Thymic Hypoplasia Research Articles

Zuogui Wan alleviated maternal kidney-yin deficiency-induced thymic epithelial cell dysfunction in newborn rats through Wnt/β-catenin signaling pathway

Ethnopharmacological relevanceKidney-yin deficiency (KYD) during pregnancy is common and associated with possibility of thymus hypoplasia in neonates. Zuogui Wan (ZGW) is a classic traditional medicine to treat KYD. Aim of studyThe Wnt/β-catenin signaling pathway is essential for thymic epithelial cell (TEC) viability, function and for thymus integrity. We evaluated whether maternal diets with ZGW in KYD rats ameliorates epithelial cell dysfunction in the fetal thymus, and investigated its underlying mechanism in which the Wnt/β-catenin signaling pathway is involved. Materials and methodsRats were randomly assigned to four groups (n = 8). Two experimental groups received KYD induction with or without ZGW supplementation. The other 2 vehicle groups were sham operated and administrated with normal saline or ZGW. KYD was established using periodically chronic shaken stimulus and threaten stress. Success of the model induction was evaluated by the general observation, changing of the body weight and plasma thyroxine level. Then, pregnant of vehicle and KYD rats were fed with or without ZGW-supplemented diet throughout the F1 gestation. Postnatal thymi samples were obtained after delivery for histological examination. In vitro, TECs of the newborn rats whose mother suffered KYD were isolated, and cultured using the serum containing ZGW with or without the supplement of Wnt4/β-catenin pathway inhibitor ICG-001. Cell viability was evaluated by CCK-8 assay. Meanwhile, the thymi tissues and TECs were collected for biochemical analysis. Levels of thymosin β4 (TMSβ4) and thymosin α1 (Tα1) were detected by ELISA assay. The mRNA and protein expression of Wnt4, β-catenin, and Foxn1 were determined by RT-qPCR and Western blot respectively. ResultsIn vivo, KYD resulted in significantly increased apoptosis of TECs and atrophy of the thymi, especially in the medullary zone. The morphological changes observed in KYD rats were ameliorated by ZGW treatment. Meanwhile, the decreased TMSβ4, Tα1, Wnt4, β-catenin, and Foxn1 levels in KYD rats were also significantly alleviated by ZGW administration. In vitro, elevated TMSβ4 and Tα1 levels accompanied with upregulated Wnt4, β-catenin, and Foxn1 expressions in the TECs were observed after ZGW intervention, however, which were significantly downregulated by ICG-001 supplement. ConclusionsMaternal kidney-yin deficiency could result in TEC dysfunction in newborn rats. ZGW was able to improve the growth and development of TEC, potentially by regulating the Wnt/β-catenin pathway.

Lymphocyte phenotype in a mouse model of 22q11.2 deletion syndrome

Abstract Mice modeling the hemizygous deletion of chromosome 22q11.2 (22qMc) have been utilized to address various clinical phenotypes associated with the disease, including cardiac malformations, altered neural circuitry and behavioral deficits. Yet, the status of the immune system, an important clinical concern among 22q11.2 deletion syndrome (22qDS) patients, has not yet been addressed in this model despite the well-known effects of the immune system in regulating body homeostasis. While infancy and early childhood in 22qDS are associated with deficient T cell numbers due to thymic hypoplasia, which can be severe in a small subset of patients, clinical studies suggest a normalization of the T cell counts by adulthood. For the first time, we have studied the immune system in 22qMc and find that adult 22qMc do not exhibit thymic hypoplasia, immunodeficiencies of lymphoid organs, or altered T cell activation. Furthermore, deletion of the 22q11.2 homologous region does not affect T cell differentiation. Thus, this model accurately reflects the normalization of the T cell compartment in adulthood, as has been reported in human 22qDS. Altogether, our data suggest that 22qMc may serve as novel model to address experimental and translational aspects of immunity in adult 22qDS.

Assessment of predisposing effect of Chicken Anaemia Virus (CAV) in Gangrenous Dermatitis (GD) outbreaks in commercial layer chicken

Gangrenous dermatitis (GD) is an economically important disease in commercial layer chicken and its severity have increased for the past few years despite effective farm management system and suitable antibiotic treatments. This study was designed to explore the immunosuppressive role of Chicken Anaemia Virus (CAV) in gangrenous dermatitis outbreaks in Namakkal region of Tamil Nadu, India. Thirty commercial white leghorn layer flocks were investigated in and around Namakkal District of Tamil Nadu State, India. Detailed farm history was collected. Serum and blood samples were collected to screen the antibody titer and haemogram, respectively. Heart blood, liver samples from dead birds and cutaneous swabs from ailing and dead carcasses were taken to identify the bacterial etiology. Detailed necropsy was conducted and the gross lesions were recorded. Thymus, bone marrow, liver and muscle were collected for screening of CAV by Polymerase chain reaction and histopathological studies. The sera samples showed 100 per cent positivity for CAV and the blood profile showed anaemic picture. The GD affected birds showed anaemia, severe serosanguinous, haemorrhagic and gangrenous lesions in wings, suncutaneous tissue and interdigital space of toes. Necropsy revealed severe gangrene, extravasation of serosanguinous fluid from the skin, hypoplasia of thymus and paleness of bone marrow. Microscopic examination showed hypoplasia / atrophy of thymus and replacement of erythropoietic tissue of bone marrow with fat cells. Cultural examination exhibited the presence of Closrtidium perfringens, Staphylococcus aureus and E. coli. The significance of the study was that CAV is the major culprit in GD outbreaks in poultry which invites the diverse etiological agents by its immunosuppressive action.

Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility.

NF-κB2/p100 (p100) is an inhibitor of κB (IκB) protein that is partially degraded to produce the NF-κB2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or IκB function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the IκB function of degradation-resistant p100.

Postnatal Outcome and Associated Anomalies of Prenatally Diagnosed Right Aortic Arch with Concomitant Right Ductal Arch: A Systematic Review and Meta-Analysis.

Right aortic arch presents a reported incidence of 0.1% of the general population; the aim of our study was to evaluate the risk of associated intracardiac (ICA), extracardiac (ECA), or chromosomal abnormalities in fetuses with right aortic arch (RAA) and concomitant right ductal arch (RDA). A systematic review of the literature selected 18 studies including 60 cases of RAA/RDA. A meta-analysis with a random effect model calculated for each outcome the pooled crude proportion of associated abnormal outcomes in cases of RAA/RDA and the pooled proportions and odds ratios in RAA with LDA or RDA. Quality assessment of the included studies was achieved using the NIH quality assessment tool for case series studies. RAA/RDA presents risk of associated conotruncal CHDs of about 30% and risk of 22q11 microdeletion in the region of 1%. Two-thirds of 22q11 microdeletions had concomitant thymic hypoplasia and no other chromosomal defects were described. Risks for ICA, ECA, 22q11 microdeletion, and aberrant left subclavian artery are not substantially different in RAA with right or left arterial duct. RAA increases the risk of associated cardiac defects regardless of laterality of the ductal arch. In isolated RDA/RAA cases, absolute risks of extracardiac associated problems or surgery are rather low, we would therefore recommend reassurance, particularly when the thymus and karyotype are normal.

History of the Discovery and Development of Biomodulina T (InmunyVital®), a Useful Immunomodulator with a Broad Range of Clinical Applications

Biomodulina T, the active ingredient in InmunyVital®, is a polypeptide thymic factor that modulates immune responses and inflammation. Biomodulina T stimulates the differentiation, maturation and proliferation of CD3 T cell populations and CD4 and CD8 T cell subpopulations. Additionally, Biomodulina T improves the ability of T cells to produce cytokines, therefore enhancing T lymphocyte function. Additionally, Biomodulina T stimulates the thymus gland and, thus, promotes the recovery of normal thymus mass and size in children with thymic hypoplasia and restores the functions of immunosenescent T cells in aging people.The thymus gland slowly shrinks with age, and the levels of the thymic factors it produces decrease in the blood. Moreover, thymus-dependent immunity, including T cell immunity and thymus- dependent antibody production, decreases with thymus size in adult people. For that reason, older adults are generally at a higher risk of becoming severely ill from infectious diseases, such as influenza, COVID-19 and other diseases. As people age, “immunosenescence” occurs; immunosenescence means that with age, the ability to produce vigorous responses to infections gradually diminishes compared to that observed at younger ages during which the thymus gland, thymic factor levels, and immune responses are healthy and strong. In addition, in older adults, low-grade, chronic systemic inflammation, called “inflamm-aging”, occurs, and this phenomenon increases susceptibility to age-related inflammatory diseases.In 1984, with the aim of developing biological response modifiers, I established the laboratory of Biomodulators in Havana, where I created and developed the immunomodulatory thymic factor that I called “Biomodulina T”. The biological activity of Biomodulina T was demonstrated in several in vitro and in vivo studies in our laboratory and in independent laboratories. An extensive series of preclinical toxicological studies were conducted in different species, such as mice, rats, guinea pigs, rabbits and dogs. All these studies demonstrated that Biomodulina T is an active and safe thymic factor.We conducted clinical trials with Biomodulina T in patients with multiple sclerosis, chronic hepatitis B, rheumatoid arthritis, Crohn's disease, Behcet's syndrome, and selective deficiency of IgA as well as in geriatric populations. In 1994, I obtained the sanitary registration of Biomodulina T as an immunomodulatory drug.Since that time, we conducted other clinical trials in children with repeated infections and primary immunodeficiencies and in adults with systemic lupus erythematosus, uveitis, myasthenia gravis, chronic obstructive pulmonary disease (COPD), and respiratory infections.This article identifies the milestones involved in the creation and development of Biomodulina T. Since its discovery 35 years ago, the first and recent reports of new scientific advances show that Biomodulina T (InmunyVital®) is a modulator of immune responses and inflammation that is very useful for restoring the immune system in young and elderly people with allergies, asthma, immunodeficiency, autoimmune diseases, and infectious diseases. Biomodulina T is also useful as an immunotherapeutic agent for improving immune responses in the context of cancer and vaccines, for reversing immunosenescence and for improving the healthspan in general aging.

Augmented autophagy suppresses thymocytes development via Bcl10/p-p65 pathway in prenatal nicotine exposed fetal mice

Tobacco smoke is a common global environmental pollutant. Maternal tobacco smoke/nicotine exposure has long-term toxic effects on immune organs. We previously found that prenatal nicotine exposure (PNE)-induced programmed immune diseases caused by fetal thymic hypoplasia, but the mechanism still unknown. Autophagy has important functions in maintaining thymopoiesis, whether autophagy was involved in PNE-inhibited fetal thymocytes development is also obscure. Therefore, this study aimed to investigate how nicotine changed the development of fetal thymocytes from the perspective of autophagy in vivo and in vitro. PNE model was established by 3 mg/kg nicotine administration in Balb/c mice from gestational day 9 to 18. The results showed that PNE reduced the percentage and absolute number of CD69−CD4+SP cells, suggesting a block of fetal thymocytes mature. PNE promoted autophagosome formation, autophagy related proteins (Beclin1, LC3I/II) expression, and upregulated α7 nAChR as well as AMPK phosphorylation in fetal thymus. Moreover, PNE promoted Bcl10 degradation via autophagy-mediated proteolysis and inhibited p65 activation, blocking the transition of thymocytes between the DP to SP stage. Further, primary thymocytes were treated with nicotine in vitro and showed induced autophagy in a dose- and time-dependent manner. In addition, nicotine-inhibited CD69−CD4+SP cells and the Bcl10/p-p65 pathway have been reversed by an autophagy inhibitor. The α7 nAChR specific antagonist abrogated nicotine-induced AMPK phosphorylation and autophagy initiation. In conclusion, our findings showed that PNE repressed the Bcl10/p-p65 development pathway of CD4+SP cells by triggering autophagy, and illuminated the developmental origin mechanism of programmed immune diseases in PNE offspring.

Initial validation of the diagnostic performance of Thymic-Thoracic Ratio as a marker of conotruncal abnormalities and for prediction of surgical prognosis in fetuses without 22q11.2 deletion

Aim The present study aimed to perform an initial validation of the Thymic-Thoracic Ratio as a sonographic marker of conotruncal defects in non-syndromic fetuses and to assess the possible correlation between the grade of thymic hypoplasia and the severity of conotruncal defects. Methods The study was conducted between January and June 2018 on singleton pregnant women who underwent fetal echocardiography at our institution. Fetuses with a diagnosis of conotruncal defects without 22q11.2 deletion composed the study group, while healthy appropriate for gestational age fetuses composed the control group. The Thymic-Thoracic Ratio was measured in all included fetuses and compared between the study and control group. A ROC curve analysis to evaluate the diagnostic performance of Thymic-Thoracic Ratio toward the diagnosis of conotruncal defects was performed, with determination of sensitivity, specificity, PPV, NPV, positive likelihood ratio, and negative likelihood ratio. The severity of conotruncal defects was defined with the Aristotle score in each newborn who underwent a surgical operation. The correlation between Thymic-Thoracic Ratio and Aristotle score was assessed. Results During the study period, 23 fetuses with conotruncal defects without 22q11.2 deletion constituted the study group, and 67 healthy appropriate for gestational age fetuses were included in the control group. The T-T ratio of the study group was significantly lower than the control group (0.32 ± 0.08 vs. 0.41 ± 0.08, p < .001). The ROC curve analysis showed an AUC of 0.80 (95% CI, 0.71–0.89, p < .001) and a T-T ratio cutoff value of 0.35 for the identification of a CTD, with a sensibility of 73.9% (95% CI: 51.6–89.8%), a specificity of 79.1% (95% CI: 67.4–88.1%) a PPV of 54.8% (95% CI: 41.8–67.3%), a NPV of 89.8% (95% CI: 81.5–94.7), a positive likelihood ratio of 3.54 (95% CI 2.09–5.98), and a negative likelihood ratio of 0.33 (95% CI 0.16–0.66). A negative correlation between Aristotle score and T-T ratio was found, with a Kendall-Tau coefficient of −0.41, p = .04. Conclusion T-T ratio measurement could be useful to identify fetuses at higher risk of conotruncal heart diseases, even without chromosomic deletion, with a cutoff of 0.35. Since a lower T-T ratio seems to be related to a worse surgical neonatal prognosis, it could be possible to provide effective counseling and refer patients to high-specialized centers for fetal echocardiography and cardiac surgery.

Prenatal diagnosis of Di George syndrome of the fetus with tetralogy of Fallot

Prenatal diagnosis of deletion 22q11.2 of the fetus in the second trimester of pregnancy, suspected on the basis of congenital heart disease (tetralogy of Fallot) in the combination with thymus hypoplasia, is presented. The pregnancy was interrupted.

Type I interferon-independent T cell impairment in a Tmem173 N153S/WT mouse model of STING associated vasculopathy with onset in infancy (SAVI)

STING-associated vasculopathy with onset in infancy (SAVI) is an autoimmune disease caused by heterozygous gain of function mutations of STING (stimulator of interferon genes) that had initially been classified as a type I interferonopathy. We recently reported a genetically engineered mouse strain carrying a common SAVI-associated STING mutation. These STING N153S/WT mice reproduce key features of SAVI, including lung inflammation, loss of T cells in spleen and blood, splenomegaly and thymic hypoplasia. Here we show that αβ T lymphocytopenia is due to disrupted T cell development and is associated with impaired T cell activation and a relative increase in γδ T cell numbers. These alterations were not rescued by additional knockout of the type I IFN receptor (IFNAR1). Collectively, our findings consolidate the concept that constitutive STING signalling leads to a SCID-like phenotype in STING N153S/WT mice.

Molecular Insights Into the Causes of Human Thymic Hypoplasia With Animal Models.

22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.

Complex Reoperation in a Patient With DiGeorge Syndrome

DiGeorge syndrome consists of a triad of features including congenital heart defects, immune deficiencies secondary to thymus hypoplasia, and hypocalcemia.1 Approximately 75% of patients with DiGeorge syndrome have cardiac defects, and surgical correction often is required.2 Cardiac defects are typically conotruncal; however, other cardiovascular abnormalities may be present and complicate repair.3 Extracardiac abnormalities may complicate perioperative management and include airway abnormalities, hypocalcemia, and immune deficiencies.

The first experience of prenatal successful diagnosis of 22q11.2 deletion syndrome

Two cases of prenatal diagnosis of a deletion syndrome 22q11.2 are presented. They are includes the cardiovascular defects in combination with hypoplasia of the thymus. In first case the pregnancy was aborted due to the heart disease, adverse for life (aortic arch interruption). In second case (right aorta arch and left aberrant subclavial artery) the pregnancy was prolonged, the chromosomal pathology was diagnosed at the age of 3 months. Modern data on clinic, diagnosis and outcome of a syndrome at the fetus, children and adults are analyzed. The possibility of the aim prenatal diagnosis of syndrome on the basis of the characteristic conotruncal abnormalities in combination with hypoplasia of thymus is presented.

Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome

Thymic hypoplasia/aplasia occurs as a part of DiGeorge syndrome, which has several known genetic causes, and with loss-of-function mutations in forkhead box N1 (FOXN1). We sought to determine the cause of selective T-cell lymphopenia with inverted kappa/lambda ratio in several kindreds. Patients were identified through newborn screening for severe combined immunodeficiency using the T-cell receptor excision circle assay. Those found to have selective T-cell lymphopenia underwent testing with chromosomal microarray analysis. Three-week-old mice heterozygous for a loss-of-function mutation in forkhead box I3 (FOXI3), a candidate gene within the common deleted region found in patients, were compared with wild-type littermates. Assessments included body and organ weights, flow cytometric analysis of thymocytes and splenocytes, and histologic/transcriptomic analyses of thymic tissue. Five kindreds with similar immunophenotypes that included selective T-cell lymphopenia had overlapping microdeletions at chromosome 2p11.2 that spanned FOXI3 and, in most cases, the immunoglobulin kappa light chain locus. Studies in a mouse knockout strain for FOXI3 revealed smaller body weights and relatively lower thymus weights in heterozygous compared with wild-type animals. Histology and flow cytometry on spleens and thymi from 3-week-old pups for T- and B-cell subsets and epithelial cells did not show any significant qualitative or quantitative differences. Transcriptomic analysis of thymic RNA revealed divergence in global transcriptomic signatures, and Ingenuity Pathway Analysis revealed predicted dysfunction in epithelial adherens junctions. Microdeletions at chromosome 2p11.2 are associated with T-cell lymphopenia and probable thymic hypoplasia in human subjects, and haploinsufficiency for FOXI3, a candidate gene within the deleted region, is the likely underlying cause.

498 Objective Evidence of Gastrointestinal Disorders in Patients With 22q11.2 Deletion Syndrome

INTRODUCTION: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion syndrome (1:3000-6000 live births) and the most common cause of DiGeorge Syndrome (congenital heart disease, parathyroid hypoplasia, thymic hypoplasia). However, the 22q11.2DS phenotype varies markedly among patients. We previously studied a smaller subset of patients with 22q11.2DS (n = 72) and found that chronic gastrointestinal (GI) symptoms were common. Here we expand our previous observations to a larger cohort (n = 175) and also present objective study data in an effort to characterize these GI problems as structural versus functional. METHODS: Adult patients with 22q11.2DS were retrospectively assessed from our cohort of &gt;1400 patients with a confirmed 22q11.2 deletion followed in the 22q and You Center at the Children's Hospital of Philadelphia. Included patients had at least one problem list, medication list, review of systems, and outpatient physician evaluation at ≥17 years of age. Broad clinical data were abstracted, including results of relevant imaging and laboratory studies. All available imaging studies were reviewed for radiologic and pathologic abnormalities. All routine laboratory studies were reviewed, and the lowest value was recorded for each test. RESULTS: 672 consecutive charts were reviewed, of which 175 met inclusion criteria. Included patients (45% F) ranged from 17 to 59 years of age (mean 26.1; SD 8.1). Chronic GI symptoms were common from childhood through adulthood (Figure 1), but congenital GI malformations were rare (4%). Additionally, autoimmune GI disorders occurred at the frequency of the general population [celiac disease (1%); inflammatory bowel disease (0.6%)]. However, motility disorders were common and accounted for the vast majority of GI symptoms (Figure 2). Pertinent laboratory results were also reported and showed a high rate of anemia (Figure 3). CONCLUSION: Specialized GI studies were performed commonly in our study population, reinforcing our prior observation that GI disorders place a significant burden on patients with 22q11.2DS. In addition to the well-described palatal abnormalities affecting this population, these studies revealed a wide range of non-structural GI problems. We conclude that a large burden of GI illness in 22q11.2DS is functional. Finally, the known chromosomal microdeletions present in patients with 22q11.2DS may provide an explanatory framework for understanding the etiology of functional GI symptoms in the general population.

22q11.2 Deletion Syndrome (DiGeorge) and Mutations in Forkhead Box N1 (FOXN1) cause a Thymic Hypoplasia through distinct Developmental Processes

Abstract Patients with 22q11.2 deletion syndrome and those with mutations in the Forkhead Box N1(FOXN1) transcription factor (Nude/SCID) can both present with a thymic hypoplasia that results in a severe T cell lymphopenia. In both clinical conditions, the thymic anlage fails to develop properly within the 3rdpharyngeal pouch during embryogenesis. We characterized the development of the thymus in mouse models of 22q11.2 deletion syndrome (22q11.2del) and a new set of mice with mutations in Foxn1that genocopied a SCID patient with novel compound heterozygous mutations in FOXN1. Both sets of mice develop hypoplastic thymic lobes. An analysis of thymopoiesis in embryos revealed distinct development problems. The hypoplastic thymii from the 22q11.2del mice were primarily sized restricted, with normal percentages of all thymocyte subsets apparent. This contrasted a severe deficiency of thymocytes due to the Foxn1mutations, which primarily affected the development and expansion of thymic epithelial cells. Comparative gene expression analyses of e13.5 fetal thymii revealed differentially regulated transcripts that define the basis of the hypoplasia. A dysregulated mesenchymal cell signature was apparent in the 22q11.2del model, which contrasted the epithelial transcript disruption due to the Foxn1mutations. These results suggest different strategies are necessary to correct the thymic tissue abnormalities in patients who present with thymic hypoplasias due to their congenital disorders.

Day 0–28 of Human Embryonic Development: Importance of Studying Cell and Tissue Interactions in Head and Heart Development

All vertebrates start their development from a zygote and the processes from this cell to a complex organism are often complicated and include many gene regulatory networks, cell migrations, cell differentiations, communication between cells and between tissues, etc. Earliest mis‐regulations in those processes lead almost always to the demise of the developing embryo – often before the women even realizes she is pregnant. This is because the most exciting and complex processes related to body plan formation happen during the first 8 weeks of embryonic development. Even more fascinating is that at the end of the first months (28 days after fertilization) the head and heart region are clearly distinguishable: the heart is beating, u‐shaped and atria and ventricles are aligned, the pharyngeal arches are present, as are eye and ear anlagen (placodes), in the brain several regions are distinct, including forebrain, midbrain, and hindbrain. There are many remarkable research groups all over the world studying one or the other system (brain, cardiovascular, craniofacial), but only few groups study the interactions between all tissues (ectoderm, mesoderm, endoderm – neural crest as special tissue derived from ectoderm). However, understanding precisely those interactions during earliest and later development will help us to understand human syndromes with the same underlying genetic defect but that present with a huge variety of phenotypes.For example, the DiGeorge Syndrome is caused by a deletion of a region at 22q11.2 that contains 30–40 genes. Due to its involvement of several system it is also called CATCH22 – Cardiac anomalies, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia. Each of those abnormalities could be caused by the involvement of cranial neural crest cells during embryonic development, even the heart anomalies as cardiac neural crest cells are part of the posterior population of cranial neural crest cells. Also, in the region of the 22q11.2 is the Tbx1 gene that was shown to be essential during earliest cardiopharyngeal mesoderm development and differentiation. The cardiopharyngeal field is a progenitor field that gives rise to the first heart field and the pharyngeal mesoderm. The latter will differentiate into the second heart field derived cardiac musculature and the branchiomeric (head) muscles. Yet, neither our knowledge of neural crest cell involvement nor our understanding of cardiopharyngeal mesoderm development, fully explains the variety of symptoms seen in DiGeorge Syndrome patients.Therefore, a detailed summary of what is currently known about the first 28 days of head and heart development and the tissue interactions will help us to understand complex syndromes. Furthermore, it will be possible to identify regions that need more research focus. Last, but not least, a better understanding of our own developmental processes also provides insights into evolutionary processes and studying animal developmental processes further contributes to a deepened knowledge of the evolutionary development of our own body. Here, I will present a summary of the first 28 days of head and heart embryonic development in humans and highlight regions of research that next generation scientists might be interested in.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Digeorge syndrome-chromosome 22q1l deletion syndrome: An update and review

The DiGeorge Syndrome was first described in 1968 as a primary immunodeficiency resulting from the abnormal development of the third and fourth pharyngeal pouches during embryonic life. It is characterized by hypocalcemia due to hypoparathyroidism, heart defects, and thymic hypoplasia or aplasia. Its incidence is 1: 3000 live births and, despite its high frequency, little is known about its natural history and progression. ←This is probably due to diagnostic difficulties and the great variety of names used to describe it, such as velocardiofacial, DiGeorge, and CATCH 22 Syndromes, as well as conotruncal facial anomaly. All represent the same genetic condition, chromosome 22q11.2 deletion, which might have several clinical expressions. To describe clinical and laboratorial data and phenotypic characteristics of patients with DiGeorge Syndrome. Patients underwent standard clinical and epidemiological protocol and tests to detect heart diseases, facial abnormalities, dimorphisms, neurological or behavioral disorders, recurrent infections and other comorbidities.

СЛУЧАЙ ВРОЖДЁННОЙ АТРЕЗИИ ХОАН У РЕБЁНКА С ПЕРВИЧНЫМ ИММУНОДЕФИЦИТОМ (СИНДРОМ ДИ ДЖОРДЖИ)

Congenital atresia of the choanas (CVC) is a violation of the patency of the nasal cavity associated with its complete or partial infection of the connective, cartilage or bone tissue. CVC is a consequence of the preservation of the nasal palatine membrane, which occurs between the 6th and 12th weeks of gestation, due to the approach and successive fusion of the posterior edge of the opener with the posterior ends of the nasal concha. According to domestic and foreign literature, for 5000-7000 newborns there is 1 observation of CVC, the population frequency of congenital malformations in individual countries ranges from 2.7 to 16.3%. The deletion syndrome of the 22nd chromosome, described as Dee Georgi syndrome or cyclic cardiofacial syndrome, is a combination of morphological, immunological and neurological changes that are the result of a deletion of the long arm of 1 copy of the 22nd chromosome - del 22q11.2. In the classical concept, this syndrome is a triad consisting of congenital heart disease, thymus hypoplasia (aplasia) and hypocalcemia, as a result of parathyroid hypoplasia. Dee Georgi - syndrome (SDD) or the case of the 22nd chromosome is the most common problem among other mutations in the human genome, it is second only to Down syndrome, trisomy on the 21st chromosome. The frequency of occurrence varies from 1: 4000 to 1: 6000 newborns. This review seeks to assess the factors that influence the outcome of transnasal endoscopic restoration of the congenital atresia of the choan. The article presents a method for eliminating congenital atresia of the choan in a child with Dee Georges syndrome with transeptal access.

Prenatal nicotine exposure induces thymic hypoplasia in mice offspring from neonatal to adulthood

Clinical study showed that smoking during pregnancy deceased the thymus size in newborns. However, the long-term effect remains unclear. This study was aimed to observe the effects of prenatal nicotine exposure (PNE) on the development of thymus and the T-lymphocyte subpopulation in mice offspring from the neonatal to adulthood. Both the thymus weight and cytometry data indicated that PNE caused persistent thymic hypoplasia in male offspring from neonatal to adult period and transient changes in female offspring from neonatal to prepuberal period. Flow cytometry analysis disclosed a permanent decreased proportion and number of mature CD4 single-positive (SP) T cells in thymus of both sex. In addition, the PNE male offspring showed a more serious thymus atrophy in the ovalbumin (OVA)-sensitized model. Moreover, increased autophagic vacuole and elevated mRNA expression of Beclin 1 were noted in PNE fetal thymus. In conclusion, PNE offspring showed thymus atrophy and CD 4 SP T cell reduction at different life stages. Mechanically, PNE induced excessive autophagy in fetal thymocytes might be involved in these changes. All the results provided evidence for elucidating the PNE-induced programmed immune diseases.