Cross-genetic determination of maternal and neonatal immune mediators during pregnancy.

BACKGROUND:The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. METHODS:This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome. RESULTS:We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype. CONCLUSIONS:Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders

Correlations in the T Cell Response to Altered Peptide Ligands

The vertebrate immune system is a wonder of modern evolution. Occasionally, however, correlations within the immune system lead to inappropriate recruitment of preexisting T cells against novel viral diseases. We present a random energy theory for the correlations in the naive and memory T cell immune responses. The non-linear susceptibility of the random energy model to structural changes captures the correlations in the immune response to mutated antigens. We show how the sequence-level diversity of the T cell repertoire drives the dynamics of the immune response against mutated viral antigens.Comment: 21 pages; 6 figures; to appear in Physica

Environmental Circadian Disruption Elevates the IL-6 Response to Lipopolysaccharide in Blood

The immune system is regulated by circadian clocks within the brain and immune cells. Environmental circadian disruption (ECD), consisting of a 6-h phase advance of the light:dark cycle once a week for 4 weeks, elevates the inflammatory response to lipopolysaccharide (LPS) both in vivo and in vitro. This indicates that circadian disruption adversely affects immune function; however, it remains unclear how the circadian system regulates this response under ECD conditions. Here, we develop an assay using ex vivo whole-blood LPS challenge to investigate the circadian regulation of immune responses in mice and to determine the effects of ECD on these rhythms. LPS-induced IL-6 release in whole blood was regulated in a circadian manner, peaking during subjective day under both entrained and free-running conditions. This LPS-induced IL-6 release rhythm was associated with daily variation in both white blood cell counts and immune cell responsiveness. ECD increased the overall level of LPS-induced IL-6 release by increasing immune cell responsiveness and not by affecting immune cell number or the circadian regulation of this rhythm. This indicates that ECD produces pathological immune responses by increasing the proinflammatory responses of immune cells. Also, this newly developed whole blood assay can provide a noninvasive longitudinal method to quantify potential health consequences of circadian disruption in humans

A characterization of extremal graphs without matching-cuts

A graph is called (matching-)immune if it has no edge cut that is also a matching. Farley and Proskurowski proved that for all immune graphs $G=(V,E)$, $|E|\geq \lceil 3(|V|-1)/2\rceil$, and constructed a large class of immune graphs attaining this lower bound for every value of $|V(G)|$, called ABC graphs. In this paper, we prove their conjecture that every immune graph that attains this lower bound is an ABC graph

Comparative global immune-related gene profiling of somatic cells, human pluripotent stem cells and their derivatives: implication for human lymphocyte proliferation.

Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), represent potentially unlimited cell sources for clinical applications. Previous studies have suggested that hPSCs may benefit from immune privilege and limited immunogenicity, as reflected by the reduced expression of major histocompatibility complex class-related molecules. Here we investigated the global immune-related gene expression profiles of human ESCs, hiPSCs and somatic cells and identified candidate immune-related genes that may alter their immunogenicity. The expression levels of global immune-related genes were determined by comparing undifferentiated and differentiated stem cells and three types of human somatic cells: dermal papilla cells, ovarian granulosa cells and foreskin fibroblast cells. We identified the differentially expressed genes CD24, GATA3, PROM1, THBS2, LY96, IFIT3, CXCR4, IL1R1, FGFR3, IDO1 and KDR, which overlapped with selected immune-related gene lists. In further analyses, mammalian target of rapamycin complex (mTOR) signaling was investigated in the differentiated stem cells following treatment with rapamycin and lentiviral transduction with specific short-hairpin RNAs. We found that the inhibition of mTOR signal pathways significantly downregulated the immunogenicity of differentiated stem cells. We also tested the immune responses induced in differentiated stem cells by mixed lymphocyte reactions. We found that CD24- and GATA3-deficient differentiated stem cells including neural lineage cells had limited abilities to activate human lymphocytes. By analyzing the transcriptome signature of immune-related genes, we observed a tendency of the hPSCs to differentiate toward an immune cell phenotype. Taken together, these data identify candidate immune-related genes that might constitute valuable targets for clinical applications

The Immune System

Modern biotherapy has been in use for some 30 years. The first types of biotherapy were nonspecific stimulators of the immune response, but advances in genetic engineering are allowing the mass production of pure biological products which are now being tested as pharmaceutical agents. Biotherapy connotes the administration of products (1) that are coded by the mammalian genome; (2) that modify the expression of mammalian genes; or (3) that stimulate the immune system. In this chapter the discussion of the immune system will be limited primarily to topics relevant to cancer or autoimmune diseases. Because understanding the new biological agents requires an understanding of both the immune response and the molecular basis of oncogenesis, this chapter first presents a summary of the structure and function of the immune system. Following a discussion of immune responses, and the cells involved in these responses, will be a discussion on the current concepts of oncogenesis, particularly oncogenes and growth factors. Because research efforts are beginning to identify many biological proteins as having a role in autoimmune and other diseases, a brief introduction to autoimmune diseases is also included at the end of the chapter