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The variable immunological self: genetic variation and nongenetic noise in Aire-regulated transcription.

ABSTRACT: The Aire transcription factor plays an important role in immunological self-tolerance by mediating the ectopic expression of peripheral self-antigens by thymic medullary epithelial cells (MECs), and the deletion of thymocytes that recognize them. In Aire-deficient humans or mice, central tolerance is incomplete and multiorgan autoimmune disease results. We examined the variability of Aire's effects on ectopic transcription among individual mice of three different inbred strains. Aire's function was, overall, quite similar in the three backgrounds, although generally stronger in C57BL/6 than in BALB/c or NOD mice, and a minority of Aire-regulated genes did show clear differences. Gene expression profiling of wild-type MECs from single mice, or from the two thymic lobes of the same mouse, revealed significantly greater variability in Aire-controlled ectopic gene expression than in Aire-independent transcripts. This "noisy" ectopic expression did not result from parental or early developmental imprinting, but from programming occurring after the formation of the thymic anlage, resulting from epigenetic effects or from the stochastic nature of Aire activity. Together, genetic and nongenetic variability in ectopic expression of peripheral antigens in the thymus make for differences in the portion of self determinants presented for tolerance induction. This variable self may be beneficial in preventing uniform holes in the T-cell repertoire in individuals of a species, but at the cost of variable susceptibility to autoimmunity.

SUBMITTER: Venanzi ES

PROVIDER: S-EPMC2572942 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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The variable immunological self: genetic variation and nongenetic noise in Aire-regulated transcription.

Venanzi Emily S ES Melamed Rachel R Mathis Diane D Benoist Christophe C

Proceedings of the National Academy of Sciences of the United States of America 20081006 41

The Aire transcription factor plays an important role in immunological self-tolerance by mediating the ectopic expression of peripheral self-antigens by thymic medullary epithelial cells (MECs), and the deletion of thymocytes that recognize them. In Aire-deficient humans or mice, central tolerance is incomplete and multiorgan autoimmune disease results. We examined the variability of Aire's effects on ectopic transcription among individual mice of three different inbred strains. Aire's function ...[more]

PMID: 18838677

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Project description:Genetically identical cells exhibit extensive phenotypic variation even under constant and benign conditions. This so-called nongenetic heterogeneity has important clinical implications: within tumors and microbial infections, cells show nongenetic heterogeneity in growth rate and in susceptibility to drugs or stress. The budding yeast, Saccharomyces cerevisiae, shows a similar form of nongenetic heterogeneity in which growth rate correlates positively with susceptibility to acute heat stress at the single-cell level. Using genetic and chemical perturbations, combined with high-throughput single-cell assays of yeast growth and gene expression, we show here that heterogeneity in intracellular cyclic AMP (cAMP) levels acting through the conserved Ras/cAMP/protein kinase A (PKA) pathway and its target transcription factors, Msn2 and Msn4, underlies this nongenetic heterogeneity. Lower levels of cAMP correspond to slower growth, as shown by direct comparison of cAMP concentration in subpopulations enriched for slower vs. faster growing cells. Concordantly, an endogenous reporter of this pathway's activity correlates with growth in individual cells. The paralogs Msn2 and Msn4 differ in their roles in nongenetic heterogeneity in a way that demonstrates slow growth and stress tolerance are not inevitably linked. Heterogeneity in growth rate requires each, whereas only Msn2 is required for heterogeneity in expression of Tsl1, a subunit of trehalose synthase that contributes to acute-stress tolerance. Perturbing nongenetic heterogeneity by mutating genes in this pathway, or by culturing wild-type cells with the cell-permeable cAMP analog 8-bromo-cAMP or the PKA inhibitor H89, significantly impacts survival of acute heat stress. Perturbations that increase intracellular cAMP levels reduce the slower-growing subpopulation and increase susceptibility to acute heat stress, whereas PKA inhibition slows growth and decreases susceptibility to acute heat stress. Loss of Msn2 reduces, but does not completely eliminate, the correlation in individual cells between growth rate and acute-stress survival, suggesting a major role for the Msn2 pathway in nongenetic heterogeneity but also a residual benefit of slow growth. Our results shed light on the genetic control of nongenetic heterogeneity and suggest a possible means of defeating bet-hedging pathogens or tumor cells by making them more uniformly susceptible to treatment.

Project description:ObjectiveThe aim of this study was to investigate the prevalence of cancer and associating clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID).MethodsIn this retrospective monocenter cohort study, we estimated the standardized incidence ratio (SIR) for different forms of cancer diagnosed in CVID patients. Furthermore, we evaluated the likely association of infectious and non-infectious CVID-related phenotypes with the diagnosis of cancer by calculation of the odds ratio. The genetic background of CVID in patients with cancer was evaluated with sequential targeted next-generation sequencing (tNGS) and whole-exome sequencing (WES). Patients' family history and WES data were evaluated for genetic predisposition to cancer.ResultsA total of 27/219 patients (12.3%) were diagnosed with at least one type of cancer. Most common types of cancer were gastric cancer (SIR: 16.5), non-melanoma skin cancer (NMSC) (SIR: 12.7), and non-Hodgkin lymphoma (NHL) (SIR: 12.2). Immune dysregulation manifesting as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was associated with the diagnosis of cancer. Furthermore, diagnosis of NMSC associated with the diagnosis of an alternative type of cancer. Studied immunological parameters did not display any significant difference between patients with cancer and those without. tNGS and/or WES yielded a definite or likely genetic diagnosis in 11.1% of CVID patients with cancer. Based on identified variants in cancer-associated genes, the types of diagnosed cancers, and family history data, 14.3% of studied patients may have a likely genetic susceptibility to cancer, falling under a known hereditary cancer syndrome.ConclusionsGastric cancer, NMSC, and NHL are the most frequent CVID-associated types of cancer. Manifestations of immune dysregulation, such as arthritis and ILD, were identified as risk factors of malignancy in CVID, whereas studied immunological parameters or the identification of a monogenic form of CVID appears to have a limited role in the evaluation of cancer risk in CVID.

Dataset Information

The variable immunological self: genetic variation and nongenetic noise in Aire-regulated transcription.

Publications

The variable immunological self: genetic variation and nongenetic noise in Aire-regulated transcription.

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