Several regions in the major histocompatibility complex confer risk for anti-CCP-antibody positive rheumatoid arthritis, independent of the DRB1 locus

Recent evidence suggests that additional risk loci for RA are present in the major histocompatibility complex (MHC), independent of the class II HLA-DRB1 locus. We have now tested a total of 1,769 SNPs across 7.5Mb of the MHC located from 6p22.2 (26.03 Mb) to 6p21.32 (33.59 Mb) derived from the Illumina 550K Beadchip (Illumina, San Diego, CA, USA). For an initial analysis in the whole dataset (869 RA CCP + cases, 1,193 controls), the strongest association signal was observed in markers near the HLA-DRB1 locus, with additional evidence for association extending out into the Class I HLA region. To avoid confounding that may arise due to linkage disequilibrium with DRB1 alleles, we analyzed a subset of the data by matching cases and controls by DRB1 genotype (both alleles matched 1:1), yielding a set of 372 cases with 372 controls. This analysis revealed the presence of at least two regions of association with RA in the Class I region, independent of DRB1 genotype. SNP alleles found on the conserved A1-B8-DR3 (8.1) haplotype show the strongest evidence of positive association (P ~ 0.00005) clustered in the region around the HLA-C locus. In addition, we identified risk alleles that are not present on the 8.1 haplotype, with maximal association signals (P ~ 0.001-0.0027) located near the ZNF311 locus. This latter association is enriched in DRB1*0404 individuals. Finally, several additional association signals were found in the extreme centromeric portion of the MHC, in regions containing the DOB1, TAP2, DPB1, and COL11A2 genes. These data emphasize that further analysis of the MHC is likely to reveal genetic risk factors for rheumatoid arthritis that are independent of the DRB1 shared epitope alleles.     

Aging and respiratory muscle metabolic plasticity: effects of endurance training.

We examined the oxidative and antioxidant enzyme activities in respiratory and locomotor muscles in response to endurance training in young and aging rats. Young adult (4-mo-old) and old (24-mo-old) female Fischer 344 rats were divided into four groups: 1) young trained (n = 12), 2) young untrained (n = 12), 3) old trained (n = 10), and 4) old untrained (n = 6). Both young and old endurance-trained animals performed the same training protocol during 10 wk of continuous treadmill exercise (60 min/day, 5 days/wk). Compared with young untrained animals, the young trained group had significantly elevated (P less than 0.05) activities of 3-hydroxyacyl-CoA dehydrogenase (HADH), glutathione peroxidase (GPX), and citrate synthase (CS) in both the costal diaphragm and the plantaris muscle. In contrast, training had no influence (P greater than 0.05) on the activity of lactate dehydrogenase within the costal diaphragm in young animals. In the aging animals, training did not alter (P greater than 0.05) activities of CS, HADH, GPX, or lactate dehydrogenase in the costal diaphragm but significantly (P less than 0.05) increased CS, HADH, and GPX activities in the plantaris muscle. Furthermore, training resulted in higher activities of CS and HADH in the intercostal muscles in the old trained than in the old untrained animals. Finally, activities of CS, HADH, and GPX were significantly (P less than 0.05) lower in the plantaris in the old untrained than in the young untrained animals; however, CS, HADH, and GPX activities were greater (P less than 0.05) in the costal diaphragm in the old sedentary than in the young untrained animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Markers that discriminate between European and African ancestry show limited variation within Africa

Markers informative for ancestry are necessary for admixture mapping and improving case-control association analyses. In particular, African Americans are an admixed population for which genetic studies require accurately evaluating admixture. This will require markers that can be used in African Americans to determine if a given genomic region is of European or African ancestry. This report shows that, despite studies indicating high intra-African sequence variation, markers with large inter-ethnic differences have only small variations in allele distribution among divergent African populations and should be valuable for evaluating admixture in complex disease genetic studies.     

Dynamic Leukocyte Populations Are Associated With Early- and Late-stage Lesions in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition typically targeting the axillary and anogenital regions of the body. The massive inflammatory cell infiltrate produced in this cryptogenic condition has led investigators in the attempt to link particular inflammatory cell fractions and cytokines to disease development, and ultimately to disease treatment. This study qualitatively and quantitatively analyzes the white blood cell fractions of macrophages, B-lymphocytes, T-lymphocytes, plasma cells, and granulocytes in 104 HS lesions on formalin-fixed paraffin-embedded tissues using immunohistochemistry (IHC). Four dermis-associated epithelial categories were investigated from persons with HS: 15 unaffected HS skin (US), 19 distended but unruptured follicle epithelium (UF), 62 migrating stratified squamous epithelium (MSSE) from ruptured follicles, and 35 degraded migrating epithelial sheets (DMES). In addition, 27 control skin (CS) from persons without HS were evaluated. Analysis of cell counts indicated that non-migratory dermal epithelium (CS, US, and UF) stimulated very little inflammatory response. However, contrary to previous studies which indicated macrophages to be the chief inflammatory cell in HS, this study showed that plasma cells were the primary cell type present in early-stage HS lesions (MSSE), whereas granulocytes were the major cell population seen in late-stage HS lesions (DMES):     

Lymphocyte cytotoxicity to influenza virus-infected cells. II. Requirement for antibody and non-T lymphocytes.

Peripheral blood lymphocytes (PBL) obtained from humans were cytotoxic for influenza virus-infected target cells. The PBL were shown to have associated influenza virus anti-hemagglutinin antibody (AHAb) detectable only by radioimmunoassay. This antibody could be removed by incubating PBL at 37 degrees C for 30 min. The lymphocyte population that was effective in this system was nonadherent and nonphagocytic cells. PBL gave comparable levels of cytotoxicity when tested by using either a xenogeneic or allogeneic virus-infected target cell. These results indicate that lymphocyte cytotoxicity to influenza virus infected cells may be mediated by small quantities of antibody and by lymphocytes that possess characteristics of K cells. No evidence for T cell-mediated cytolysis was found with this xenogeneic system.     

Olfactory studies using ethyl bromoacetate and other chemically active odorants

Eleven chemically active odorants were tested to determine theireffectiveness and specificity in inhibiting electroolfactogram(EOG) responses in the frog olfactory mucosa. These inhibitoryagents probably act by several different mechanisms, but theyall produced a comparable degree of inhibition when approximatelythe same amount of inhibitor had been applied. One agent, ethylbromoacetate, produced a specific pattern of inhibition in whichresponses to all odorants tested were inhibited except responsesto certain amines. A related agent, ethyl chloroacetate, produceda similar, but less well-defined specific effect. Non-specificinhibitory effects were produced by seven of the agents tested.Two agents produced no inhibition, presumably because theirlow vapor pressure prevented the application of sufficient reagentin the vapor phase. The majority of the effective inhibitorsare alkylating agents or substrates for nucleophilic additionwhich react with sulfhydryl or amino groups of proteins. Bycontrast, the inhibitory effect of diethylamine is probablythe result of its basicity. The basicity would enable neutralizationreactions with acidic groups of proteins or other substancesin the microenvironment of the receptors. Several lines of evidencelead to the conclusion that the inhibitory action of the chemicallyactive odorants is principally the result of disruption of molecularolfactory receptors in the membranes of olfactory neurons, andthat sulfhydryl, amino, and carboxyl groups are of importanceto the function of olfactory receptors, ion channels, or receptor/ionophoremacromolecules. ¹Present address: PSC Box 511, Peterson AFB, Colorado Springs,Colorado 80914, USA. ²Permanent address: Department of Chemistry, New Mexico Instituteof Mining and Technology, Socorro, New Mexico 87801, USA.