Balanced Bcl-3 expression in murine CD4+ T cells is required for generation of encephalitogenic Th17 cells.

The function of NF-κB family members is controlled by multiple mechanisms including the transcriptional regulator Bcl-3, an atypical member of the IκB family. By using a murine model of conditional Bcl-3 overexpression specifically in T cells, we observed impairment in the development of Th2, Th1, and Th17 cells. High expression of Bcl-3 promoted CD4+ T-cell survival, but at the same time suppressed proliferation in response to TCR stimulation, resulting in reduced CD4+ T-cell expansion. As a consequence, T-cell-specific overexpression of Bcl-3 led to reduced inflammation in the small intestine of mice applied with anti-CD3 in a model of gut inflammation. Moreover, impaired Th17-cell development resulted in the resistance of Bcl-3 overexpressing mice to EAE, a mouse model of multiple sclerosis. Thus, we concluded that fine-tuning expression of Bcl-3 is needed for proper CD4+ T-cell development and is required to sustain Th17-cell mediated pathology.

A genetic basis for IFN-gamma production and T-bet expression in humans.

Th1 and Th2 cytokines secreted by polarized effector T cells play a pivotal role in the development of autoimmune and allergic diseases. However, the genetic basis of cytokine production by T lymphocytes in humans is poorly understood. In this study, we investigated the genetic contribution to cytokine production and regulation of T cell-specific transcription factors in a prospective twin study. We found a substantial genetic contribution to the production of Th1 cytokines such as IFN-gamma and TNF-alpha with heritabilities of 0.85 (95% confidence intervals, 0.74-0.95) and 0.72 (0.50-0.93), respectively, whereas no genetic influence on production of the Th2 signature cytokine IL-4 was observed. Furthermore, the intrapair variability in IFN-gamma production by isolated T cells was lower in monozygotic than in dizygotic twins. In contrast to GATA-3, NFAT, and NF-kappaB, intrapair variability of T-bet, the master transcription factor of Th1 cells, was very low among monozygotic and high among dizygotic twins, indicative of a strong genetic influence on T-bet (heritability 0.93, 95% confidence interval, 0.84-1.0). Our data provide novel insights into the genetic regulation of human Th cell polarization. These data suggest that signature cytokines and cytokine signaling events of Th1 rather than Th2 cells are genetically determined and implicate that Th2-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. This concept is highlighted by the recent finding that inactivation of the T-bet gene in mice results in development of clinical hallmark features of asthma.

Genetic and environmental influences on the fibrinolytic system: a twin study.

The determination of heritability is a key issue to assess the predictive power of polymorphisms for disease in clinical studies. The aim of this study was to determine the heritability of proteins and activation markers of the fibrinolytic system in a large cohort of healthy twins. Heritability was calculated as 0.76 for thrombin activatable fibrinolysis inhibitor (TAFI), 0.44 for plasminogen activator inhibitor-1 (PAI-1), and 0.43 for tissue plasminogen activator. No significant genetic influence was observed for alpha2-antiplasmin-plasmin-complex and D-dimer. Heritability explained by single gene polymorphisms was 25.2% for TAFI 505G>A, 31.5% for 1542C>G, and 50.0% for combination of both. The influence on TAFI levels of 1542C>G (CC-->GG, median: -80.5%) was considerably stronger than that of 505G>A (GG-->AA, median: +49.3%) and in both cases there seems to be a dose-response relationship. Significant environmental influences on TAFI levels were observed for combined interaction terms (age*sex and bmi*sex). The PAI-1 4G/5G polymorphism explained 56.4% of the calculated heritability. The genetic variables accounting for the 43% heritability of tPA remain unknown. Our data show that the production of several key components of the fibrinolytic system is strongly genetically determined. This genetic influence is accounted for in large part but not completely by a limited number of polymorphisms within the respective genes associated with plasma levels of the gene products.