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1.  Onset of Immune Senescence Defined by Unbiased Pyrosequencing of Human Immunoglobulin mRNA Repertoires 
PLoS ONE  2012;7(11):e49774.
The immune system protects us from foreign substances or pathogens by generating specific antibodies. The variety of immunoglobulin (Ig) paratopes for antigen recognition is a result of the V(D)J rearrangement mechanism, while a fast and efficient immune response is mediated by specific immunoglobulin isotypes obtained through class switch recombination (CSR). To get a better understanding on how antibody-based immune protection works and how it changes with age, the interdependency between these two parameters need to be addressed. Here, we have performed an in depth analysis of antibody repertoires of 14 healthy donors representing different gender and age groups. For this task, we developed a unique pyrosequencing approach, which is able to monitor the expression levels of all immunoglobulin V(D)J recombinations of all isotypes including subtypes in an unbiased and quantitative manner. Our results show that donors have individual immunoglobulin repertoires and cannot be clustered according to V(D)J recombination patterns, neither by age nor gender. However, after incorporating isotype-specific analysis and considering CSR information into hierarchical clustering the situation changes. For the first time the donors cluster according to age and separate into young adults and elderly donors (>50). As a direct consequence, this clustering defines the onset of immune senescence at the age of fifty and beyond. The observed age-dependent reduction of CSR ability proposes a feasible explanation why reduced efficacy of vaccination is seen in the elderly and implies that novel vaccine strategies for the elderly should include the “Golden Agers”.
doi:10.1371/journal.pone.0049774
PMCID: PMC3511497  PMID: 23226220
2.  A Small, Variable and Irregular Killer Cell Ig-Like Receptor Locus Accompanies the Absence of MHC-C and MHC-G in Gibbons1 
The killer cell Ig-like receptors (KIR) of natural killer (NK) cells recognize major histocompatibility complex (MHC) class I ligands and function in placental reproduction and immune defense against pathogens. During the evolution of monkeys, great apes and humans, an ancestral KIR3DL gene expanded to become a diverse and rapidly evolving gene family of four KIR lineages. Characterising the KIR locus are three framework regions, defining two intervals of variable gene-content. By analysis of four KIR haplotypes from two species of gibbon, we find that the smaller apes do not conform to these rules. Although diverse and irregular in structure, the gibbon haplotypes are unusually small, containing only two to five functional genes. Comparison with the predicted ancestral hominoid KIR haplotype indicates that modern gibbon KIR haplotypes were formed by a series of deletion events, which created new hybrid genes as well as eliminating ancestral genes. Of the three framework regions, only KIR3DL3 (lineage V), defining the 5’ end of the KIR locus, is present and intact on all gibbon KIR haplotypes. KIR2DL4 (lineage I) defining the central framework region has been a major target for elimination or inactivation, correlating with the absence of its putative ligand, MHC-G, in gibbons. Similarly, the MHC-C driven expansion of lineage III KIR genes in great apes has not occurred in gibbons because they lack MHC-C. Our results indicate that the selective forces shaping the size and organisation of the gibbon KIR locus differed from those acting upon the KIR of other hominoid species.
doi:10.4049/jimmunol.0903016
PMCID: PMC3017126  PMID: 20026738
Comparative Immunology/Evolution; Reproductive Immunology; Natural Killer Cells; Cell Surface Molecules; MHC
3.  Genome comparison of the epiphytic bacteria Erwinia billingiae and E. tasmaniensis with the pear pathogen E. pyrifoliae 
BMC Genomics  2010;11:393.
Background
The genus Erwinia includes plant-associated pathogenic and non-pathogenic Enterobacteria. Important pathogens such as Erwinia amylovora, the causative agent of fire blight and E. pyrifoliae causing bacterial shoot blight of pear in Asia belong to this genus. The species E. tasmaniensis and E. billingiae are epiphytic bacteria and may represent antagonists for biocontrol of fire blight. The presence of genes that are putatively involved in virulence in E. amylovora and E. pyrifoliae is of special interest for these species in consequence.
Results
Here we provide the complete genome sequences of the pathogenic E. pyrifoliae strain Ep1/96 with a size of 4.1 Mb and of the non-pathogenic species E. billingiae strain Eb661 with a size of 5.4 Mb, de novo determined by conventional Sanger sequencing and next generation sequencing techniques. Genome comparison reveals large inversions resulting from homologous recombination events. Furthermore, comparison of deduced proteins highlights a relation of E. billingiae strain Eb661 to E. tasmaniensis strain Et1/99 and a distance to E. pyrifoliae for the overall gene content as well as for the presence of encoded proteins representing virulence factors for the pathogenic species. Pathogenicity of E. pyrifoliae is supposed to have evolved by accumulation of potential virulence factors. E. pyrifoliae carries factors for type III secretion and cell invasion. Other genes described as virulence factors for E. amylovora are involved in the production of exopolysaccharides, the utilization of plant metabolites such as sorbitol and sucrose. Some virulence-associated genes of the pathogenic species are present in E. tasmaniensis but mostly absent in E. billingiae.
Conclusion
The data of the genome analyses correspond to the pathogenic lifestyle of E. pyrifoliae and underlines the epiphytic localization of E. tasmaniensis and E. billingiae as a saprophyte.
doi:10.1186/1471-2164-11-393
PMCID: PMC2897811  PMID: 20565991
4.  A Novel System of Polymorphic and Diverse NK Cell Receptors in Primates 
PLoS Genetics  2009;5(10):e1000688.
There are two main classes of natural killer (NK) cell receptors in mammals, the killer cell immunoglobulin-like receptors (KIR) and the structurally unrelated killer cell lectin-like receptors (KLR). While KIR represent the most diverse group of NK receptors in all primates studied to date, including humans, apes, and Old and New World monkeys, KLR represent the functional equivalent in rodents. Here, we report a first digression from this rule in lemurs, where the KLR (CD94/NKG2) rather than KIR constitute the most diverse group of NK cell receptors. We demonstrate that natural selection contributed to such diversification in lemurs and particularly targeted KLR residues interacting with the peptide presented by MHC class I ligands. We further show that lemurs lack a strict ortholog or functional equivalent of MHC-E, the ligands of non-polymorphic KLR in “higher” primates. Our data support the existence of a hitherto unknown system of polymorphic and diverse NK cell receptors in primates and of combinatorial diversity as a novel mechanism to increase NK cell receptor repertoire.
Author Summary
Most receptors of natural killer (NK) cells interact with highly polymorphic major histocompatibility complex (MHC) class I molecules and thereby regulate the activity of NK cells against infected or malignant target cells. Whereas humans, apes, and Old and New World monkeys use the family of killer cell immunoglobulin-like receptors (KIR) as highly diverse NK cell receptors, this function is performed in rodents by the diverse family of lectin-like receptors Ly49. When did this functional separation occur in evolution? We followed this by investigating lemurs, primates that are distantly related to humans. We show here that lemurs employ the CD94/NKG2 family as their highly diversified NK cell receptors. The CD94/NKG2 receptors also belong to the lectin-like receptor family, but are rather conserved in “higher” primates and rodents. We could further demonstrate that lemurs have a single Ly49 gene like other primates but lack functional KIR genes of the KIR3DL lineage and show major deviations in their MHC class I genomic organisation. Thus, lemurs have evolved a “third way” of polymorphic and diverse NK cell receptors. In addition, the multiplied lemur CD94/NKG2 receptors can be freely combined, thereby forming diverse receptors. This is, therefore, the first description of some combinatorial diversity of NK cell receptors.
doi:10.1371/journal.pgen.1000688
PMCID: PMC2757895  PMID: 19834558

Results 1-4 (4)