Summary
The analysis of patient blood transcriptional profiles offers a means to investigate immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically-relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease datasets. Mapping changes in gene expression at the module-level generated disease-specific transcriptional fingerprints which provide a stable framework for the visualization and functional interpretation of microarray data. These transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Thus, this work describes the implementation and application of a methodology designed to support systems-scale analysis of the human immune system in translational research settings.
Objective: We hypothesized that type 1 diabetes (T1D) is accompanied by changes in gene expression in peripheral blood mononuclear cells due to dysregulation of adaptive and innate immunity, counterregulatory responses to immune dysregulation, insulin deficiency, and hyperglycemia.Research Design and Methods: Microarray analysis was performed on peripheral blood mononuclear cells from 43 patients with newly diagnosed T1D, 12 patients with newly diagnosed type 2 diabetes (T2D), and 24 healthy controls. One-and 4-month follow-up samples were obtained from 20 of the T1D patients.Results: Microarray analysis identified 282 genes differing in expression between newly diagnosed T1D patients and controls at a false discovery rate of 0.05. Changes in expression of IL1B, early growth response gene 3, and prostaglandin-endoperoxide synthase 2 resolved within 4 months of insulin therapy and were also observed in T2D, suggesting that they resulted from hyperglycemia. With use of a knowledge base, 81 of 282 genes could be placed within a network of interrelated genes with predicted functions including apoptosis and cell proliferation. IL1B and the MYC oncogene were the most highly connected genes in the network. IL1B was highly overexpressed in both T1D and T2D, whereas MYC was dysregulated only in T1D.
Conclusion
high pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.
Staphylococcus aureus has emerged as a significant pathogen causing severe invasive disease in otherwise healthy people. Despite considerable advances in understanding the epidemiology, resistance mechanisms, and virulence factors produced by the bacteria, there is limited knowledge of the in vivo host immune response to acute, invasive S. aureus infections. Herein, we report that peripheral blood mononuclear cells from patients with severe S. aureus infections demonstrate a distinctive and robust gene expression profile which is validated in a distinct group of patients and on a different microarray platform. Application of a systems-wide modular analysis framework reveals significant over-expression of innate immunity genes and under-expression of genes related to adaptive immunity. Simultaneous flow cytometry analyses demonstrated marked alterations in immune cell numbers, with decreased central memory CD4 and CD8 T cells and increased numbers of monocytes. CD14+ monocyte numbers significantly correlated with the gene expression levels of genes related to the innate immune response. These results demonstrate the value of applying a systems biology approach that reveals the significant alterations in the components of circulating blood lymphocytes and monocytes in invasive S. aureus infections.
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