Despite the retrospective nature of the study and the inhomogeneous patient sample, we found good long-term effects of the KD on seizure frequency, EEG and neurological development.
Foxp3 + CD4 + regulatory T cells (T reg ) have a crucial role in controlling CD4 + T-cell activation, proliferation, and effector function. However, the molecular mechanisms regulating T reg function remain poorly understood. Here we assessed the role of IL-7, a key cytokine regulating T-cell homeostasis, in suppressor capacity of T reg . Using a skin allograft model in which transplant acceptance is controlled by the number of transferred T reg , we find that T reg impair the proliferation of allogeneic CD4 + T cells, decrease production of IFNγ by effector T cells, and prevent early and increase late IL-7 induction by lymph node stromal cells. Increased IL-7 availability enhanced T reg survival, stabilized T reg molecular signature, enhanced surface IL-2Rα expression, and improved IL-2 binding of T reg , which diminished proliferation of alloreactive CD4 + T cells. Sequestration of IL-7 or impairment of IL-7R signaling after allograft transplantation abolished T reg -mediated tolerance by limiting their suppressive capacity. Aged Il7rα-ΔT reg mice displayed mild symptoms of autoimmunity correlating with impaired expansion of effector T reg in response to IL-2. Thus, IL-7R signaling on T reg supports the functional activity of effector T reg by increasing their IL-2 sensitivity in the lymph node during peripheral and allograft tolerance. R egulatory T cells (T reg ) express the transcription factor Foxp3and maintain peripheral tolerance through the suppression of potentially self-reactive T cells (1, 2). T reg deficiency and mutations in FoxP3 result in the development of autoimmune diseases in both humans and mice. The molecular mechanisms underlying the function and stability of the T reg compartment have not been fully elucidated (2-5). T reg constitutively express IL-2Rα (6), in which IL-2 has been shown to regulate T reg survival, expansion, and suppressive function under both homeostatic and activation conditions (7,8). T reg impaired in IL-2Rα signaling fail to suppress effector T-cell responses (7). Because T reg themselves are unable to produce their own IL-2, due to FoxP3-dependent repression of the interleukin-2 (IL-2) gene (9), T reg are susceptible to IL-2 concentrations and need to compete for it in secondary lymphoid organs (SLO) (10). Therefore, competition for IL-2 with conventional T cells is one of the proposed suppressive mechanism of T reg (6).Recently, it was shown that central T reg (cT reg ), defined by CD44 low and CD62L high expression, completely depend on IL-2 during homeostatic and inflammatory conditions, whereas effector T reg (eT reg ), defined by CD44 high and CD62L low expression, require inducible T-cell costimulator (ICOS) signaling (11). Because T reg not only use IL-2 for expansion and proliferation, but also for survival and pool maintenance, it is unclear if IL-2 competition occurs at low IL-2 concentration (as suggested in ref. 12). Moreover, IL-2 signaling via STAT5 (13) stabilizes FOXP3 expression and increases expression of suppressive T reg molecules including ICOS, ...
Background and ObjectivesAccurate diagnosis of febrile seizures in children presenting after paroxysmal episodes associated with fever, is hampered by the lack of objective postictal biomarkers. The aim of our study was to investigate whether FS are associated with increased levels of serum copeptin, a robust marker of arginine vasopressin secretion.MethodsThis was a prospective emergency-setting cross-sectional study of 161 children between six months and five years of age. Of these, 83 were diagnosed with febrile seizures, 69 had a febrile infection without seizures and nine had epileptic seizures not triggered by infection. Serum copeptin and prolactin levels were measured in addition to standard clinical, neurophysiological, and laboratory assessment. Clinical Trial Registration: NCT01884766.ResultsCirculating copeptin was significantly higher in children with febrile seizures (median [interquartile range] 18.9 pmol/L [8.5-36.6]) compared to febrile controls (5.6 pmol/L [4.1-9.4]; p <0.001), with no differences between febrile and epileptic seizures (21.4 pmol/L [16.1-46.6]; p = 0.728). In a multivariable regression model, seizures were the major determinant of serum copeptin (beta 0.509; p <0.001), independently of clinical and baseline laboratory indices. The area under the receiver operating curve for copeptin was 0.824 (95% CI 0.753-0.881), significantly higher compared to prolactin (0.667 [0.585-0.742]; p <0.001). The diagnostic accuracy of copeptin increased with decreasing time elapsed since the convulsive event (at 120 min: 0.879 [0.806-0.932] and at <60 min: 0.975 [0.913-0.997]).ConclusionsCirculating copeptin has high diagnostic accuracy in febrile seizures and may be a useful adjunct for accurately diagnosing postictal states in the emergency setting.
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