The Postnatal Leptin Surge Supports Immune Cell Function in Rats.

BACKGROUND: Leptin plays an important role in the regulation of the immune response. There is a physiological surge of leptin in rodents during the neonatal period, which has mainly been studied in the context of brain development. However, little is known about the effects of this neonatal leptin surge on immunity. Therefore, we investigated whether blocking this leptin surge could affect several immune functions. METHODS: Male and female rats were injected subcutaneously with 5 mg/Kg/day of rat pegylated super leptin antagonist during the neonatal period (PND5-9). On the peripubertal period, relevant functions as well as cytokine release by spleen leukocytes were studied in these animals. RESULTS: The results showed that the animals significantly display an impaired anti-tumor NK activity and chemotactic and proliferation capacity of lymphocytes in response to mitogens. In addition, several cytokine concentrations, released under mitogen-stimulated conditions, were also altered. CONCLUSION: In conclusion, the neonatal leptin surge seems to be involved in the establishment of an adequate immune response and cytokine profile, which are crucial for the maintenance of a healthy life.

Unbiased Screening Identifies Functional Differences in NK Cells After Early Life Psychosocial Stress.

Early Life Adversity (ELA) is closely associated with the risk for developing diseases later in life, such as autoimmune diseases, type-2 diabetes and cardiovascular diseases. In humans, early parental separation, physical and sexual abuse or low social-economic status during childhood are known to have great impact on brain development, in the hormonal system and immune responses. Maternal deprivation (MD) is the closest animal model available to the human situation. This paradigm induces long lasting behavioral effects, causes changes in the HPA axis and affects the immune system. However, the mechanisms underlying changes in the immune response after ELA are still not fully understood. In this study we investigated how ELA changes the immune system, through an unbiased analysis, viSNE, and addressed specially the NK immune cell population and its functionality. We have demonstrated that maternal separation, in both humans and rats, significantly affects the sensitivity of the immune system in adulthood. Particularly, NK cells' profile and response to target cell lines are significantly changed after ELA. These immune cells in rats are not only less cytotoxic towards YAC-1 cells, but also show a clear increase in the expression of maturation markers after 3h of maternal separation. Similarly, individuals who suffered from ELA display significant changes in the cytotoxic profile of NK cells together with decreased degranulation capacity. These results suggest that one of the key mechanisms by which the immune system becomes impaired after ELA might be due to a shift on the senescent state of the cells, specifically NK cells. Elucidation of such a mechanism highlights the importance of ELA prevention and how NK targeted immunotherapy might help attenuating ELA consequences.

Development of Proliferative Response of Thymic Lymphocytes to T-Cell Mitogen in Rats Exposed to Endocrine Disrupter DDT during Ontogeny.

We studied the formation of proliferative response of thymic lymphocytes to T-cell mitogen in rats exposed to endocrine disrupter DDT during prenatal and postnatal ontogeny. Developmental exposure to the endocrine disruptor was found to attenuate proliferative response during puberty and adulthood due to maintenance of higher proliferation rate of thymic lymphocytes in comparison with age-matched controls. Insufficient proliferative response to mitogens in rats developmentally exposed to the endocrine disrupter increases the risk of impairment of cell-mediated reactions of adaptive immunity.

The Human Microbiome and Child Growth - First 1000 Days and Beyond.

The assembly of microbial communities within the gastrointestinal tract during early life plays a critical role in immune, endocrine, metabolic, and other host developmental pathways. Environmental insults during this period, such as food insecurity and infections, can disrupt this optimal microbial succession, which may contribute to lifelong and intergenerational deficits in growth and development. Here, we review the human microbiome in the first 1000 days - referring to the period from conception to 2 years of age - and using a developmental model, we examine the role of early microbial succession in growth and development. We propose that an 'undernourished' microbiome is intergenerational, thereby perpetuating growth impairments into successive generations. We also identify and discuss the intertwining host-microbe-environment interactions occurring prenatally and during early infancy, which may impair the trajectories of healthy growth and development, and explore their potential as novel microbial targets for intervention.

Developmental induction of human T-cell responses against Candida albicans and Aspergillus fumigatus.

The origin of human T-cell responses against fungal pathogens early in life is not clearly understood. Here, we show that antifungal T-cell responses are vigorously initiated within the first years of life against lysates and peptides of Candida albicans or Aspergillus fumigatus, presented by autologous monocytes. The neonatal responding T-cell pool consists of 20 different TCR-Vß families, whereas infant and adult pools display dramatically less variability. Although we demonstrate no bias for anti-fungal IL-4 expression early in life, there was a strong bias for anti-fungal IL-17 production. Of note, only T-cells from neonates and infants show an immediate co-expression of multiple cytokines. In addition, only their T-cells co-express simultaneously transcription factors T-bet and RORγt in response to fungi and subsequently their target genes IL-17 and IFNγ. Thus, T-cells of neonates and infants are predetermined to respond quickly with high plasticity to fungal pathogens, which might give an excellent opportunity for therapeutic interventions.

Active suppression of intestinal CD4(+)TCRαß(+) T-lymphocyte maturation during the postnatal period.

Priming of the mucosal immune system during the postnatal period substantially influences host-microbial interaction and susceptibility to immune-mediated diseases in adult life. The underlying mechanisms are ill defined. Here we show that shortly after birth, CD4 T cells populate preformed lymphoid structures in the small intestine and quickly acquire a distinct transcriptional profile. T-cell recruitment is independent of microbial colonization and innate or adaptive immune stimulation but requires ß7 integrin expression. Surprisingly, neonatal CD4 T cells remain immature throughout the postnatal period under homeostatic conditions but undergo maturation and gain effector function on barrier disruption. Maternal SIgA and regulatory T cells act in concert to prevent immune stimulation and maintain the immature phenotype of CD4 T cells in the postnatal intestine during homeostasis. Active suppression of CD4 T-cell maturation during the postnatal period might contribute to prevent auto-reactivity, sustain a broad TCR repertoire and establish life-long immune homeostasis.

Early postnatal growth in children with HLA-conferred susceptibility to type 1 diabetes.

AIMS/HYPOTHESIS: An association between increased length/height and weight gain and risk of type 1 diabetes (T1D) has been reported in children. We set out to investigate the potential contribution of T1D human leukocyte antigen (HLA) risk genotypes to this association in two countries with a contrasting disease incidence. METHODS: In Estonia and Finland, length and weight were monitored up to the age of 24 months in 688 subjects. According to their HLA genotypes, the children were divided into four groups, those with very high, high or moderate risk for T1D, as well as a neutral/control group. Relative length and weight (SDS) were assessed and compared at 3, 6, 12, 18 and 24 months using World Health Organization (WHO) growth curves. RESULTS: The mean relative length at the age of 24 months was lower in the group with the very high risk HLA genotype compared to the controls (p < 0.05). The mean relative weight differed between those two groups at the age of 12, 18 and 24 months (p < 0.05). When Estonian and Finnish cohorts were analyzed separately, the relative length showed similar but non-significant trends in both countries, while in Estonia the changes in weight at some time points still remained significant (p < 0.05). CONCLUSIONS: Children with the highest HLA-conferred risk for T1D gained less weight and length during the first 24 months of life, and this feature was more pronounced in the Estonian children.

Assessing a theoretical risk of dolutegravir-induced developmental immunotoxicity in juvenile rats.

HIV-1 integrase inhibitors (INIs) are a promising class of antiretrovirals for the treatment of HIV in adults; there is interest in expanding their use into pediatric populations. A theoretical concern for developmental immunotoxicity was raised after a publication suggested that two HIV INI tool compounds inhibited in vitro cleavage activity of recombination activating genes 1 and 2 (RAG1/2) through the inhibition of their binding to recombination signal sequences. RAG1/2 are required for the development of mature B and T lymphocyte populations. The potential effects of the investigational INI dolutegravir on RAG1/2 were addressed by developing assays in juvenile rats to measure T cell receptor (TCR) Vß usage by flow cytometry as an indicator of TCR repertoire diversity and a T cell dependent antibody response (TDAR) as an indicator of immunosuppression. These endpoints were incorporated into a juvenile rat toxicity study, along with immunophenotyping, hematology, and histopathology of immunologic organs. Dose levels of 0, 0.5, 2, or 75mg/kg/day dolutegravir were given via oral gavage from postnatal day 4 through 66. At the highest dose, there was decreased body weight gain and two preweanling deaths; however, there were no treatment-related effects on developmental parameters. There were no effects on immunologic competence, as measured by TDAR, and no effects on lymphocyte subsets or CD4 and CD8 TCR Vß usage in peripheral blood. Histopathology of immunologic organs (spleen, thymus, lymph nodes) and hematology evaluation revealed no effects. The no observed adverse effect level for immunotoxicity endpoints was 75mg/kg/day.

CLEC-2 and Syk in the megakaryocytic/platelet lineage are essential for development.

The C-type lectin receptor CLEC-2 signals through a pathway that is critically dependent on the tyrosine kinase Syk. We show that homozygous loss of either protein results in defects in brain vascular and lymphatic development, lung inflation, and perinatal lethality. Furthermore, we find that conditional deletion of Syk in the hematopoietic lineage, or conditional deletion of CLEC-2 or Syk in the megakaryocyte/platelet lineage, also causes defects in brain vascular and lymphatic development, although the mice are viable. In contrast, conditional deletion of Syk in other hematopoietic lineages had no effect on viability or brain vasculature and lymphatic development. We show that platelets, but not platelet releasate, modulate the migration and intercellular adhesion of lymphatic endothelial cells through a pathway that depends on CLEC-2 and Syk. These studies found that megakaryocyte/platelet expression of CLEC-2 and Syk is required for normal brain vasculature and lymphatic development and that platelet CLEC-2 and Syk directly modulate lymphatic endothelial cell behavior in vitro.

The effect of past food avoidance due to allergic symptoms on the growth of children at school age.

BACKGROUND: The influence of food avoidance due to allergic symptoms in infancy on the growth of children at school age has not been well evaluated. METHODS: To determine the growth of schoolchildren who avoided eggs, milk, or wheat due to immediate allergic symptoms in infancy (food avoiders in infancy) (FAI), a questionnaire on the presence of allergic diseases, as well as present height and weight, was administered to the parents of 14,669 schoolchildren. 11,473 subjects had available data. The height and weight standard deviation scores (HtSDS and WtSDS) and body mass index percentile (BMI percentile) of each subject were calculated. RESULTS: FAI had significantly lower WtSDS than non-FAI (P = 0.01). Among those with avoidance at age 3 years, those who avoided two or more foods and those who avoided milk had significantly lower HtSDS than their counterparts (P = 0.02 and 0.04, respectively). FAI had a significantly lower prevalence of obesity (P = 0.01) and overweight (P = 0.002), while there was no difference in the prevalence of underweight (P = 0.58), resulting in a significantly higher prevalence of appropriate weight (P = 0.01) compared to non-FAI. Significantly lower prevalence of obesity and overweight was observed even among those who terminated the avoidance by age 3 years. CONCLUSIONS: FAI were less likely to be obese or overweight, resulting in a higher prevalence of appropriate weight at school age. Further investigation should contribute to better management of food allergy and obesity.

[Comparison of routine serological investigations performed in three different laboratories in Poland for the diagnosis of pertussis]. / Porównanie wyników serologicznych badan w kierunku krztusca rutynowo prowadzonych w trzech róznych laboratoriach w polsce.

We compared the 2.653 results of routine serological investigations performed in three different laboratories in Poland for the diagnosis of pertussis. One of the laboratories used the NovaLisa Bordetella pertussis kit produced by NovaTec GmbH and the two others used Bordetella pertussis ELISA kit produced by Genzyme Virotech GmbH. In first laboratory the diagnostic level of IgA antibodies to the pertussis toxin was observed in 11.0%, IgG in 52.7% and IgM in 27.4% serum samples. In the second and third laboratory the diagnostic level of IgA antibodies were found respectively in 22.2% and 40.1%, IgG in 46.8% and 66.4% and IgM only in 8.7% and 4.8% serum samples. In total, IgA antibodies were found in 28.0%, IgG antibodies in 56.0% and IgM antibodies in 14.3% serum samples obtained from patients suspected in clinical investigation for pertussis. We have observed that the frequency of detection of the antibodies in children and adolescents increased with age reaching its peak among individuals with age range between 11-20 years. We also found statistical significant higher frequency of IgA, IgG and IgM antibodies to B. pertussis in outpatients than in hospital patients.

V(D)J recombinase-mediated processing of coding junctions at cryptic recombination signal sequences in peripheral T cells during human development.

V(D)J recombinase mediates rearrangements at immune loci and cryptic recombination signal sequences (cRSS), resulting in a variety of genomic rearrangements in normal lymphocytes and leukemic cells from children and adults. The frequency at which these rearrangements occur and their potential pathologic consequences are developmentally dependent. To gain insight into V(D)J recombinase-mediated events during human development, we investigated 265 coding junctions associated with cRSS sites at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in peripheral T cells from 111 children during the late stages of fetal development through early adolescence. We observed a number of specific V(D)J recombinase processing features that were both age and gender dependent. In particular, TdT-mediated nucleotide insertions varied depending on age and gender, including percentage of coding junctions containing N-nucleotide inserts, predominance of GC nucleotides, and presence of inverted repeats (Pr-nucleotides) at processed coding ends. In addition, the extent of exonucleolytic processing of coding ends was inversely related to age. We also observed a coding-partner-dependent difference in exonucleolytic processing and an age-specific difference in the subtypes of V(D)J-mediated events. We investigated these age- and gender-specific differences with recombination signal information content analysis of the cRSS sites in the human HPRT locus to gain insight into the mechanisms mediating these developmentally specific V(D)J recombinase-mediated rearrangements in humans.

Maternal antibodies in a wild altricial bird: effects on offspring immunity, growth and survival.

1. In many animals immunity is not fully developed until adulthood but the young still need protection against various sets of pathogens. Thus, bird nestlings are highly dependent on antibodies received from their mother (in the eggs) during their rapid early growth period. The relationship between maternal immunity and the development of neonates' own immunity has been poorly studied. 2. It has been suggested that immune function plays an important part in mediating resource competition between different life-history traits, e.g. growth and reproduction. Maternal investment of antibodies has potentially permanent effects on offspring phenotype. Thus, the trade-offs between the immune function and other important life-history traits in the offspring will also affect the fitness of the mother. 3. Our supplemental feeding experiment in the magpie Pica pica indicates that the immunoglobulin levels of offspring at hatching are dependent on a mother's nutritional condition. In addition, the amount of maternal immunoglobulins transferred to offspring increases along the laying order within a nest. 4. We also found that at the age of 8-10 days the immunoglobulin production of the offspring has already begun. Furthermore, the maternal immunoglobulin levels of the offspring at hatching were positively related to their immunoglobulin levels on day 10. 5. Maternal immunoglobulins did not significantly affect offspring growth, but there was a negative relationship between self-produced immunoglobulins and growth over the first 10 days, indicating a trade-off between these traits. Nestlings' weight, however, had a positive relationship with immunoglobulin production suggesting that the observed trade-off between growth and immunoglobulin production is due to catch-up growth of nestlings with a low hatching weight. We found that within nests nestlings with higher maternal antibody levels had higher survival rate until day 20, but between nests there was an opposite relationship. 6. Evidently, there is a trade-off, in magpies, between maternal resources, immune function and growth, shaping the evolution of maternal investment in offspring immunity.

Effect of dietary ribonucleotides on infant immune status. Part 1: Humoral responses.

The objective of this study was to further explore previously identified effects of supplemental ribonucleotides on infant immune status as measured by antibody responses to routine infant immunizations. Infants were randomized to a milk-based formula with (FN, n = 138) or without (F, n = 147) 72 mg ribonucleotides/L. A cohort of human milk-fed (HMF, n = 192) infants was also followed. Subjects were given Haemophilus influenzae type b (Hib), diphtheria tetanus acellular pertussis, and oral poliovirus vaccinations at 2, 4, and 6 mo of age, and specific antibody responses were assessed at 2, 6, 7, and 12 mo. Growth and safety data were also monitored. Using a two-group repeated measures analysis (RMA), FN-fed infants had significantly higher poliovirus type 1 neutralizing antibody (PV-VN1) responses than F-fed infants (p = 0.045). Using three-group RMA, PV-VN1 responses in HMF infants were not different from FN-fed infants, while HMF-fed infant PV-VN1 responses were significantly higher than F-fed infants at 6 (p = 0.0004) and 12 mo (p = 0.0001). FN-fed infants had responses to Hib Farr, diphtheria, tetanus toxoid, oral poliovirus-specific IgA, and PV-VN3 not significantly different from those of F and HMF infants. Growth, gastrointestinal tolerance, and adverse events were equivalent among the three groups. The FN-associated increase in PV-VN1 response and nonstatistically significant trends toward increased Hib and diphtheria antibody responses were consistent with observations from earlier studies, indicating immune benefits of nucleotide supplementation of infant formula.

The ontogenic development of innate immune parameters of cod (Gadus morhua L.).

The aim of this study was to monitor the ontogenic development of innate immune parameters of cod (Gadus morhua L.) and to determine the presence of maternal IgM. The general protein composition and enzyme activity was also studied. At intervals, samples were collected of fertilized cod eggs and larvae from 3 days after fertilization until 57 days after hatching. Cell lysates were prepared and analysed by Western blotting using antibodies prepared against cod IgM, the complement component C3 and C-reactive protein (CRP) as well as against cod serum proteins and haemoglobin. Antibodies against salmon cathepsins and against several mammalian proteins of immunological significance were also used. Maternal IgM was not detected but C3 and the closely associated apolipoprotein A-I were present from the time of embryo organogenesis. C-reactive protein was not detected and none of the antibodies against mammalian immune parameters cross-reacted with the cod material. Protein and proteomic analysis showed that the major proteins of the egg samples were vitellogenin derived maternal proteins. Other non-vitellogenin maternal proteins, not yet identified, were also detected in the fertilized eggs. Cathepsin was present in all samples, but other enzyme activity was restricted to larval samples from 4 days after hatching when feeding had commenced. Haemoglobin was not detected until 10 days after hatching.