Immune cell phenotype and functional defects in Netherton syndrome

Background

Netherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete.

Results

We analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17?years, and healthy age-matched controls. The proportion of B cells (CD19⁺) and naïve B cells (CD27^?, IgD⁺) were high while memory B cells (CD27⁺) and switched memory B cells (CD27⁺IgM^?IgD^?), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21^low, CD38l^ow) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naïve CD4⁺ T cells was reduced significantly and the proportion of CD8⁺ T central memory significantly elevated. An increased proportion of CD57⁺ CD8⁺ T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16⁺ and CD27^? NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity.The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L⁺ T cells, naïve CD4⁺ and CD27⁺ CD8⁺ T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naïve T cells and terminal differentiated effector memory CD8⁺ cells and decreased the proportion of activated B cells and plasmablasts in three patients studied.

Conclusions

This study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.

     

Non‐native plant species benefit from disturbance: a meta‐analysis

Disturbances, such as fire and grazing, are often claimed to facilitate plant species richness and plant invasions in particular, although empirical evidence is contradictory. We conducted a meta‐analysis to synthesize the literature on how non‐native plant species are affected by disturbances. We explored whether the observed impact of disturbance on non‐native plant communities is related to its type and frequency, to habitat type, study approach (observational or experimental), and to the temporal and spatial scales of the study. To put the results in a broader context, we also conducted a set of parallel analyses on a data set involving native plant species. The diversity and abundance of non‐native plant species were significantly higher at disturbed sites than at undisturbed sites, while the diversity and abundance of native plant species did not differ between the two types of sites. The effect of disturbance on non‐native plant species depended on the measure used to evaluate the impact (species diversity or abundance) and on disturbance type, with grazing and anthropogenic disturbances leading to higher diversity and abundance of non‐native plant species than other disturbance types examined. The impact of disturbance on non‐natives was also associated with study approach, habitat type and temporal scale, but these factors covaried with disturbance type, complicating the interpretation of the results. Overall, our results indicate that disturbance has a positive impact particularly on non‐native plant species (at least when they are already present in the community), and that the strength of this impact depends primarily on the disturbance type. Synthesis Empirical evidence of the effect of disturbances on plant species richness is contradictory. Here we use a meta‐analysis to synthesize the published literature on how different types of disturbances influence the diversity and abundance of plant species, focusing in particular on non‐native plants. Our study supports the hypothesis that disturbances generally facilitate the diversity and abundance of non‐native plant species, although the strength of this facilitation depends primarily on the disturbance type.     

Longitudinal study of the renin angiotensin aldosterone system in purebred Spanish broodmares during pregnancy

During pregnancy, the coordinated interaction of the components of the renin-angiotensin-aldosterone system (RAAS) plays a vital role in accommodating the cardiovascular, haemodynamic and haematological needs imposed by foetal development and the placenta. This significantly influences the birth weight of the neonate and foetal viability. Although the evolution of each of the components of this system has been widely described in various species, it has not yet been clarified in the mare. Thus, the objectives of the present research were: 1) to establish reference values for renin (REN), angiotensin II (ANG-II) and aldosterone (ALD) concentrations in Spanish broodmares, and 2) to analyse the evolution of the aforementioned components during pregnancy.Thirty-one Purebred Spanish broodmares aged between 5 and 15 years old were studied for 11 months of pregnancy and compared to a control group composed of 11 non-pregnant Spanish mares. Morning venous blood samples were drawn on a monthly basis during pregnancy and pre-treated to prevent degradation until subsequent analysis. Serum REN, ANG-II and ALD concentrations were analysed by competitive immunoassay. This study found that pregnancy in Purebred Spanish broodmares is characterised by a gradual increase in REN concentrations, variable fluctuations in ALD concentrations, and no significant modifications in ANG-II concentrations. These results could provide potentially valuable information in understanding the physiological basis of the RAAS in mares, since we have been able to establish specific reference ranges for these components, as well as obtaining information on their evolution during pregnancy. As is often the case in other animal species, the increase in RAAS activity is a natural physiological process that occurs during pregnancy in Spanish broodmares. This may also be related to certain metabolic and hormone responses that contribute to the control of homeostasis in pregnant mares.     

Zn2+ -Promoted Hydrolysis of 3′,5′-Dinucleoside Monophosphates and Polyribonucleotides. The Effect of Nearest Neighbours on the Cleavage of Phosphodiester Bonds

Abstract

Pseudo first-order rate constants for the Zn²⁺ -promoted cleavage of 15 different dinucleoside monophosphates, 4 different ribo homopogmers and RNA III from baker's yeast have been determined. Furthermore, the distribution of various nucleosides at the 3′-and 5′-terminus of the oligomeric hdrolysls products of RNA has been quantified. On these bases, the effect of nearest neighbours on the metal-ion-promoted hydrolysis of the internucleosidic phosphodiester bonds of RNA is discussed.     

Gender‐dependent effects of water quality and conspecific density on the feeding rate of fish – factors behind sexual growth dimorphism

Sexual growth dimorphism is common among animals, growth rate differing between the genders. Growth dimorphism is common also in fish, but the regulatory mechanisms remain unclear. Variations in feeding rate may lead to sexual growth dimorphism in fish, the growth rate of females decreasing steeper than the growth rate of males when feeding rate decreases. Because water quality strongly affects the prey detection by fish, variations in water quality could affect sexual growth dimorphism. Additionally, variations in fish density could affect dimorphism through food competition. We studied experimentally with perch Perca fluvialitis, whether the effects of decreasing water transparency and increasing fish density on the feeding rate of planktivorous fish are gender‐dependent. We expected that the feeding efficiency of females decrease steeper with increasing water colour and increasing fish density than the feeding rate of males. Additionally, we collected field data and studied the effects of water colour on the growth rate of male and female perch. The results showed that the effect of water colour on the feeding rate of perch was gender‐dependent, while perch density had no effect on the feeding rate difference between males and females. In highly humic water, the feeding rate of male and female perch did not differ, but in clear water females showed a significantly higher feeding rate than males. The results suggested that due to their high energy demand, female perch were feeding at high rate in both water colours, while the feeding rate of males in the clear water experiments was much lower than their possible maximum rate. This was probably due to the decreased feeding activity of males to reduce predation risk. The results were supported by field data, which revealed a significant effect of water colour on the gender growth difference in planktivorous 3‐year‐old perch. The results suggested that variations in water quality may be a factor behind the population‐dependency of dimorphism in fish.     

Cost of reproduction in Callosobruchus maculatus: effects of mating on male longevity and the effect of male mating status on female longevity

One of the most studied life-history trade-offs is that resulting from the cost of reproduction: a trade-off arises when reproduction diverts limited resources from other life-history traits. We examine the cost of reproduction in male, and the effect of male mating status on female Callosobruchus maculatus seed beetles. Cost of reproduction for male C. maculatus was manifested as reduced longevity. There was also a positive relationship between male body size and male longevity. Females mated to males that had already copulated twice did not live as long as females mated to males that had copulated once or not at all. The third copulation of males also lasted longer than the two previous ones. We conclude that even though the cost of reproduction for males has been studied much less than that in females, there is growing evidence that male reproductive effort is more complex than has traditionally been thought.     

Chronic myeloid leukemia patients in prolonged remission following interferon-α monotherapy have distinct cytokine and oligoclonal lymphocyte profile

Before the era of tyrosine kinase inhibitors (TKIs), interferon-alpha (IFN-α) was the treatment of choice in chronic myeloid leukemia (CML). Curiously, some IFN-α treated patients were able to discontinue therapy without disease progression. The aim of this project was to study the immunomodulatory effects of IFN-α in CML patients in prolonged remission and isolate biological markers predicting response. Due to rarity of patients on IFN-α monotherapy, a relatively small cohort of patients still on treatment (IFN-ON, n = 10, median therapy duration 11.8 years) or had discontinued IFN-α therapy but remained in remission for >2 years (IFN-OFF, n = 9) were studied. The lymphocyte immunophenotype was analyzed with a comprehensive flow cytometry panel and plasma cytokine levels were measured with multiplex bead-based assay. In addition, the clonality status of different lymphocyte subpopulations was analyzed by TCR γ/δ rearrangement assay. Median NK-cell absolute number and proportion from lymphocytes in blood was higher in IFN-OFF patients as compared to IFN-ON patients or controls (0.42, 0.19, 0.21×10⁹/L; 26%, 12%, 11%, respectively, p<0.001). The proportion of CD8+ T-cells was significantly increased in both patient groups and a larger proportion of T-cells expressed CD45RO. Most (95%) patients had significant numbers of oligoclonal lymphocytes characterized by T-cell receptor γ/δ rearrangements. Strikingly, in the majority of patients (79%) a distinct clonal Vγ9 gene rearrangement was observed residing in γδ⁺ T-cell population. Similar unique clonality pattern was not observed in TKI treated CML patients. Plasma eotaxin and MCP-1 cytokines were significantly increased in IFN-OFF patients. Despite the limited number of patients, our data indicates that IFN-α treated CML patients in remission have increased numbers of NK-cells and clonal γδ⁺ T-cells and a unique plasma cytokine profile. These factors may relate to anti-leukemic effects of IFN-α in this specific group of patients and account for prolonged therapy responses even after drug discontinuation.     

miRNA expression profiling for identification of potential breast cancer biomarkers

To identify micro RNA (miRNA) biomarker candidates for early detection of breast cancer and detection of minimal residual breast cancer, we performed miRNA expression profiling in pooled RNA samples from breast tumors, and from bone marrow mononuclear cells, peripheral blood mononuclear cells and plasma from healthy controls. We found substantially higher levels of five miRNAs in the breast tumors compared to the normal samples. However, validation of these miRNA levels, and seven other candidates selected from the literature, in individual samples from healthy controls and patients with non-metastatic breast cancer did not suggest further examination of their biomarker potential.     

Relationship between progesterone, oestrone sulphate and cortisol and the components of renin angiotensin aldosterone system in Spanish purebred broodmares during pregnancy

The coordinated interaction of the components of the renin angiotensin aldosterone system (RAAS) with reproductive hormones such as progesterone, oestrogens and cortisol during pregnancy has been widely reported to play a vital role in foetal and placental development in various species, significantly influencing the proper achievement of pregnancy and foetal viability at birth. These interactions have not yet been clarified in mares. Thus, the purpose of the present research was to analyse the relationship between cortisol (CORT), progesterone (P4) and oestrone sulphate (OESTRONE), and the components of the RAAS, renin (REN), angiotensin II (ANG-II) and aldosterone (ALD) concentrations in Spanish broodmares during pregnancy.Venous blood samples were obtained monthly from a total of 31 Purebred Spanish broodmares aged between 5 and 15 years during the 11 months of pregnancy. Plasma and serum REN, ANG-II, ALD, P4, OESTRONE and CORT concentrations were analysed by competitive immunoassay. Pregnancy in Purebred Spanish broodmares is characterised by a progressive increase in REN and ALD, a decrease in CORT levels, variable fluctuations in P4 and OESTRONE and no variations in ANG-II concentrations (P < 0.05). Serum P4 was not correlated with either ALD or CORT. The OESTRONE and REN levels were not correlated, while OESTRONE and ALD showed a positive correlation (r = 0.16; P < 0.05). These results suggest that the sustained stimulation of the RAAS in normal pregnancy in Spanish broodmares is not totally dependent on the changes in P4 and CORT concentrations, despite the involvement of OESTRONE in the secretion of ALD. This brings into question the possible involvement of oestrogen in the secretion of ALD by a mechanism which is not exclusively dependent on REN. Consequently, at physiological levels, OESTRONE is not the only stimulus for REN synthesis, and the mineralocorticoids ALD and CORT do not show a competitive mechanism with P4 during pregnancy in mares. Other mechanisms which do not depend on these hormones should be considered in the modification of the RAAS during pregnancy in Spanish mares.