In autumn , the Ernst Schering Research Foundation Workshop sponsored the 45th in its series of conferences devoted to emerging areas in basic and applied biomedical research. These conferences bring together a critical mass of top scientists working in an impor- tant area in an intimate setting that fosters the free exchange of knowledge and ideas.
In this spirit, Workshop 45 assembled leaders in the field of chemokines - hemotactic cytokines that coordinate leukocyte trafficking - amid the scenic vineyards and wineries of Napa Valley, to discuss the latest concepts of how these molecules regulate the immune response and disease.
Chemokines were se- lected as a conference topic because they have revitalized the study of leukocyte trafficking and are widely considered to be potential new targets for drug development, in diseases ranging from acute in- flammation and autoimmunity to HIV and cancer. Discovered in the s, the chemokine superfamily currently has 43 human members, making it the largest subset of cytokines.
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Mem- bers are defined by conserved sequences and a common three-di- mensional fold, and can be divided into two major functional groups - homeostatic and inflammatory - depending on whether they are produced constitutively, and thereby control basal lymphocyte traf- ficking, or whether they must be induced, for example by pathogens or injury, and thereby control deployment of effector leukocytes in emergencies.
Seroconversion date was estimated as the midpoint between the last seronegative and the first seropositive HIV-1 antibody test date mean interval 0. The censoring date was the earliest of the date of the last recorded visit, or July 31, for the ALIVE cohort, or December 31, for all other cohorts, to avoid the confounding effect of highly active anti-retroviral therapy HAART. A panel of 72 EA and 72 AA samples representing extreme phenotypes for infection and progression rapid progression, long term non-progression, and infection resistance were used for SNP identification.
A visual inspection of the data with Kaplan-Meier survival curves was performed to determine the genetic models to be used in the Cox PH regression model. A dominant genetic model was tested for all genetic factors in this study, except for CCR5 recessive  , . To determine the best explanatory set of genetic variants, while minimizing the number of comparisons in model selection, We used StepAIC procedure to build Cox proportional hazards models for the AIDS phenotype based on stepwise regression, Akaike information criteria AIC , and the best subset selection .
A shrinkage below 0. To control for potential population stratification, we adjusted the regression analysis with eigenvector values . Eigenvector values were obtained by performing principal component analysis of , SNPs from a previous GWAS study carried out in the same samples . In the Cox regression analysis, eigenvector values for the top two principle components were included as covariates.
The genomic inflation factor in this seroconverter population showed minimal systematic overall bias due to population structure in regards to disease progression phenotype as it was quite close to 1. P values represent significance of departure from the null hypothesis that the pair is in equilibrium. All P values are two-tailed. Haploview was used for the LD plots. The detailed modeling method is presented in Text S1. Once the stable cell lines were established, they were examined for chemotactic responses to chemokines. The cells were also tested for migration in response to chemotactic peptides using formayl peptide receptors, including W peptide and MMK-1 Text S1.
Linkage disequilibrium of variants in 3p21 chemokine receptor genes.
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The models are shown with virtual bonds connecting the CA atoms. The atoms in residue are shown in spacefill view, with the carbons in white, oxygens in red and nitrogens in blue. The hydroxyl OH group of Y forms a hydrogen bond with the nitrogen atom of glycine , which is not present in the F allele.
We thank E. Binns-Roemer and Y. Zhou for technical support and Dr. Limou for critical reading of the manuscript. Abstract Chromosome 3p21—22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV Author Summary Human chemokine receptors are cell surface proteins that may be utilized by HIV-1 for entry into host cells.
Barsh, Stanford University School of Medicine, United States of America Received: February 28, ; Accepted: August 3, ; Published: October 27, This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Introduction Functional variation in the human leukocyte antigen HLA class I genes and in chemokine receptors affects HIV susceptibility, viral load, and rates of disease progression  — .
Download: PPT. Figure 1. Polymorphisms in seven chemokine receptor genes on the Chromosome 3p21— Results Identification of chemokine coreceptor variants We resequenced selected chemokine receptor genes in the chromosome 3p21—22 region in 72 African Americans and 72 European Americans with three extreme phenotypes resistance to HIV infection, very rapid or slow progression to AIDS to assess the extent of exonic variation and to identify rare variants. Table 1. Characteristics and allele frequencies of the chemokine receptor variants. Linkage disequilibrium LD of chemokine receptor variants on 3p21—22 The SNPs considered fell into two distinct haplotype blocks Figure 1.
Genetic associations with progression to AIDS The identification of independent additional genetic factors in this region, particularly for 3p21, is complicated by a moderate to high level of LD Figure S1. Figure 2. Figure 3. Table 2. Effects of chemokine receptor variants on AIDS progression.
Effects of combined chemokine coreceptor variants on AIDS progression Using stepwise selection determined by the Akaike information criteria AIC , we built an optimal prediction model with the genetic variants that were associated with AIDS progression in this or previous studies Table 3. Table 3. Sequential stepwise regression for Cox PH model selection and maximum likelihood estimates of genetic covariates associated with AIDS progression.
Three-dimensional protein structure prediction. Surrogate migration assay using CCR3. Chemotaxis of CCRL2. Resequencing and SNP identification A panel of 72 EA and 72 AA samples representing extreme phenotypes for infection and progression rapid progression, long term non-progression, and infection resistance were used for SNP identification. Supporting Information.
Cytokines and Chemokines: Disease Models, Mechanisms, and Therapies
Figure S1. Figure S2. Figure S3. Figure S4. Figure S5. Table S1. Table S2. Primer sequences for PCR amplification and direct sequencing.
Text S1. Supplementary methods. Acknowledgments We thank E. References 1. Genetic and environmental factors are important in the pathogenesis of vitiligo. Genetic studies concern mainly patients with NSV. Among melanocyte proteins TYR encodes tyrosinase, which is an enzyme that catalyzes melanin biosynthesis, and it is a major autoantigen that is implicated in generalized vitiligo 7.
Another gene associated with vitiligo is the NALP1 gene, which regulates inflammation and cell death of myeloid and lymphoid cells. NALP1 produces inflammatory products such as caspase1 and caspase7, which activate the cytokine interleukin-1beta which is expressed at high levels in patients with vitiligo 8.
The deficiency of TSLP gene expression produces the dominance of the Th1 immune response, which is involved in vitiligo development. This cytokine acts through chemokines that are small glycoproteins active for a wide variety of cell types.