NBAS Variants Are Associated with Quantitative and Qualitative NK and B Cell Deficiency

Purpose

Biallelic pathogenic NBAS variants manifest as a multisystem disorder with heterogeneous clinical phenotypes such as recurrent acute liver failure, growth retardation, and susceptibility to infections. This study explores how NBAS-associated disease affects cells of the innate and adaptive immune system.

Methods

Clinical and laboratory parameters were combined with functional multi-parametric immunophenotyping methods in fifteen NBAS-deficient patients to discover possible alterations in their immune system.

Results

Our study revealed reduced absolute numbers of mature CD56^dim natural killer (NK) cells. Notably, the residual NK cell population in NBAS-deficient patients exerted a lower potential for activation and degranulation in response to K562 target cells, suggesting an NK cell–intrinsic role for NBAS in the release of cytotoxic granules. NBAS-deficient NK cell activation and degranulation was normalized upon pre-activation by IL-2 in vitro, suggesting that functional impairment was reversible. In addition, we observed a reduced number of naïve B cells in the peripheral blood associated with hypogammaglobulinemia.

Conclusion

In summary, we demonstrate that pathogenic biallelic variants in NBAS are associated with dysfunctional NK cells as well as impaired adaptive humoral immunity.

     

HMf, a DNA-binding protein isolated from the hyperthermophilic archaeon Methanothermus fervidus, is most closely related to histones.

Methanothermus fervidus grows optimally at 83 degrees C. A protein designated HMf (histone M. fervidus) has been isolated from this archaeal hyperthermophile that binds to double-stranded DNA molecules and increases their resistance to thermal denaturation. HMf binding to linear double-stranded DNA molecules of greater than 2 kilobase pairs also increases their electrophoretic mobilities through agarose gels. Visualization of this compaction process by electron microscopy has demonstrated the formation of quasispherical, macromolecular HMf-DNA complexes. HMf is a mixture of approximately equal amounts of two very similar polypeptides designated HMf-1 and HMf-2. Determination of the DNA sequence of the gene encoding HMf-2 (hmfB) has revealed that over 30% of the amino acid residues in HMf-2 are conserved in the consensus sequences derived for eucaryal histones H2A, H2B, H3, and H4. These archaeal polypeptides and eucaryal histones appear therefore to have evolved from a common ancestor and are likely to have related structures and functions.     

Age-dependent alterations in nitrous oxide requirement of mice

To determine the relationship of nitrous oxide requirement to age in mice, the authors repeatedly tested the righting-reflex response in stock CD-1 mice at 50 to 703 days of age. Over this age range, nitrous oxide requirement (+/- SE) progressively decreased from 1.48 +/- 0.02 atm to 1.09 +/- 0.06 atm. A second set of experiments measured changes in nitrous oxide requirement with age in mice selectively bred for resistance (HI mice) and susceptibility (LO mice) to nitrous oxide anesthesia. When tested at two months of age, selected HI and LO mice had nitrous oxide ED50 values of approximately 2.0 and 1.1 atm, respectively. At 11 to 14 months, the nitrous oxide ED50 of the HI mice had decreased to approximately 1.5 atm. In contrast, the nitrous oxide ED50 of the LO mice showed a much smaller decrease over this age range. Thus, the separation in nitrous oxide requirement between the HI and LO lines tended to disappear with age. By correlating the difference in anesthetic requirement between the HI and LO mice with biochemical and biophysical alterations in the central nervous system, studies on aging that use selectively bred lines may be helpful in investigating the mechanism of anesthetic action and the mechanism by which aging affects anesthetic action.     

MAC values of thiopental and fentanyl in rats

A comparison of the effects of thiopental or fentanyl with those of inhaled anesthetics requires the establishment of a comparable level of anesthetic potency. Accordingly, using the response of male Sprague-Dawley rats to tail-clamping, we determined the ED50S for thiopental and fentanyl. Half of the rats were pretreated with phenobarbital. After subcutaneous injection of various doses of thiopental or fentanyl, each rat was tested for movement in response to tail-clamping at 15-min intervals for 2 h. In untreated rats, the maximal effect of thiopental (i.e., the lowest ED50 value was 107 +/- 10 mg/kg, mean +/- SEM) occurred 75 min after injection. Although higher values were found at other times, differences from the nadir were relatively small. In rats pretreated with phenobarbital, the lowest value (130 +/- 8 mg/kg) occurred at 60 min. The lowest ED50S for fentanyl (52 +/- 7 micrograms/kg for control rats, and 73 +/- 14 micrograms/kg for pretreated rats) were found at 15 min.     

Relationship and prognostic value of microvascular obstruction and infarct size in ST-elevation myocardial infarction as visualized by magnetic resonance imaging

Background  

Both infarct size and microvascular obstruction (MO) assessed by cardiac magnetic resonance imaging (CMR) are known to be predictors for adverse clinical outcome after ST-elevation myocardial infarction (STEMI). We hypothesized that a ratio of MO and infarct size (MO/infarct size) might be an even stronger predictor for outcome after STEMI, which has not been investigated yet.     

Mechanism of age-related and nitrous oxide-associated anesthetic sensitivity: the role of brain catecholamines

To provide a neurochemical basis for differences in their anesthetic requirements, the authors examined mice selectively bred for resistance (HI) and susceptibility (LO) to nitrous oxide anesthesia for brain levels of catecholamines. Concentrations of norepinephrine and dopamine in whole brain were 26% and 13% higher (P less than 0.001), respectively, in HI mice than in LO mice. Whole-brain levels of 3,4-dihydroxyphenylacetic acid, a major metabolite of dopamine, were the same for both HI and LO groups of mice. The authors then analyzed portions of the HI and LO mice brains for concentrations of norepinephrine and dopamine. A significant correlation was found between norepinephrine content in the medulla and nitrous oxide requirement. In other regions of the brain (cerebellum, cerebral cortex, hippocampus, pons, midbrain, hypothalamus), no significant differences in norepinephrine or dopamine levels could be detected. Differences in anesthetic requirements between resistant and susceptible mice decrease from 0.99 to 0.53 atm as they aged from 100 days to 600 days old, paralleling the decline in differences in norepinephrine levels in medulla oblongata between HI and LO mice from 1.6 to 0.73 ng/mg protein. Thus, the difference in anesthetic requirement between HI and LO mice may arise from alterations in catecholamine content in specific regions of the brain.