Background: IgG(4)-related disease (IgG(4)-RD) is an immune-mediated fibrotic disorder that has been linked to CD4(+) cytotoxic T lymphocytes (CD4(+)CTLs). The effector phenotype of CD4(+)CTLs and... Show moreBackground: IgG(4)-related disease (IgG(4)-RD) is an immune-mediated fibrotic disorder that has been linked to CD4(+) cytotoxic T lymphocytes (CD4(+)CTLs). The effector phenotype of CD4(+)CTLs and the relevance of both CD8(+) cytotoxic T lymphocytes (CD8(+)CTLs) and apoptotic cell death remain undefined in IgG(4)-RD.Objective: We sought to define CD4(+)CTL heterogeneity, characterize the CD8(+)CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG(4)-RD.Methods: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data.Results: We establish that among circulating CD4(+)CTLs in IgG(4)-RD, CD27(lo)CD28(lo)CD57(hi) cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8(+)CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8(+) T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR.Conclusions: CD4(+)CTLs and CD8(+)CTLs may induce apoptotic cell death in tissues of patients with IgG(4)-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin. Show less
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have... Show moreMost common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits(1), but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait(2,3). The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways. Show less
