Wild-derived mouse strains, a valuable model to study B cell responses

In the present report, we revisited the B cell responsiveness of 7 wild-derived mouse strains to various toll-like receptor ligands (TLR-L). We found that 2 of them, namely PWK and STF presented profound defects in B cell proliferative responses to most of the TLR-L. Yet, their macrophage responses were largely unaffected, suggesting that regulation of TLR pathways are distinct in B cells and macrophages. We also showed that, anti-CD40 mAbs rescued the low proliferative responses to CpG in both PWK and STF B cells. In the other hand, CpG synergized with LPS to induce high levels of proliferation in STF B cells, which did not respond to LPS alone. Cytokine or immunoglobulin (Ig) productions, in vitro, were less impaired than the proliferative responses to LPS or CpG alone. In STF B cells, both ERK, P38 and JNK pathways were affected following in vitro TLR4 or TLR9 signaling. Moreover, while the basal levels of Ig secreting cells and of serum Igs were similar to that of control mice, antibody responses to both TI and TD antigens were severely affected, mainly in STF mice. Our findings therefore highlight the relevance of wild-derived mouse strains and TLR-L to study B cell physiology.     

Interplay of drug metabolizing CYP450 enzymes and ABC transporters in the blood-brain barrier

The recent identification of drug-metabolizing enzymes cytochrome P450 (CYP) in the human blood-brain barrier (BBB) raises the question of whether these enzymes act in concert with ATP-binding cassette (ABC) transporters to limit the brain distributions of drugs. We recently demonstrated several CYP genes in freshly isolated human brain microvessels; the main isoforms expressed were CYP1B1 and CYP2U1. Many studies using different experimental approaches have revealed that P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and the multidrug resistance-associated protein 4 (MRP4, ABCC4) are the main ABC transporters in the human BBB. The first part of this review covers recent studies on the expression, regulation and function of CYP450 and ABC transporters in the rodent and human BBBs. The second part focuses on the possible interplay between some CYPs and certain ABC transporters at the BBB, which makes it a determining element of brain drug concentrations and thus of the effects of centrally acting drugs.     

Neuroplasticity Regulation by Noradrenaline in Mammalian Brain

The neuromodulator noradrenaline (NA) is released in almost all brain areas in a highly diffused manner. Its action is slow, as it acts through G protein-coupled receptors, but its wide release in the brain makes NA a crucial regulator for various fundamental brain functions such as arousal, attention and memory processes [102]. To understand how NA acts in the brain to promote such diverse actions, it is necessary to dissect the cellular actions of NA at the level of single neurons as well as at the level of neuronal networks. In the present article, we will provide a compact review of the main literatures concerning the NA actions on neuroplasticity processes. Depending on which subtype of adrenoceptor is activated, NA differently affects intrinsic membrane properties of postsynaptic neurons and synaptic plasticity. For example, β-adrenoceptor activation is mainly related to the potentiation of synaptic responses and learning and memory processes. α2-adrenoceptor activation may contribute to a high-order information processing such as executive function, but currently the direction of synaptic plasticity modification by α2-adrenoceptors has not been clearly determined. The activation of α1-adrenoceptors appears to mainly induce synaptic depression in the brain. But its physiological roles are still unclear: while its activation has been described as beneficial for cognitive functions, it may also exert detrimental effects in some brain structures such as the prefrontal cortex.Key Words: Noradrenaline, LTP, LTD, neuromodulation, synaptic plasticity.     

Intestinal CD103+ dendritic cells: master regulators of tolerance?

CD103(+) dendritic cells (DCs) in the intestinal mucosa play a crucial role in tolerance to commensal bacteria and food antigens. These cells originate in the lamina propria (LP) and migrate to the mesenteric lymph nodes (MLNs), where they drive the differentiation of gut-homing FoxP3(+) regulatory T cells by producing retinoic acid from dietary vitamin A. Local 'conditioning' factors in the LP might also contribute to this tolerogenic profile of CD103(+) DCs. Considerably less is understood about the generation of active immunity or inflammation in the intestinal mucosa. This might require alterations in pre-existing CD103(+) DCs, arrival of new DCs, or the action of a distinct DC population. Here, we discuss our current knowledge of this as yet incompletely understood population.     

Laterality Preference and Cognition: Cross-Syndrome Comparison of Patients with Trisomy 21 (Down), del7q11.23 (Williams–Beuren) and del22q11.2 (DiGeorge or Velo-Cardio-Facial) Syndromes

We report on a cross-syndrome comparison of hand, foot, eye and ear laterality in three groups of individuals with different genetic disorders (trisomy 21, del7q11.23, and del22q11.2) to test the relationship between atypical laterality and intellectual disability. These groups were compared to a group of typically developing persons. Hand, foot, eye and ear laterality was assessed using item tasks, conducted twice, and Bishop’s card-reaching test. Ordering of the mean IQ score for each of the three groups was as follows: trisomy 21 < del7q11.23 < del22q11.2. We observed the same ordering as for IQ, particularly in mixed handedness, degree of laterality, hand and foot consistency. The existence of a cognitive threshold, below which lateral preference is atypical, advocates for a causal link between cognition and laterality in those with low IQ although unknown other factors underlying both could determine this association.     

Neonatal lung immune responses show a shift of cytokines and transcription factors toward Th2 and a deficit in conventional and plasmacytoid dendritic cells

The high incidence of lung‐damaging life‐threatening respiratory infections in infants may be related to the immaturity of their immune systems. To determine whether lung immune features differ in early life compared with those in adulthood, whole lung as well as lung T lymphocyte and DC responses were investigated in BALB/c neonates versus adults. Higher expression of GATA‐3 and rapid and sustained production of type 2 cytokines by lung explants after in vitro exposure to anti‐CD3 was the hallmark of the neonatal period, suggestive of a Th2 bias. Neonatal lung GATA‐3‐producing cells were identified as CD3⁺, CD4 and CD8 double‐negative T lymphocytes, a subset found at a higher frequency in neonatal than adult lung. The neonatal lungs contained fewer conventional DCs, with a lower ratio of CD103⁺ to CD11b⁺ DCs, and a much lower number of plasmacytoid DCs in comparison with adult lungs. Yet, when stimulated in vivo by BCG, neonatal lung DCs matured and primed adult naïve CD4⁺ T cells toward Th1 as efficiently as adult BCG‐primed lung DCs. Conversely, both adult and neonatal BCG‐primed lung DCs induced a Th2 cytokine response from neonatal naïve lymph node T cells, suggestive of an intrinsic feature of neonatal T lymphocytes.     

The child behavior checklist broad-band scales predict subsequent psychopathology: A 5-year follow-up

OBJECTIVE: To evaluate the utility of the Child Behavior Check list (CBCL) for identifying children of parents with panic disorder or major depression at high-risk for future psychopathology. METHODS: Baseline Internalizing and Externalizing CBCL T-scores were used to predict subsequent depressive, anxiety, and disruptive behavior disorders at a 5-year follow-up in children of parents with panic disorder, major depression, or neither disorder. RESULTS: The Internalizing scale predicted subsequent agoraphobia, generalized anxiety disorder, separation anxiety disorder, and social phobia. In contrast, the Externalizing scale predicted subsequent disruptive behavior disorders and major depression. CONCLUSIONS: The convergence of these results with previous findings based on structured diagnostic interviews suggests that the CBCL broad-band scales can inexpensively and efficiently help identify children at high risk for future psychopathology within a population of children already at risk by virtue of parental psychopathology.