported here, this general algorithm was deduced by comparing blocks of binder peptides with blocks of non-binder peptides. Thus, we compared blocks of binder peptides to DR1 (60 peptides [29]), DRB1*1101 (52 peptides [30]), DRB1*0401 (52 peptides [30]), DR1, DR2, DR5, DR52a (63 peptides [33]), and 47 peptides binding to a variety of HLA-DR molecules [9 -12, 14, 31, 33, 43-55] with 43 peptides that were unable to bind to DR1, DR2, DR5 or DR52a [33]. This afforded the algorithm DRGen shown in Table 5.…”

Section: Resultsmentioning

confidence: 99%

“…The shorter TDh peptides are usually 9 amino acids long [34], an observation that has been confirmed by others [29,30] when eluting peptides from DR1, HLA DRB1*1101, and HLA DRB1*0401 molecules expressed by filamentous M13 phages. In all three cases the eluted peptides were 9 amino acids long.…”

Section: Determinants Recognized By T-helper Cellsmentioning

confidence: 86%

“…Since our algorithms are based on blocks of 8 amino acids, but the algorithm of Southwood et al [42], of Hammer et al [40], and of Marshall et al [32] use 9, 9, and 11 amino acid blocks, respectively, we adapted their algorithms to the prediction using 8 amino acid blocks. This was done because when their algorithms were tested using blocks of 9 or 11 amino acids like in their original algorithm, the sensitivity of the predictions against the 9-mer peptides eluted from DR1 [29], DRB1*1101, and DRB1*0401 [30], was lower than the one attained using blocks of 8 amino acids (data not shown). Indeed, none of [41].…”

Section: Discussionmentioning

confidence: 99%

“…Several groups have published algorithms for the prediction of TDh from proteins. These algorithms are based on several principles: (i) amino acid sequence patterns [25]; (ii) tendency of peptides to form amphypathic alpha helices [26]; (iii) tendency of peptides to form strip-of-helices [27]; (iv) amino acid sequence analogies with known T cell epitopes [7,28]; (v) peptides eluted from M13 phages display libraries [29,30]; (vi) elution of peptides from HLA-DR molecules [31]; and (vii) prediction of peptide binding by comparison with a model peptide [32]. However, as discussed in the present publication, these algorithms have a wide range of sensitivities and specificities.…”

Section: Determinants Recognized By T-helper Cellsmentioning

confidence: 99%

“…Thus, 77 blocks of 8 amino acids encompassed by 43 peptides, that according to O'Sullivan et al [33], were unable to bind to DR1, DR2, DR5, or DR52a, were compared with similar blocks from 60, 52, and 52 binder peptides, eluted from DR1, DRB1*1101, and DRB1*0401 molecules, respectively, expressed by filamentous M13 phages [29,30]. For the case of DR1, besides the 43 peptides that were unable to bind to any of the four HLA-DR tested, another 28 non-binder peptides to DR1 [33] were considered.…”

Section: Average Amino Acid Frequenciesmentioning

confidence: 99%

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Specific and general HLA-DR binding motifs: comparison of algorithms

et al. 2000

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Using panels of peptides well characterized for their ability to bind to HLA DR1, DRB1*1101, or DRB1*0401 molecules, algorithms were deduced to predict binding to these molecules. These algorithms consist of blocks of 8 amino acids containing an amino acid anchor (Tyr, Phe, Trp, Leu, Ile, or Val) at position i and different amino acid combinations at positions i؉2 to i؉7 depending on the class II molecule. The sensitivity (% of correctly predicted binder peptides) and specificity (% of correctly predicted non-binder peptides) of these algorithms, were tested against different independent panels of peptides and compared to other algorithms reported in the literature. Similarly, using a panel of 232 peptides able to bind to one or more HLA molecules as well as 43 non-binder peptides, we deduced a general motif for the prediction of binding to HLA-DR molecules. The sensitivity and specificity of this general motif was dependent on the threshold score used for the predictions. For a score of 0.1, the sensitivity and specificity were 84.7% and 69.8%, respectively. This motif was validated against several panels of binder and non-binder peptides reported in the literature, as well as against 35, 15-mer peptides from hepatitis C virus core protein, that were synthesized and tested in a binding assay against a panel of 19 HLA-DR molecules. The sensitivities and specificities against these panels of peptides were similar to those attained against the panels used to deduce the algorithm. These results show that comparison of binder and non-binder peptides, as well as correcting for the relative abundance of amino acids in proteins, is a useful approach to deduce performing algorithms to predict binding to HLA molecules.

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Section: Resultsmentioning

confidence: 99%

Section: Determinants Recognized By T-helper Cellsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Determinants Recognized By T-helper Cellsmentioning

confidence: 99%

Section: Average Amino Acid Frequenciesmentioning

confidence: 99%

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Specific and general HLA-DR binding motifs: comparison of algorithms

et al. 2000

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Reevaluation of the importance of polymorphic HLA class II alleles and amino acids in the susceptibility of individuals of different populations to type I diabetes

Zamani

Cassiman

1998

Am. J. Med. Genet.

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Several publications have shown that certain alleles at the HLA-DRB1, -DQA1, and -DQB1 loci are associated with insulin-dependent diabetes mellitus (IDDM). Many of these studies have claimed that HLA-DQalpha1Arg52 and DQbeta1Asp57 showed the strongest association with IDDM, but these results could not be confirmed in different populations. We have recently found that DRbeta1Lys71+ provided major susceptibility to IDDM and that DQbeta1Asp57- had an additive effect to DRbeta1Lys71+ [Zamani et al., 1994a: Eur J Hum Genet 2:177-184]. This was confirmed with haplotype analysis in multiplex IDDM families [Zamani et al., 1996a: J Med Genet 33:899-905]. Therefore, we have reanalyzed the data from the literature on the association of the human leucocyte antigen (HLA) DRB1, DQB1, and DQA1 with IDDM in different ethnic groups to determine whether different amino acids in the antigen binding cleft of HLA class II molecules play a preponderant role in the development of IDDM. The results showed that the DRbeta1Lys71+ allele provided the highest relative risk for IDDM in the Belgian, Danish, Greek Taiwanese, and Chinese population while this was not the case in Norwegians, Sardinians, and Algerians. Indeed, in the Sardinian and Algerian population the DRB1*0401 allele encoding Lys71+ is very rare. Nevertheless, the few positive cases were always in the patient group. We also measured the clinical relevance of the testing for DRbeta1Lys71, DQbeta1Asp57, and DQalpha1Arg52 by calculating a prevalence-corrected positive predictive value (PcPPV), a prevalence corrected negative predictive value (PcNPV), the sensitivity and specificity of these tests. The results indicated that the sensitivity of the test for DRbeta1Lys71+ was lower than for DQalpha1Ag52+ and DQbeta1Asp57-, while testing for DRbeta1Lys71+ was more specific than testing for DQbeta1Asp57- and DQalpha1Arg52+ and that the DRbeta1Lys71+ allele had a higher PcPPV than DQalpha1Arg52+ and DQbeta1Asp57- in all studied populations. These results also showed that testing for DRbeta1LyS71+/+ can be useful in IDDM risk assessment particularly in populations with a high prevalence (P) of IDDM such as the Danish (P[IDDM] = 0.65%). PcPPV for DRbeta1Lys71+/+ was 0.2313 in the Danish, indicating a 23.13% risk for an individual who is homozygous for the genotype DRbeta1Lys71+/+ to develop IDDM. Some mechanisms which might explain the role of these HLA class II alleles in susceptibility to IDDM are discussed.

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Three T-cell epitopes within the C-terminal 265 amino acids of the matrix protein pp65 of human cytomegalovirus recognized by human lymphocytes

Khattab

Lindenmaier²,

Frank³

et al. 1997

J. Med. Virol.

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Although a T-cell response in human cytomegalovirus (HCMV)-immune individuals exists against the most abundantly expressed protein pp65 of the virus matrix, less is known about the determinants that evoke this response. The aim of the study was to identify regions within HCMV pp65 (ppUL83) that contain sequences for the cellular immune response by the use of three recombinant overlapping beta-galactosidase pp65 fusion proteins (C74, C35, and C47), covering the C-terminal 265 amino acids of the entire pp65 sequence. Two T-cell epitope determinants were recognized by human lymphocytes of healthy, HCMV-seropositive, human leukocyte antigen (HLA)-typed individuals. One T-cell determinant (amino acids [aa] 303-388) was localized in the mid-region of the entire pp65 sequence and a second T-cell determinant (aa 477-561) within the C-terminal region. By fine mapping with synthetic hexadecamer peptides three T-cell epitopes were identified within these two regions: P10-I (aa 361-376) in the mid-region, P3-II (aa 485-499), and P6-II (aa 509-524) in the C-terminal region. Inhibition studies with monoclonal antibodies to HLA class I or class II revealed a class II restricted response to peptides P10-I or P6-II, respectively. P10-I responders shared the HLA-DR11 allele and P6-II responders the -DR3 allele. Therefore, these T-cell epitopes of HCMV pp65 might be presented in association with particular HLA class II alleles.

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Promiscuous and allele-specific anchors in HLA-DR-binding peptides

Cited by 370 publications

References 23 publications

Specific and general HLA-DR binding motifs: comparison of algorithms

Specific and general HLA-DR binding motifs: comparison of algorithms

Reevaluation of the importance of polymorphic HLA class II alleles and amino acids in the susceptibility of individuals of different populations to type I diabetes

Three T-cell epitopes within the C-terminal 265 amino acids of the matrix protein pp65 of human cytomegalovirus recognized by human lymphocytes

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