HLA‐B27: portraying immunodominant viral epitopes

Castro, José A. Łópez de

doi:10.1002/eji.200425875

Cited by 11 publications

(6 citation statements)

References 31 publications

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“…sible explanations include a molecular mimicry between foreign and self-peptides presented by HLA-B27, the high binding capacity of HLA-B27, the unusual tendency of HLA-B27 to misfold, the involvement of non-canonical forms of HLA-B27 such as heavy chain homodimers, the failure of B27 ligands to engage KIR3DL1, leading to an increased natural killer activation or linkage disequilibrium with other immune response genes. 36,37 .…”

Section: Discussionmentioning

confidence: 99%

Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution

Neumann‐Haefelin

McKiernan

Ward³

et al. 2006

Hepatology

194

195

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Virus-specific CD8؉ T cell responses play an important role in the natural course of infection; however, the impact of certain CD8؉ T cell responses in determining clinical outcome has not been fully defined. A well-defined cohort of women inoculated with HCV from a single source showed that HLA-B27 has a strong association with spontaneous clearance. The immunological basis for this association is unknown. However, the finding is especially significant because HLA-B27 has also been shown to have a protective role in HIV infection. We report the identification of an HLA-B27 restricted hepatitis C virus (HCV)-specific CD8؉ T cell epitope that is recognized in the majority of recovered HLA-B27 positive women. In chronically HCV-infected individuals, analysis of the corresponding viral sequence showed a strong association between sequence variations within this epitope and expression of HLA-B27, indicating allele-specific selection pressure at the population level. T he hepatitis C virus (HCV) is a small positivestranded RNA virus within the Flaviviridae family that persists in 70% of infected individuals. Growing evidence suggests that the cellular host immune response against HCV plays an important role in the outcome of infection. Indeed, viral clearance is temporarily associated with sustained HCV-specific CD4ϩ and CD8ϩ T cell responses that accumulate in the infected liver. [1][2][3] In addition, the important antiviral role of virusspecific CD8ϩ T cells has recently been directly demonstrated by CD8ϩ cell depletion studies in chimpanzees. 4 The mechanisms that lead to the failure of the virus-specific T cell response and the persistence of HCV in most patients are still not well understood. 5 Several different pathways, such as a primary failure to induce T cells, functional exhaustion, or the emergence of viral escape mutations, have been discussed. [5][6][7] Indeed, a growing body of evidence suggests that T cell escape mutations develop early during acute HCV infection and that they remain fixed in the circulating quasispecies for several years. [8][9][10][11][12][13][14][15][16][17] However, the development of escape mutations during HCV infection is not universal. For example, viral clearance can occur with minimal epitope variation before From the

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Section: Discussionmentioning

confidence: 99%

Dominant influence of an HLA-B27 restricted CD8+ T cell response in mediating HCV clearance and evolution

Neumann‐Haefelin

McKiernan

Ward³

et al. 2006

Hepatology

194

195

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“…Supporting this model were observations that peptides bound to the Bw4 + allotype B*2705 do not permit interaction with KIR3DL1 if they have a charged residue at either position 7 or 8 (11). That ~25% of B*2705-binding peptides have charged residues at position 7 or 8 suggests this is no trivial effect (12, 13). And analysis of the binding of four Bw4 + A*2402 tetramers to four KIR3DL1 allotypes revealed even greater discrimination: only 6 of the 16 possible interactions occurred (14).…”

Section: Introductionmentioning

confidence: 99%

Polymorphic Sites Away from the Bw4 Epitope That Affect Interaction of Bw4+ HLA-B with KIR3DL1

Sanjanwala

Draghi

Norman

et al. 2008

The Journal of Immunology

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KIR3DL1 is a polymorphic, inhibitory NK cell receptor specific for the Bw4 epitope carried by subsets of HLA-A and HLA-B allotypes. The Bw4 epitope of HLA-B*5101 and HLA-B*1513 is determined by the NIALR sequence motif at positions 77, 80, 81, 82, and 83 in the α1 helix. Mutation of these positions to the residues present in the alternative and nonfunctional Bw6 motif showed that the functional activity of the Bw4 epitopes of B*5101 and B*1513 is retained after substitution at positions 77, 80, and 81, but lost after substitution of position 83. Mutation of leucine to arginine at position 82 led to loss of function for B*5101 but not for B*1513. Further mutagenesis, in which B*1513 residues were replaced by their B*5101 counterparts, showed that polymorphisms in all three extracellular domains contribute to this functional difference. Prominent were positions 67 in the α1 domain, 116 in the α2 domain, and 194 in the α3 domain. Lesser contributions were made by additional positions in the α2 domain. These positions are not part of the Bw4 epitope and include residues shaping the B and F pockets that determine the sequence and conformation of the peptides bound by HLA class I molecules. This analysis shows how polymorphism at sites throughout the HLA class I molecule can influence the interaction of the Bw4 epitope with KIR3DL1. This influence is likely mediated by changes in the peptides bound, which alter the conformation of the Bw4 epitope.

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“…HLA-B27 has a peptidebinding cleft (formed by the alpha 1 and alpha 2 domains of the alpha chain) that has six side-pockets (designated by the letters A through F) that accommodate the side chains of the amino acids of the bound nonamer peptides. HLA-B27 binds and presents peptides to CD8+ T cells with high efficiency and is associated with comparatively better protection from viral diseases, such as influenza or AIDS [11,12], than other HLA alleles. Therefore, it seemed logical to concentrate in the antigen presenting properties of HLA-B27 in order to understand its possible role in disease pathogenesis.…”

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confidence: 99%