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Brain ; 2018 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985992


The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.

Clin Cancer Res ; 24(17): 4187-4200, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29444930


Purpose: Immunotherapeutic treatment strategies for glioblastoma (GBM) are under investigation in clinical trials. However, our understanding of the immune phenotype of GBM-infiltrating T cells (tumor-infiltrating lymphocytes; TILs) and changes during disease progression is limited. Deeper insight is urgently needed to therapeutically overcome tumor-induced immune exhaustion.Experimental Design: We used flow cytometry and cytokine assays to profile TILs and peripheral blood lymphocytes (PBLs) from patients with GBM, comparing newly diagnosed or recurrent GBM to long-term survivors (LTS) and healthy donors. TCR sequencing was performed on paired samples of newly diagnosed and recurrent GBM.Results: We identified a clear immune signature of exhaustion and clonal restriction in the TILs of patients with GBM. Exhaustion of CD8+ TILs was defined by an increased prevalence of PD-1+, CD39+, Tim-3+, CD45RO+, HLA-DR+ marker expression, and exhibition of an effector-/transitional memory differentiation phenotype, whereas KLRG1 and CD57 were underrepresented. Immune signatures were similar in primary and recurrent tumors; however, restricted TCR repertoire clonality and a more activated memory phenotype were observed in TILs from recurrent tumors. Moreover, a reduced cytokine response to PHA stimulation in the blood compartment indicates a dysfunctional peripheral T-cell response in patients with GBM. LTS displayed a distinct profile, with abundant naïve and less exhausted CD8+ T cells.Conclusions: TILs and PBLs exhibit contrasting immune profiles, with a distinct exhaustion signature present in TILs. While the exhaustion profiles of primary and recurrent GBM are comparable, TCR sequencing demonstrated a contracted repertoire in recurrent GBM, concomitant with an increased frequency of activated memory T cells in recurrent tumors. Clin Cancer Res; 24(17); 4187-200. ©2018 AACRSee related commentary by Jackson and Lim, p. 4059.

Front Immunol ; 8: 1505, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29181000


Prenatal glucocorticoids are routinely administered to pregnant women at risk of preterm delivery in order to improve survival of the newborn. However, in half of the cases, birth occurs outside the beneficial period for lung development. Glucocorticoids are potent immune modulators and cause apoptotic death of immature T cells, and we have previously shown that prenatal betamethasone treatment at doses eliciting lung maturation induce profound thymocyte apoptosis in the offspring. Here, we asked if there are long-term consequences on the offspring's immunity after this treatment. In the non-obese diabetic mouse model, prenatal betamethasone clearly decreased the frequency of pathogenic T cells and the incidence of type 1 diabetes (T1D). In contrast, in the lupus-prone MRL/lpr strain, prenatal glucocorticoids induced changes in the T cell repertoire that resulted in more autoreactive cells. Even though glucocorticoids transiently enhanced regulatory T cell (Treg) development, these cells did not have a protective effect in a model for multiple sclerosis which relies on a limited repertoire of pathogenic T cells for disease induction that were not affected by prenatal betamethasone. We conclude that prenatal steroid treatment, by inducing changes in the T cell receptor repertoire, has unforeseeable consequences on development of autoimmune disease. Our data should encourage further research to fully understand the consequences of this widely used treatment.

EBioMedicine ; 26: 146-151, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29129700


BACKGROUND: Paracetamol is the first choice for antipyretic or analgesic treatment throughout pregnancy. Products with Paracetamol are readily available over the counter and therefore easily accessible for self-medication. Epidemiological data on Paracetamol intake pattern during pregnancy and its potential immunological effects are sparse. We aimed to analyze a possible association between Paracetamol medication and numbers of hematopoietic stem cells (HSC) in cord blood. METHODS: The objective was addressed in the PRINCE (PRENATAL DETERMINANTS OF CHILDREN'S HEALTH) study, a population-based prospective pregnancy cohort study initiated in 2011 at the University Medical Center in Hamburg, Germany. 518 healthy pregnant women with singleton pregnancies were recruited during the first trimester. Three examinations were scheduled at the end of the 1st (gestational week 12-14), the 2nd (gestational week 22-24) and the 3rd trimester (gestational week 34-36). For 146 of these women, cord blood flow cytometry data were available. Paracetamol intake was assessed for each trimester of pregnancy. FINDINGS: Among the 518 enrolled women, 40% took Paracetamol as main analgesic treatment during pregnancy. The intake frequency and dosage of Paracetamol varied between the women and was overall low with a tendency towards higher frequencies and higher dosages in the third trimester. Paracetamol intake, particularly during the third trimester, resulted in decreased relative numbers of HSCs in cord blood, independent of maternal age, first-trimester BMI, parity, gestational age and birth weight (-0.286 (95% CI -0.592, 0.021), p=0.068). INTERPRETATION: Prenatal Paracetamol intake, especially during the third trimester, may be causally involved in decreasing HSCs in cord blood.

Acetaminofen/efeitos adversos , Analgésicos/efeitos adversos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Dor/tratamento farmacológico , Acetaminofen/administração & dosagem , Adulto , Analgésicos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Sangue Fetal/efeitos dos fármacos , Idade Gestacional , Células-Tronco Hematopoéticas/patologia , Humanos , Dor/patologia , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos