Evolutionary relationship between human major histocompatibility complexHLA-DR haplotypes

An anti-malarial vaccine is urgently needed, especially against P. falciparum which causes 2 to 3 million deaths each year, mostly in Sub-Saharan African children. This vaccine should contain molecules from the parasite's different developmental stages due to the parasite's remarkable complexity and genetic variability. The first approach using synthetic peptides from different parasite stage molecules (the SPf66 malaria vaccine) conferred limited protective efficacy in Aotus monkeys and in large field-trials carried out in different parts of the world SPf66 contains red blood cell (RBC) binding merozoite peptides for which immune responses against them are genetically controlled by HLA-DR region. Therefore, a systematic search of conserved high activity binding peptides (HABP) was undertaken aimed at using them as immunogens. However, these peptides were poorly immunogenic and had poor protection-inducing capacity against experimental challenge with a P. falciparum strain highly infective for Aotus monkeys an experimental model with an immune system quite similar to humans. Modifications were thus made to key residues to render them immunogenic and protection-inducing. These native and modified HABPs' three-dimensional structure was determined by (1)H-NMR studies and their ability in forming stable Major Histocompatibility Class II - peptide (MHCII-peptide) complexes was correlated with their ability to bind in vitro to purified HLA-DR beta1* molecules. Our experimental data suggests a correlation between modified HABPs' three-dimensional structure, HLA-DR beta1* binding preferences and their protection-inducing capacity in monkeys. Furthermore, the data presented here indicates that a synthetic peptide vaccine's three-dimensional structural features dictate both HLA-DR beta1* allele binding preference (imposing genetic restriction on the immune response) and on these vaccines' protection-inducing value. Basic knowledge of a parasite's functionally active peptides, their 3D structure and their interaction for forming the MHC II- peptide-TCR complex will thus contribute towards designing fully effective multi-component, multi-stage subunit-based malarial vaccines.

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“…The others (DRβ2, DRβ6, DRβ7 DRβ8 and DRβ9) are considered to be pseudogenes since their products are neither translated nor expressed [71,72].…”

Section: The Mhc-peptide -Tcr Complex Structurementioning

confidence: 99%

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Patarroyo

Cifuentes

Salazar

et al. 2005

CMC

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“…Two major classes of MHC-encoded cell surface proteins have been characterized in detail: Class I molecules are expressed ubiquitously while the expression of class I1 molecules is restricted to those cells actively participating in specialized functions of the immune system. The HLA complex has been studied intensely and the genomic map of this 4 Mbp region is most advanced [45]. In humans there are five different DR haplotype groups (DRl, DR51, DR52, DR8 and DR53; see [45].…”

Section: Gaarbage Gaarnish or Gaarotte?mentioning

confidence: 99%

“…The HLA complex has been studied intensely and the genomic map of this 4 Mbp region is most advanced [45]. In humans there are five different DR haplotype groups (DRl, DR51, DR52, DR8 and DR53; see [45]. Each DR haplotype contains one DRA gene and a varying number of DRB genes and pseudogenes [45].…”

Section: Gaarbage Gaarnish or Gaarotte?mentioning

confidence: 99%

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On simple repetitive DNA sequences and complex diseases

et al. 1997

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Simple repetitive DNA sequences are abundantly interspersed in eukaryote genomes and therefore useful in genome research and genetic fingerprinting in plants, fungi and animals, including man. Recently, simple repeats were also identified in some prokaryotic genomes. Hence the same probes can be applied for multilocus DNA fingerprinting in medically relevant bacteria. Simple repeats including composite dinucleotide microsatellites are differentially represented in different compartments of eukaryote genomes. Expanded triplet blocks in and around certain genes may, for example, cause so-called trinucleotide diseases in man. As a consequence, simple repetitive sequences should also be characterized with respect to their influences on the DNA structure, gene expression, genomic (in)stability and their development on an evolutionary time scale. Here three examples of microsatellites in the human major histocompatibility complex (HLA) are investigated, a (GT)n microsatellite situated 2 kb 5' off the lymphotoxin alpha (LTA) gene, a (GAA)n block in the 5' part of the HLA-F gene and a composite (GT)n(GA)m stretch in the second intron of HLA-DRBl genes. Grossly differing mutation rates are evident in these elements as well as varying linkage disequilibria. The unfolding of these simple repeats in distant human populations is covered including Caucasians, Bushmen and South American Indians. Furthermore, implications of simple repeat neighboring genes are discussed for the multifactorial diseases multiple sclerosis (MS), rheumatoid arthritis (RA) and early onset pauciarticular arthritis (EOPA). Polymorphisms of HLA-DRBl and T cell receptor beta variable (TCRBV) genes confer susceptibility for these autoimmune diseases as demonstrable by intronic simple repeat variability. Microsatellite polymorphisms within the TNF region reveal linkage disequilibria with HLA-DRBl and different promotor alleles of the TNFA gene. Disease associations with TNFA microsatellite alleles are, on the one hand, secondary to associations with HLA-DRBl genes (in MS) or they represent additional risk factors (in RA, EOPA) on the other hand. Evolutionary persistence, various structural conformations and the specific binding of nuclear proteins to several simple repeat sequences refute the preconceptions of biological insignificance for all of these ubiquitously interspersed elements.

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“…Due to the degree of genetic polymorphism of MHC-II molecules codified in the so called H uman L eukocyte A ntigen D - R elated genetic region (HLA-DR) [9], 16 alleles named HLA-DRβ1*01 to HLA-DRβ1*16 with more than 300 variants have been identified, and serologically, functionally, evolutively and molecular classified [10], [11]. These alleles are grouped into five groups or haplotypes by following the same principles: HLA-DR1 including HLA-DRβ1*101,10,103,104 alleles; HLA-DR51 including HLA-DRβ1*15 and 16 alleles; HLA-DR52 including HLA-DRβ1*03,11,12,13 and 14 alleles; HLA-DR8 including only HLA-DRβ1*08 and HLA-DR53 including HLA-DRβ1*04,07,09 alleles [12].…”

Section: Introductionmentioning

confidence: 99%

Variations in the Electrostatic Landscape of Class II Human Leukocyte Antigen Molecule Induced by Modifications in the Myelin Basic Protein Peptide: A Theoretical Approach

et al. 2009

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The receptor-ligand interactions involved in the formation of the complex between Class II Major Histocompatibility Complex molecules and antigenic peptides, which are essential for establishing an adaptive immunological response, were analyzed in the Class II Human Leukocyte Antigen (HLA) - Myelin Basic Protein (MBP) peptide complex (HLA-DRβ1*1501-MBP) using a multipolar molecular electrostatic potential approach. The Human Leukocyte Antigen - peptide complex system was divided into four pockets together with their respective peptide fragment and the corresponding occupying amino acid was replaced by each of the remaining 19 amino acids. Partial atomic charges were calculated by a quantum chemistry approach at the Hatree Fock/3-21*G level, to study the behavior of monopole, dipole and quadrupole electrostatic multipolar moments. Two types of electrostatic behavior were distinguished in the pockets' amino acids: “anchoring” located in Pocket 1 and 4, and “recognition” located in Pocket 4 and 7. According to variations in the electrostatic landscape, pockets were ordered as: Pocket 1>Pocket 9≫Pocket 4≈Pocket 7 which is in agreement with the binding ability reported for Class II Major Histocompatibility Complex pockets. In the same way, amino acids occupying the polymorphic positions β13R, β26F, β28D, β9W, β74A, β47F and β57D were shown to be key for this Receptor-Ligand interaction. The results show that the multipolar molecular electrostatic potential approach is appropriate for characterizing receptor-ligand interactions in the MHC–antigenic peptide complex, which could have potential implications for synthetic vaccine design.

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Evolutionary relationship between human major histocompatibility complexHLA-DR haplotypes

Cited by 34 publications

References 53 publications

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

On simple repetitive DNA sequences and complex diseases

Variations in the Electrostatic Landscape of Class II Human Leukocyte Antigen Molecule Induced by Modifications in the Myelin Basic Protein Peptide: A Theoretical Approach

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Evolutionary relationship between human major histocompatibility complexHLA-DR haplotypes

Cited by 34 publications

References 53 publications

Based on HLA-DR&#946;1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Based on HLA-DR&#946;1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

On simple repetitive DNA sequences and complex diseases

Variations in the Electrostatic Landscape of Class II Human Leukocyte Antigen Molecule Induced by Modifications in the Myelin Basic Protein Peptide: A Theoretical Approach

Contact Info

Product

Resources

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Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides

Based on HLA-DRβ1* Allele Binding Specificities, Striking Differences in Distance and TCR Contacting Residue Orientation can be Observed in Modified Protection-Inducing Malarial Synthetic Peptides