Small Thymus Research Articles

P0011THE ROLE OF AQUAPORIN-11 (AQP11) IN THE THYMUS DEVELOPMENT

Abstract Background and Aims Some aquaporins transport not only water but also small non-ionic molecules such as glycerol. In fact, aquaporin-9 (AQP9) has been shown to transport glycerol which is critical to support memory T cell survival through metabolic fitness (Cui G et al. Cell. 161:750, 2015). As AQP11 is widely expressed and transport glycerol as well as water, AQP11 may also play a role in immunological system, which will expand the repertoire of the aquaporin research field. Method The AQP11 expression in the thymus was examined by RT-PCR, Western blot and immunohistochemistry in mice. Phenotypic analysis and microarray analysis of the thymus were conducted in wild and AQP11 null mice at 21 day old before the development of uremia due to polycystic kidneys. Results Both mRNA and protein expressions of AQP11 in the thymus were higher than those of the kidney by RT-PCR and Western blot. Interestingly, the size of the thymus from AQP11 null mice was smaller than that of the wild mice: 28mg vs. 56mg, even after the correction by the body weight: 0.59 % vs. 0.82 %, as the body size of AQP11 null mice was smaller. The vacuolated medullary epithelial cells were observed in the thymus of AQP11 null mice with narrowed cortex. The immunohistochemical analysis revealed the AQP11 expression at the stromal-epithelial cells in the thymus. The microarray analysis of the gene expression in the thymus was compared between the wild and AQP11 null thymus by the annotation analysis based on the David Bioinformatics Resources 6.8 (beta). The up-regulated 66 genes more than 1.5 folds in AQP11 null thymus are mainly related to the PI3K/Akt signaling pathway to promote metabolism, proliferation, cell survival, growth and angiogenesis. On the other hand, the down-regulated 55 genes less than half in AQP11 null thymus are related to energy production and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Further RT-qPCR analysis confirmed the enhanced expression of Egfr (Epidermal Growth Factor Receptor), Itgb4 (Integrin beta-4) and Il2ra (interleukin 2 receptor alpha) and the diminished expression of aquaglyceroporin AQP7, Pck1 (Phosphoenolpyruvate carboxy-kinase 1) and Ucp1 (Mitochondrial uncoupling protein 1). The up-regulated genes for growth signaling was unexpected with the smaller thymus but may support the survival of the hypoplastic thymus as a compensation. On the other hand, the down-regulated genes may compromise fat-glucose-energy metabolism in the thymus leading to the smaller thymus, which may be aggravated by the decreased expression of AQP7, another glycerol channel. Conclusion AQP11 may play an important role in the metabolic control of the developing thymus possibly through its glycerol transport. The smaller thymus with narrower cortex in AQP11 null mice may lead to immunological dysfunction, which is currently under study.

BRAF V600E and Pten deletion in mice produces a histiocytic disorder with features of Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is characterized by the accumulation of Langerin (CD207)-expressing histiocytes. Mutational activation of mitogen-activated protein kinase pathway genes, in particular BRAF, drives most cases. To test whether activated BRAF is sufficient for the development of LCH, we engineered mice to express BRAF V600E under the control of the human Langerin promoter. These mice have shortened survivals, smaller lymphoid organs, absent Leydig cells, and fewer epidermal LCs than controls, but do not accumulate histiocytes. To test whether the absence of histiocyte proliferation could be due to oncogene-induced senescence, we engineered homozygous Pten loss in the same cells that expressed BRAF V600E. Like mice with intact Pten, these mice have shortened survivals, smaller thymi, and absent Leydig cells. However, loss of Pten also leads to the accumulation of CD207+ histiocytes in spleen, thymus, and some lymph nodes. While many CD207+ histiocytes in the thymus are CD8-, reminiscent of LCH cells, the CD207+ histiocytes in the spleen and lymph nodes are CD8+. These mice also accumulate large numbers of CD207- cells in the lamina propria (LP) of the small intestine. Both the lymphoid and LP phenotypes are likely due to human Langerin promoter-driven BRAF V600E expression in resident CD8+ dendritic cells in the former and LP dendritic cells in the latter and confirm that Pten loss is required to overcome inhibitory pathways induced by BRAF V600E expression. The complex phenotype of these mice is a consequence of the multiple murine cell types in which the human Langerin promoter is active.

Protective Role of the Somatostatin Receptor Subtype 4 in the Indomethacin‐Induced Gastrointestinal Mucosal Injury Model

Since gastrointestinal ulceration is still associated with high mortality despite advancements in the endoscopic and pharmacological management, precise understanding of the mucosal defensive and protective mechanisms is important. The neuropeptide somatostatin is present in the endocrine cells and sensory nerves, is analogues were shown to reduce mucosal blood flow, pepsin and gastric acid secretion. Its endocrine functions are mediated by the receptors sst2,3,5, and our group discovered that the anti‐inflammatory and analgesic actions are exerted via the sst4 receptor. Sst4 agonists are preclinically tested as novel drug candidates in theses areas. Therefore, we investigated the role of sst4 in gastrointestinal injury.Sst4 gene‐deleted (sst4 −/−) mice and wildtype counterparts (sst4 +/+) were treated s.c. with 35 mg/kg indomethacine (IDM) or its vehicle. Macroscopic and microscopic mucosal lesions in the stomach and small intestine were evaluated by the ImageJ program and semiquantitative histopathological scoring after 4 and 48 h, respectively. Small intestinal length, thymus, adrenal glands, spleen weight and plasma glucose levels were measured. Neutrophil myeloperoxidase (MPO) activity and plasma extravasation were measured by bioluminescent/fluorescent ex vivo imaging after 24 h.Macroscopic lesion area and MPO activity in the gastric mucosa were significantly greater in IDM‐treated sst4−/− mice than in wildtypes 4 h and 24 h after IDM administration, respectively. Similar tendency was observed in the duodenum and jejunum even after 48 h. However, IDM did not induce mucosal plasma extravasation in either group at the 24 h timepoint. Thymus weight was significantly less in sst4−/− mice than in sst4+/+ ones. Histopathological scores, small intestinal length, adrenal and spleen weight, and plasma glucose level were not altered by the sst4 deletion.These results provide evidence for a protective role of the sst4 receptor against chemical injury‐induced gastrointestinal mucosal damage. This shows the safety of sst4 agonist drug candidates in the gastrointestinal tract, and even highlights their potential use for gastroprotective indication.Support or Funding InformationGINOP‐2.3.2‐15‐2016‐00050 – PEPSYS, GINOP‐2.3.2 STAY ALIVE, EFOP‐3.6.2‐16‐2017‐00008, ÚNKP‐18‐3 New National Excellence Program of the Ministry of Human CapacitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

ZEB2 and LMO2 Drive Immature T-Cell Lymphoblastic Leukemia Via Distinct Oncogenic Mechanisms

ZEB2, a E-box binding homeobox transcription factor, is able to induce epithelial-to-mesenchymal transition in the context of solid tumors. As such, its expression is correlated with cancer cell invasion, dissemination and metastasis, but also with the acquisition of cancer stem cell properties and therapy resistance.Using conditional knockout mice, we previously have shown that ZEB2 is an essential hematopoietic transcription factors, indispensable for normal embryonic(1) and adult(2) hematopoiesis. In addition, using conditional overexpressing mice we have demonstrated that ZEB2 is a bona fide driver of an immature subtype of T-ALL with increased leukemia-initiating potential(3).Here, we investigated the effects of ZEB2 overexpression on normal T-cell differentiation. Already from young age, ZEB2-overexpressing mice have a smaller thymus, with increased percentages of early T-cell precursors. Detailed flow cytometric analysis indicate a T-cell differentiation delay at the beta-selection checkpoint, with accumulation of DN3 (CD4- CD8- CD44- CD25+) cells. Using in vitro differentiation assays on OP9-DL1 stromal cells, we demonstrate that the perturbed T-cell differentiation is independent of the thymic micro-environment. Lowering the dose of exogenous interleukin-7 levels in the culture media can partially rescue this phenotype, which suggests that ZEB2-overexpressing thymocytes are delayed in T-cell differentiation due to their inability to downregulate the interleukin-7 receptor (IL7R) levels.Both the perturbed T-cell differentiation, and the latency/penetrance of immature subtype of the T-ALL formed in ZEB2-overexpressing mice is similar to what has been described for LMO2-overexpressing mice. Based on this phenocopy, we hypothesized that ZEB2 and LMO2 induce immature T-ALL via converging oncogenic pathway and/or via regulating similar crucial genes for the T-cell differentiation program. However, in contrast to LMO2, ZEB2-overexpresssing pre-leukemic thymocytes do not display aberrant self-renewal potential as demonstrated by transplantation experiments in sublethal irradiated syngeneic hosts. In addition, by using multiple Cre-transgenic lines, allowing the expression of ZEB2 at different stages of T-cell differentiation, we demonstrate that the oncogenic potential of ZEB2 is independent of the perturbed T-cell differentiation observed during the early stage of the disease.Based on these results we conclude that ZEB2 and LMO2 both drive the development of an immature subtype of T-ALL, but via distinct oncogenic mechanisms.(1) Goossens S. et al., Blood 2011 May 26; 117(21):5620-30.(2) Li J. et al., Blood 2017 Jan 26; 129(4):460-472.(3) Goossens S. et al., Nat Commun. 2015 Jan 7;6:5794. DisclosuresNo relevant conflicts of interest to declare.

ORAL ADMINISTRATION OF RAW WHITE KIDNEY BEANS (PHASEOLUS VULGARIS L. VAR. BELDIA) INDUCES OVERGROWTH OF FECAL COLIFORMS AND LACTOBACILLI IN WISTAR RATS

Objective: The comprehensive dynamics of fecal microbiota in response to the ingestion of toxic bean lectins or phytohemagglutinins has not been well studied. The study aimed at evaluating the gavage effects of a raw Beldia bean variety on food intake, growth performance, gastrointestinal organs, and fecal microflora in Wistar rats.Methods: Twenty young adult male rats were randomly allotted into two groups of 10 rats each: Control rats were gavaged with 300 mg of a rodent pellet flour suspension and experimental rats were orogastrically fed a dose of 300 mg Beldia bean flour suspension (BBFS). Individual food intake, body weight, and fecal score were taken daily. To assess the impact on the gut flora, fecal samples were collected every day for 10 days. All animals were sacrificed on day 10, to obtain blood and internal organs samples.Results: The results revealed that the gavage of a BBFS to rats had no marked influence on average daily of food intake and weight gain. No significant differences were found in the weights of the small intestine, spleen, liver, and thymus of rats given raw Beldia diet. The counts of coliforms and lactobacilli on pooled fecal specimens of BBFS-fed rats were increased significantly compared to controls.Conclusion: In summary, the exposure to raw Beldia beans altered the fecal microbiota, without adverse effects on animals.

Detection of Succinate by Intestinal Tuft Cells Triggers a Type 2 Innate Immune Circuit

In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis and a tritrichomonad protist both secreted succinate as a metabolite. Invivo sensing of the tritrichomonad required SUCNR1, whereas N.brasiliensis was SUCNR1 independent. These findings define a paradigm wherein tuft cells monitor microbial metabolites to initiate type 2 immunity and suggest the existence of othersensing pathways triggering the response to helminths.

Fetal thymus size evaluation using two-dimensional ultrasound in co-relation to fetal biometry as a sensitive parameter change in pregnancies complicated with fetal growth restriction (FGR)

Objective: Fetal thymus size evaluation through measuring its ultrasonographic maximum transverse diameter, in relation to fetal biometry changes in pregnancies complicated with FGR. Methods: Our study included 66 singleton pregnancies with intact membranes, aged (18 to 40 y) between 28 and 36 weeks of gestation with FGR,Patients with fetal or maternal infections, chromosomal or fetal congenital anomalies, or IUFD and patients start labor were excluded. All patientsunderwentultrasound evaluation weekly during the third trimester after history taking; examination and labinvestigation were performed, where measurements of themaximum transverse diameter of the fetal thymus and fetal biometry (BPD percentile,FL percentile, AC percentile,EFW percentile,and Single deepest vertical pocket) were obtained. The small thymus was defined as a thymus perimeter ≤ 5th percentile according to a fetal thymus nomogram, then Patients were classified into 2 groupsaccording to whether they had a small transverse thymus diameter ( 5th %).The co-relation between fetal thymus size, obstetric history and fetal biometry changes by ultrasonography were performed. Results: The sixty-six FGR pregnancies were classified to 55 patients with thymus diameter less than 5th percentile and 11 patients with thymus diameter more than 5th percentile. The co-relation between thymus diameter less and more than 5th percentile and obstetric history showed that no statistically significant difference as regarding history of abortion, history of stillbirth, history of preterm labor andhistory of IUGR but there was statistically significant difference as regarding gestational age (GA) mean at enrollment (32.04 ± 2.7 vs. 36.5 ± 1.04) meaning IUGR fetuses with a thymus diameter 5th percentile) [3.2 ± 2.7 vs. 6.6 ± 2.2 & 3.06 ± 2.6 vs. 6.09 ± 2.5]. 90.91% of IUGR fetuses with normal thymus diameter (>5th percentile) have adequate amniotic fluid as estimated by single deepest vertical pocket versus 34.55% of IUGR fetuses with thymus diameter <5th percentile with a statistically significant difference. All IUGR fetuses with oligohydramnios (n=20) had small thymus < 5th %. Conclusion: There is a highlypositive correlation between thymus transversediameter and AC, EFW, and AF vertical pocket inpregnancies complicated with FGR.

Small fetal thymus and adverse obstetrical outcome: a systematic review and a meta-analysis.

The aim of this study was to explore the association between small fetal thymus on ultrasound and adverse obstetrical outcome. Medline, Embase, Cochrane and Web of Science databases were searched. Primary outcome was the risk of preterm birth before 37 and 34weeks of gestation in fetuses with, compared to those without, a small thymus on ultrasound. occurrence of chorioamnionitis, intrauterine growth restriction, neonatal sepsis, gestational age at birth, birthweight, neonatal morbidity and preeclampsia. Twelve studies including 1744 fetuses who had ultrasound assessment of thymus during pregnancy were included. Women with preterm premature rupture of the membranes or with preterm labor were at higher risk of preterm birth before 37weeks (p=0.01), or before 34weeks (p<0.001) for fetuses with a small fetal thymus compared to those without a small thymus, and the risk of chorioamnionitis was higher when the thymus was small (p<0.001). Fetuses with small thymus were not at higher risk of intrauterine growth restriction (p=0.3). A small thymus increased the risk of neonatal sepsis (p=0.007) and morbidity (p=0.003), but not the risk of preeclampsia (p=0.9). A small fetal thymus is associated with a higher risk of preterm birth, chorioamnionitis, neonatal sepsis and morbidity, but not with intrauterine growth restriction and preeclampsia.

Loss of G\u03b1i proteins impairs thymocyte development, disrupts T-cell trafficking, and leads to an expanded population of splenic CD4+PD-1+CXCR5+/\u2212 T-cells

Thymocyte and T cell trafficking relies on signals initiated by G-protein coupled receptors. To address the importance of the G-proteins Gαi2 and Gαi3 in thymocyte and T cell function, we developed several mouse models. Gαi2 deficiency in hematopoietic progenitors led to a small thymus, a double negative (DN)1/DN2 thymocyte transition block, and an accumulation of mature single positive (SP) thymocytes. Loss at the double positive (DP) stage of thymocyte development caused an increase in mature cells within the thymus. In both models an abnormal distribution of memory and naïve CD4 T cells occurred, and peripheral CD4 and CD8 T cells had reduced chemoattractant responses. The loss of Gαi3 had no discernable impact, however the lack of both G-proteins commencing at the DP stage caused a severe T cell phenotype. These mice lacked a thymic medullary region, exhibited thymocyte retention, had a peripheral T cell deficiency, and lacked T cell chemoattractant responses. Yet a noteworthy population of CD4+PD-1+CXCR5+/− cells resided in the spleen of these mice likely due to a loss of regulatory T cell function. Our results delineate a role for Gαi2 in early thymocyte development and for Gαi2/3 in multiple aspects of T cell biology.

The immune deficiency of chromosome 22q11.2 deletion syndrome

The syndrome originally described by Dr. Angelo DiGeorge had immunodeficiency as a central component. When a 22q11.2 deletion was identified as the cause in the majority of patients with DiGeorge syndrome, the clinical features of 22q11.2 deletion syndrome became so expansive that the immunodeficiency became less prominent in our thinking about the syndrome. This review will focus on the immune system and the changes in our understanding over the past 50 years. Initially characterized as a pure defect in T cell development, we now appreciate that many of the clinical features related to the immunodeficiency are well downstream of the limitation imposed by a small thymus. Dysfunctional B cells presumed to be secondary to compromised T cell help, issues related to T cell exhaustion, and high rates of atopy and autoimmunity are aspects of management that require consideration for optimal clinical care and for designing a cogent monitoring approach. New data on atopy are presented to further demonstrate the association.

Retinoic Acid Receptor γ Regulates B and T Lymphopoiesis via Nestin-Expressing Cells in the Bone Marrow and Thymic Microenvironments.

Vitamin A has essential but largely unexplained roles in regulating lymphopoiesis. We have previously shown that retinoic acid receptor (RAR) γ-deficient mice have hematopoietic defects, some phenotypes of which were microenvironment induced. Bone marrow (BM) microenvironment cells identified by either their expression of nestin (Nes) or osterix (Osx) have previously been shown to have roles in regulating lymphopoiesis. We therefore conditionally deleted Rarγ in Nes- or Osx-expressing microenvironment cells. Osx cell-specific deletion of Rarγ had no impact on hematopoiesis. In contrast, deletion of Rarγ in Nes-expressing cells resulted in reductions in peripheral blood B cells and CD4(+) T cells, accompanied by reductions of immature PreB cells in BM. The mice lacking Rarγ in Nes-expressing cells also had smaller thymi, with reductions in double-negative 4 T cell precursors, accompanied by reduced numbers of both TCRβ(low) immature single-positive CD8(+) cells and double-positive T cells. In the thymus, Nes expression was restricted to thymic stromal cells that expressed cerebellar degeneration-related Ag 1 and lacked expression of epithelial cell adhesion molecule. These cells expressed platelet-derived growth factor α and high transcript levels of Rars, Cxcl12, and stem cell factor (Scf). Short-term treatment of mice with all-trans retinoic acid resulted in increased PreB lymphopoiesis in BM and an increase in thymic double-negative 4 T cells, inverse to that observed upon Nes cell-specific deletion of Rarγ. Collectively, these studies show that RARγ is a regulator of B and T lymphopoiesis via Nes-expressing cells in the BM and thymic microenvironments, respectively.

Loss of Pten Disrupts the Thymic Epithelium and Alters Thymic Function.

The thymus is the site of T cell development and selection. In addition to lymphocytes, the thymus is composed of several types of stromal cells that are exquisitely organized to create the appropriate environment and microenvironment to support the development and selection of maturing T cells. Thymic epithelial cells (TECs) are one of the more important cell types in the thymic stroma, and they play a critical role in selecting functional T cell clones and supporting their development. In this study, we used a mouse genetics approach to investigate the consequences of deleting the Pten tumor suppressor gene in the TEC compartment of the developing thymus. We found that PTEN deficiency in TECs results in a smaller thymus with significantly disordered architecture and histology. Accordingly, loss of PTEN function also results in decreased T cells with a shift in the distribution of T cell subtypes towards CD8+ T cells. These experiments demonstrate that PTEN is critically required for the development of a functional thymic epithelium in mice. This work may help better understand the effects that certain medical conditions or clinical interventions have upon the thymus and immune function.

Prognostic Value of Fetal Thymus Size in Intrauterine Growth Restriction

Our aim was to evaluate the size of the fetal thymus by sonography in pregnancies with intrauterine growth restriction (IUGR) and to search for a possible relationship between a small fetal thymus and adverse perinatal outcomes. The transverse diameter of the fetal thymus was prospectively measured in 150 healthy and 143 IUGR fetuses between 24 and 40 weeks' gestation. The fetuses with IUGR were further divided according to normal or abnormal Doppler assessment of the umbilical and middle cerebral arteries and ductus venosus. Measurements were compared with reference ranges from controls. To determine which perinatal outcomes were independently associated with a small fetal thymus, a multivariate logistic regression analysis was performed. Thymus size was significantly lower in IUGR fetuses compared to controls (P < .05). Among IUGR fetuses, thymus size was significantly smaller in IUGR fetuses with abnormal Doppler flow compared to normal flow (P < .05). A small thymus in IUGR fetuses was independently associated with early delivery (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.05-1.49; P= .023), respiratory distress syndrome (OR, 1.36; 95% CI, 1.09-1.78; P= .005), early neonatal sepsis (OR, 1.65; 95% CI, 1.11-2.42; P= .001), and a longer stay in the neonatal intensive care unit (OR, 1.33; 95% CI, 1.08-1.71; P = .017). Intrauterine growth restriction is associated with fetal thymic involution, and a small fetal thymus is an early indicator of adverse perinatal outcomes in pregnancies complicated by IUGR.

Impairment of IL-17 Immunity to Candida and IFN-g Immunity to Mycobacterium in Humans with Bi-Allelic Rorc mutations

Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis (CMC), which is characterized by infections of the skin, nails, oral and genital mucosae with Candida albicans. Inborn errors of human IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD), a rare congenital disorder characterized by susceptibility to infections by poorly virulent intracellular pathogens such as Mycobacterium bovis Bacille Calmette-Guérin vaccines (BCG) and non-tuberculosis Mycobacterium. Rarely, patients may be affected by both candidiasis and mycobacteriosis, including some patients with IL-12p40 and IL-12Rβ1 deficiencies that impair IFN-γ immunity and IL-17 immunity. We studied seven patients from three unrelated consanguineous kindreds with this unusual combination of infectious diseases without known genetic disorder. We combined whole exome sequencing and genome wide linkage analysis, and discovered bi-allelic loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. All of the seven patients suffered from severe mycobacterial infections, and six also exhibited mild CMC. RORγT is the key transcription factor of Th17 cells, which produce IL-17 and IL-22. Therefore, as predicted by the mouse model, RORγT deficiency prevented the development of IL-17-producing T cells, which accounts for the patients' CMC. Consistent with the phenotype of Rorc-/- mice, these patients presented with mild T cell lymphopenia, small thymus, lack of palpable axillary and cervical lymph nodes, and absence of MAIT and iNKT cells.The patients' severe infections with mycobacteria were not predicted by previous studies of Rorc-/- mice. To explain this unexpected phenotype, we focused on IFN-γ immunity. Leukocytes from RORC-/- patients showed impaired IFN-γ production in response to a mycobacterial challenge, and this defect is probably attributable to the functional impairment of CD4+ CCR6+ CXCR3+ αβ T cells, γδT cells, or both. These findings also suggested that IFN-γ treatment may be beneficial for RORC-/- patients. Moreover, this phenotype does not seem to be human-specific, as we also found that Rorc-/- mice deficient were susceptible to mycobacterial infection. We thus discovered that human RORC is essential not only for the development of IL-17-producing lymphocytes protecting the mucocutaneous barriers against Candida, but also for the activation of IFN-g-producing T cells, and for systemic protection against Mycobacterium. DisclosuresNo relevant conflicts of interest to declare.

32-OR

Objectives Pre-eclampsia is associated with a breakdown of maternal immune tolerance, although the role of fetal immunity is unknown. Nevertheless, morphological change of the fetal thymus is observed in pre-eclampsia. The aim of this study was to investigate fetal thymus size at mid-gestation, and its relationship to pre-eclampsia. We hypothesized that the fetal thymus would be smaller in women later diagnosed with pre-eclampsia. Methods This was a prospective cohort study performed at Nepean Hospital, Australia. Pregnant women carrying a single fetus were recruited between 15/1/2011 and 15/7/2013, during their mid-gestation scan. Within an image of the right ventricular outflow tract, fetal thymus diameter was measured as its widest diameter, perpendicular to a line connecting the sternum and spine. The Nepean obstetric database was later searched to identify pre-eclampsia diagnoses. Logistic regression techniques modelled the odds of pre-eclampsia based on fetal thymus diameter, adjusted for confounding variables. Results In total, 886 pregnancies were included (pre-eclampsia = 24, control = 862). In univariate analysis, a 1 mm decrease in thymus diameter was associated with a significantly increased odds of pre-eclampsia (OR 1.41 (1.17–1.69); p = 0.0003). Multiple logistic regression, which adjusted for gestation and maternal BMI, also showed a small thymus diameter to be significantly linked to pre-eclampsia (OR 1.47 (1.22, 1.78); p Conclusions This prospective study offers high quality evidence that the fetal thymus is altered at mid-gestation, well before any clinical manifestations of pre-eclampsia. Whether this signifies a primary role for fetal immunity in disease pathogenesis is yet to be determined. Disclosures D. Eviston: None. A. Quinton: None. A. Martin: None. R. Benzie: None. M. Peek: None. R. Nanan: None.

Revisiting thymus function.

OPINION article Front. Immunol., 28 August 2014Sec. T Cell Biology Volume 5 - 2014 | https://doi.org/10.3389/fimmu.2014.00411

Factors Associated with Thymic Size at Birth among Low and Normal Birth-Weight Infants

To study the effect of gestational and perinatal exposures on thymic size in 366 normal birth weight and 426 low birth weight (LBW) neonates in Guinea-Bissau in West Africa. In a cross-sectional study, thymic size was measured at birth by the use of ultrasound. Information on possible determinants was collected from pregnancy cards, hospital records, and interviews with the mother. We used the log-transformed thymic index and thymus/weight index as outcome measures. Data were analyzed with adjusted linear regression models providing geometric mean ratios (GMRs) with 95% CI. Determinants of thymic size among normal birth weight infants were pathologic amniotic fluid (adjusted GMR for thymic index: 0.84 [0.74-0.96]) and male sex (GMR: 1.13 [1.06-1.22]). Among LBW infants, birth season (1.11 [1.01-1.22]), maternal body temperature (0.89 [0.79-0.98]), antibiotic treatment at the time of labor (0.84 [0.70-1.00]), number of pregnancy consultations (1.03 [1.00-1.05]), maternal age (0.91 [0.84-0.98]), Apgar score (1.06 [1.03-1.10]), and infant convulsions (0.44 [0.29-0.65]) were all independent determinants of thymic index but not all were determinants of thymus/weight index. Pathologic amniotic fluid and cesarean delivery were associated with thymus/weight index among LBW infants (0.85 [0.75-0.95] and 0.80 [0.67-0.96]) but were only borderline significant for thymic index. Exposures mainly related to stress and infections were associated with a smaller thymus, mainly in LBW infants.

Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency

Biotinidase deficiency is an autosomal recessively inherited metabolic disorder that can be easily and effectively treated with pharmacological doses of the vitamin, biotin. Untreated children with profound biotinidase deficiency may exhibit neurological, cutaneous and cellular immunological abnormalities, specifically candida infections. To better understand the immunological dysfunction in some symptomatic individuals with biotinidase deficiency, we studied various aspects of immunological function in a genetically engineered knock-out mouse with biotinidase deficiency. The mouse has no detectable biotinidase activity and develops neurological and cutaneous symptoms similar to those seen in symptomatic children with the disorder. Mice with profound biotinidase deficiency on a biotin-restricted diet had smaller thymuses and spleens than identical mice fed a biotin-replete diet or wildtype mice on either diet; however, the organ to body weight ratios were not significantly different. Thymus histology was normal. Splenocyte subpopulation study showed a significant increase in CD4 positive cells. In addition, in vitro lymphocyte proliferation assays consistently showed diminished proliferation in response to various immunological stimuli. Not all symptomatic individuals with profound biotinidase deficiency develop immunological dysfunction; however, our results do show significant alterations in cellular immunological function that may contribute and/or provide a mechanism(s) for the cellular immunity abnormalities in individuals with biotinidase deficiency.

Thymus development and infant and child mortality in rural Bangladesh.

Background Data from West Africa indicate that a small thymus at birth and at 6 months of age is a strong and independent risk factor for infection-related mortality up to 24 and 36 months of age, respectively. We investigated the association between thymus size (thymic index, TI) in infancy and subsequent infant and child survival in a contemporary South Asian population.Methods The study focused on the follow-up of a randomized trial of prenatal nutritional interventions in rural Bangladesh (ISRCTN16581394), with TI measured longitudinally in infancy (at birth and weeks 8, 24 and 52 of age) and accurate recording of mortality up to 5 years of age.Results A total of 3267 infants were born into the Maternal and Infant Nutrition Interventions, Matlab study; data on TI were available for 1168 infants at birth, increasing to 2094 infants by 52 weeks of age. TI in relation to body size was largest at birth, decreasing through infancy. For infants with at least one measure of TI available, there were a total of 99 deaths up to the age of 5 years. No association was observed between TI and subsequent mortality when TI was measured at birth. However, an association with mortality was observed with TI at 8 weeks of age [odds ratio (OR) for change in mortality risk associated with 1 standard deviation change in TI: all deaths: OR = 0.64, 95% confidence interval (CI) 0.41, 0.98; P = 0.038; and infection-related deaths only: OR = 0.32, 95% CI 0.14, 0.74; P = 0.008]. For TI when measured at 24 and 52 weeks of age, the numbers of infection-related deaths were too few (3 and 1, respectively) for any meaningful association to be observed.Conclusion These results confirm that thymus size in early infancy predicts subsequent survival in a lower mortality setting than West Africa. The absence of an effect at birth and its appearance at 8 weeks of age suggests early postnatal influences such as breast milk trophic factors.

Clinical and immunological features of infants born from mothers with threatened miscarriage

Most of researchers denote predominance of morbid conditions, originated from prenatal period of life, in infant disease structure. To their mind, these points to the interrelation between these diseases and mother’s somatic health and het gestation course. The goal of the research was to study how the feto-maternal disease influences clinical and immunological status of infants at neonatal age. The observance has been held under 73 infants, born from mothers with different types of gestation. The first group contained infants, born from mothers with physiologic gestation course, the second group - infants, born from mothers with threatened miscarriage. The clinical laboratory examination of newborns and infants included evaluation of anthropometric characteristics, somatic status, ultrasound examination of thymus, indexes of cellular immunity. The examiners used diagnostic immunoenzymometric test-systems of JSC «Vektor-Best» and standardized methods. The newborns of the second group had the most apparent aberrations of physical growth and development. The central nervous system depression in the form of encephalitic depression syndrome has been detected as the common consequence of severe prenatal fetal hypoxia and neonatal asphyxia of second group newborns. Moreover, infants, born from mothers with threatened miscarriage, predominantly had «abnormal small thymus’s syndrome». The results of immunological examinations showed that infants’ cellular-immunity changes depended on nature of mother’s gestation disorders (suppressor type dependence). The developing of evident immune suppression with signs of immunological tolerance disorder has been detected amongst infants, born from mothers with threatened miscarriage. The initial symptoms were allergenic dermhelminthiasis.