Pocket 4 of the HLA-DR(α,β 1*0401) molecule is a major determinant of T cells recognition of peptide.

Fu, Xin-Ting; Bono, Chris; Woulfe, Susan L.; Swearingen, Craig; Summers, Neena L.; Sinigaglia, Francesco; Sette, Alessandro; Schwartz, Benjamin D.; Karr, Robert W.

doi:10.1084/jem.181.3.915

Cited by 98 publications

(69 citation statements)

References 49 publications

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“…We propose that the Dβ residues 13, 70, 71, 74 and 78, which are located in peptide-binding pocket 4, may exert a major and disproportionate influence on the outcome of T-cell recognition as compared with other polymorphic residues (11). From these studies, the sheep with the resistance-associated RK motif at position β 70/71 could induce proliferative responses of B-cells in vivo, and the animals had the ability to rapidly produce neutralizing antibody against BLV in the early infectious phase.…”

Section: Discussionmentioning

confidence: 98%

The Influence of Ovine MHC Class IIDRB1Alleles on Immune Response in Bovine Leukemia Virus Infection

Konnai

Takeshima

Tajima

et al. 2003

Microbiology and Immunology

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We have reported previously that the alleles of the ovine leukocyte antigen (OLA)‐DRB1 gene that encode the Arg‐Lys (RK) motif and the Ser‐Arg (SR) motif at positions β70/71 of the OLA‐DRβ1 domain are associated with resistance and susceptibility, respectively, to development of bovine leukemia virus (BLV)‐induced ovine lymphoma. Here, to investigate the different immune response in sheep that carried alleles associated with resistance and susceptible for 30 weeks after infection with BLV, we selected sheep that had the RK/RK or SR/SR genotype among the 52 sheep analyzed by polymerase chain reaction‐restriction fragment length polymorphism and DNA sequencing of PCR product for the OLA‐DRB1 exon 2 and infected them with BLV. Although the number of BLV‐infected cells and virus titer had been maintaining low levels throughout the experimental period, the sheep with the RK/RK genotype could induce expansion of CD5− B‐cells and rapid production of neutralizing antibody in the early phase of infection. The level of incorporation of [3H]thymidine by peripheral blood mononuclear cells from the sheep with RK/RK genotype gave a strong response to BLV virion antigen and synthetic antigenic peptides that corresponded to T‐helper epitope of the BLV envelope glycoprotein gp51. In contrast, the sheep with SR/SR genotype showed a strong response to BLV virion antigen and synthetic antigenic peptides that corresponded to T‐cytotoxic and B‐cell epitopes. In such cases, the animals with the RK/RK strongly expressed IFN‐7, the animals with SR/SR genotype strongly expressed IL‐2. To determine the proliferating cells, we tried a blocking assay with monoclonal antibodies such as anti‐CD4, ‐CD8 and ‐DR molecule. We found that these proliferating cells were MHC‐restricted CD4+ T‐cells.

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Section: Discussionmentioning

confidence: 98%

The Influence of Ovine MHC Class IIDRB1Alleles on Immune Response in Bovine Leukemia Virus Infection

Konnai

Takeshima

Tajima

et al. 2003

Microbiology and Immunology

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“…Glutamic acid at position 69 corresponds to position 71 of DRβ and occurs in pocket 4. This pocket is involved in controlling antigen-specific T-cell responses (Fu et al, 1995) and is associated with susceptibility to tuberculoid leprosy (Zerva et al, 1996). A single amino acid change at position 71 of DRβ is sufficient to alter the peptide-binding characteristics and susceptibility to rheumatoid arthritis , and clearly shows the close relationship between peptide binding and disease susceptibility.…”

Section: Discussionmentioning

confidence: 99%

Further investigation of the role of HLA-DPB1 in adult Hodgkin’s disease (HD) suggests an influence on susceptibility to different HD subtypes

et al. 1999

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Summary It has been suggested in a number of studies that susceptibility to adult Hodgkin's disease (HD) is influenced by the HLA class II region, and specifically by alleles at the HLA-DPB1 locus. Since HD is diagnostically complex, it is not clear whether different HLA-DPB1 alleles confer susceptibility to different HD subtypes. To clarify this we have extended a previous study to type DPB1 alleles in 147 adult HD patients from a single centre. We have analysed patients with nodular sclerosing (NS), mixed cellularity (MC) or lymphocyte predominant (LP) HD, and gender in relation to HLA-DPBI type, in comparison with 183 adult controls. The results confirmed previously reported associations of DPB1*0301 with HD susceptibility (relative risk (RR) = 1.42; 95% confidence interval (CI) 0.86-2.36) and DPB1*0201 with resistance to HD (RR = 0.49; CI 0.27-0.90). However, analysis by HD subtype and gender showed that *0301-associated susceptibility was confined to females with HD (RR = 2.46; CI 1.02-5.92), and *0201-associated resistance to females with NS-HD (RR = 0.28; CI 0.10-0.79). Susceptibility to NS-HD was also associated in females with *1001 (RR = 11.73; CI 1.32-104.36), and resistance with *1101 (RR = 0.08; CI 0.01-0.65). In contrast, susceptibility to LP-HD was associated in males with *2001 (RR = 32.14; CI 3.17-326.17), and to MC-HD with *3401 (RR = 16.78; CI 2.84-99.17). Comparison of DPB1-encoded polymorphic amino-acid frequencies in patients and controls showed that susceptibility to MC-HD was associated with Leucine at position 35 of DPB1 (RR = 8.85; CI 3.04-25.77), and ). In contrast, Glutamic acid 69 was significantly associated with resistance to MC-HD (RR = 0.14; CI 0.03-0.60). Certain DPB1 alleles and individual DPβ1 polymorphic amino acid residues may thus affect susceptibility and resistance to specific HD subtypes. This may be through their influence on the binding of peptides derived from an HD-associated infectious agent, and the consequent effect on immune responses to the agent.

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“…This binding is dependent on the establishment of adequate electrostatic or Van der Waals forces in the interaction [18]. With respect to binding of HLA-DR to a peptide, several pockets of the DR molecule are involved [19]. However, peptide-specific binding is thought to be within the allele-specific motif located in pocket 4.…”

Section: Discussionmentioning

confidence: 99%

“…They appear to utilize electrostatic forces in determining antigenic peptide specificity of the HLA-DRB1 molecule. For instance, poor binding of DR1 to positively charged residues at this position [20] is thought to be due to unfavourable electrostatic interactions with arginine b71 [19] within the pocket. It was in this pocket that we examined HLA-DRB1 alleles for peculiarities in amino acid charges available for binding to M. leprae in subjects with and without leprosy.…”

Section: Discussionmentioning

confidence: 99%

“…Positions 74 and 37 participate in the formation of pocket 4, with codon 74 at the top of the pocket while position 37 is part of the floor of the pocket [19]. It is possible that the presence of leucine in these two positions, apart from contributing to hydrophobicity in the binding pocket, has a direct effect synonymous to observations on site-directed mutagenesis experiments at these positions [19,24]. Our study may then be foremost in observing the putative effect of leucine substitution either at the top or floor of the peptide binding groove of pocket 4 of DRB1 alleles in interaction with M. leprae.…”

Section: Discussionmentioning

confidence: 99%

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HLA-DRB1 leprogenic motifs in Nigerian population groups

et al. 1999

Clinical and Experimental Immunology

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SUMMARYAmino acid residues involved in the peptide binding groove of HLA-DRB1 alleles were examined in three Nigerian ethnic groups with leprosy (n ¼ 287) and 170 controls to determine the role of DRB1 alleles in disease outcome with Mycobacterium leprae. Nine positively charged motifs and two others with neutral charge to the binding groove were detected. These motifs occurred more frequently in leprosy (leprogenic) than was expected by chance (P < 0·0001). In contrast, five motifs with net negative or 'modified' neutral charges to the pocket were negatively associated with leprosy. We conclude that clinical outcome of infection with M. leprae is largely determined by a shared epitope in DRB1 alleles marked by several motifs. These motifs occur in otherwise normal DRB1 alleles, characterized by net positive or neutral charges in the binding groove. We hypothesize that these polarities cause poor binding of DRB1 to M. leprae. On presentation, the signal via the T cell receptor results in muted cellmediated immunity. The resulting response translates to various forms of leprosy depending on degree of charge consonance between M. leprae and host DRB1 allele. Other factors within or without the HLA complex, such as the T cell receptor repertoire, may also influence the resulting disease.

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Pocket 4 of the HLA-DR(α,β 1*0401) molecule is a major determinant of T cells recognition of peptide.

Cited by 98 publications

References 49 publications

The Influence of Ovine MHC Class IIDRB1Alleles on Immune Response in Bovine Leukemia Virus Infection

The Influence of Ovine MHC Class IIDRB1Alleles on Immune Response in Bovine Leukemia Virus Infection

Further investigation of the role of HLA-DPB1 in adult Hodgkin’s disease (HD) suggests an influence on susceptibility to different HD subtypes

HLA-DRB1 leprogenic motifs in Nigerian population groups

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