Distinct immune trajectories in patients with chromosome 22q11.2 deletion syndrome and immune-mediated diseases.

BACKGROUND: Identification of biomarkers associated with immune-mediated diseases in 22q11.2 deletion syndrome is an evolving field. OBJECTIVES: We sought to use a carefully phenotyped cohort to study immune parameters associated with autoimmunity and atopy in 22q11.2 deletion syndrome to define biomarkers associated with immune-mediated disease in this syndrome. METHODS: Chart review validated autoimmune disease and atopic condition diagnoses. Laboratory data were extracted for each subcohort and plotted according to age. A random-effects model was used to define statistical significance. RESULTS: CD19, CD4, and CD4/45RA lymphocyte populations were not different from the general cohort for patients with atopic conditions. CD4/45RA T cells were significantly lower in the subjects with immune thrombocytopenia compared with the general cohort, and CD4 T-cell counts were lower in patients with autoimmune thyroid disease. CONCLUSIONS: The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies.

Experience with cultured thymus tissue in 105 children.

BACKGROUND: Currently, there are no approved therapies to treat congenital athymia, a condition of immune deficiency resulting in high early mortality due to infection and immune dysregulation. Multiple syndromic conditions, such as complete DiGeorge syndrome, 22q11.2 deletion syndrome, CHARGE (coloboma, heart defects, choanal atresia, growth or mental retardation, genital hypoplasia, and ear anomalies and/or deafness) syndrome, diabetic embryopathy, other genetic variants, and FOXN1 deficiency, are associated with congenital athymia. OBJECTIVE: Our aims were to study 105 patients treated with cultured thymus tissue (CTT), and in this report, to focus on the outcomes of 95 patients with treatment-naive congenital athymia. METHODS: A total of 10 prospective, single-arm open-label studies with patient enrollment from 1993 to 2020 form the basis of this data set. Patients were tested after administration of CTT for T-cell development; all adverse events and infections were recorded. RESULTS: A total of 105 patients were enrolled and received CTT (the full analysis set). Of those patients, 10 had diagnoses other than congenital athymia and/or received prior treatments. Of those 105 patients, 95 patients with treatment-naive congenital athymia were included in the efficacy analysis set (EAS). The Kaplan-Meier estimated survival rates at year 1 and year 2 after administration of CTT in the EAS were 77% (95% CI = 0.670-0.844) and 76% (95% CI = 0.657-0.834), respectively. In all, 21 patients died in the first year before developing naive T cells and 1 died in the second year after receipt of CTT; 3 subsequent deaths were not related to immunodeficiency. A few patients developed alopecia, autoimmune hepatitis, psoriasis, and psoriatic arthritis after year 1. The rates of infections, autologous graft-versus-host-disease manifestations, and autoimmune cytopenias all decreased approximately 1 year after administration of CTT. CONCLUSION: Treatment with CTT led to development of naive T cells with a 1-year survival rate of 77% and a median follow-up time of 7.6 years. Immune reconstitution sufficient to prevent infections and support survival typically develops 6 to12 months after administration of CTT.

Chromatin Modifications in 22q11.2 Deletion Syndrome.

PURPOSE: Chromosome 22q11.2 deletion syndrome is a common inborn error of immunity. The early consequences of thymic hypoplasia are low T cell numbers. Later in life, atopy, autoimmunity, inflammation, and evolving hypogammaglobulinemia can occur and the causes of these features are not understood. This study utilized an unbiased discovery approach to define alterations in histone modifications. Our goal was to identify durable chromatin changes that could influence cell behavior. METHODS: CD4 T cells and CD19 B cells underwent ChIP-seq analysis using antibodies to H3K4me3, H3K27ac, and H4ac. RNA effects were defined in CD4 T cells by RNA-seq. Serum cytokines were examined by Luminex. RESULTS: Histone marks of transcriptional activation at CD4 T cell promoters and enhancers were globally increased. The promoter activation signature had elements related to T cell activation and inflammation, concordant with effects seen in the transcriptome. B cells, in contrast, had a minimally altered epigenetic landscape in 22q11.2. Both cell types had an "edge" effect with markedly altered chromatin adjacent to the deletion. CONCLUSIONS: People with 22q11.2 deletion have altered CD4 T cell chromatin and a transcriptome concordant with the changes in the epigenome. These effects support a disease model where qualitative changes to T cells occur in addition to quantitative defects that have been well characterized. This study offers unique insight into qualitative differences in the T cells in 22q11.2 deletion, an aspect that has received limited attention.

Clinical Features in a Large Cohort of Patients With 22q11.2 Deletion Syndrome.

OBJECTIVES: To evaluate various clinical aspects, specifically regarding immune status, in a large cohort of patients with DiGeorge syndrome. STUDY DESIGN: Data were collected for 98 patients with DiGeorge syndrome treated at a tertiary medical center. This included general information, laboratory results, and clinical features. RESULTS: The median age at diagnosis was 2.0 years (range, 0.0-36.5 years). The most common symptoms that led to diagnosis were congenital heart defect, speech delay, palate anomalies, and developmental delay. Common clinical features included recurrent infections (76 patients), congenital heart diseases (61 patients), and otorhinolaryngology disorders (61 patients). Twenty patients had anemia; the incidence was relatively high among patients aged 6-59 months. Thrombocytopenia was present in 20 patients. Recurrent chest infections were significantly higher in patients with T cell and T cell subset deficiencies. Decreased T cell receptor excision circles were more common with increasing age (P < .001). Of the 27 patients hospitalized due to infection, pneumonia was a leading cause in 13. CONCLUSIONS: Awareness of DiGeorge syndrome's typical and uncommon characteristics is important to improve diagnosis, treatment, surveillance, and follow-up.

Symptomatic hypocalcemia after treatment for hyperthyroidism in a woman with chromosome 22q11.2 deletion syndrome complicated by Graves' disease: longitudinal changes in the number of subsets of CD4 and CD8 lymphocytes after thyroidectomy.

Chromosome 22q11.2 deletion syndrome is a multisystem genetic disorder that presents with hypocalcemia due to congenital hypoparathyroidism; cardiovascular, renal, and facial anomalies; and skeletal defects. This syndrome is also associated with an increased risk of autoimmune disease. We report here on a 33-year-old Japanese woman with 22q11.2 deletion syndrome complicated by Graves' disease. The patient had facial abnormalities and a history of a surgical procedure for a submucous cleft palate at age 3 years. At age 33, the patient was diagnosed with Graves' disease because both hyperthyroidism and thyroid stimulating hormone receptor antibody were present. The patient's serum calcium level was within the normal range, but symptomatic hypocalcemia developed 1 month after treatment with methimazole was started for thyrotoxicosis. Methimazole was discontinued because it caused liver dysfunction, so the patient underwent total thyroidectomy to treat her Graves' disease. We examined longitudinal changes in the number of subsets of CD4 and CD8 lymphocytes, including regulatory T (T reg) cells and PD-1+CD4+ and PD-1+CD8+ T cells, after treatment by total thyroidectomy. A flowcytometry analysis demonstrated that circulating PD-1+CD4+ and PD-1+CD8+ T cells gradually decreased over time, as did circulating T reg cells and circulating CD19+ B cells. These findings suggest that PD-1-positive CD4+ and CD8+ T cells and T reg cells may have been associated with the autoimmunity in our patient with chromosome 22q11.2 deletion syndrome complicated by Graves' disease.

Care of Children with DiGeorge Before and After Cultured Thymus Tissue Implantation.

BACKGROUND: Children with complete DiGeorge anomaly (cDGA) have congenital athymia plus a myriad of other challenging clinical conditions. The term cDGA encompasses children with congenital athymia secondary to 22q11.2DS, CHARGE syndrome (coloboma, heart defects, choanal atresia, growth or mental retardation, genital abnormalities, and ear abnormalities and/or deafness), and other genetic abnormalities. Some children have no known genetic defects. Since 1993, more than 100 children with congenital athymia have been treated with cultured thymus tissue implantation (CTTI). Naïve T cells develop approximately 6 to 12 months after CTTI. Most of the children had significant comorbidities such as heart disease, hypoparathyroidism, and infections requiring complex clinical care post cultured thymus tissue implantation (CTTI). OBJECTIVE: The purpose of this guidance is to assist multidisciplinary teams in caring for children with cDGA both before and after CTTI. METHODS: Thirty-one specialists, in addition to the authors, were asked to share their experience in caring for children with cDGA at Duke University Health System, before and after CTTI. These specialists included physicians, nurses, dentists, therapists, and dieticians. RESULTS: The goal of a multidisciplinary approach is to have children in the best possible condition for receiving CTTI and provide optimal care post CTTI through development of naïve T cells and beyond. The CTT (cultured thymus tissue) must be protected from high doses of steroids which can damage CTT. Organs must be protected from adverse effects of immunosuppression. CONCLUSION: Creating a multidisciplinary team and a detailed plan of care for children with cDGA is important for optimal outcomes.

Humoral Immunodeficiency and Immune Globulin Replacement Therapy (IGRT) Usage in DiGeorge Syndrome.

PURPOSE: An analysis of patients in the United States Immunodeficiency Network (USIDNET) registry previously described a discordance in the reported prevalence of humoral immune deficiency in patients with DiGeorge syndrome (DGS) and its treatment. The primary purpose of this study is to evaluate the rates of humoral immunodeficiency and immune globulin replacement therapy (IGRT) use in patients with DiGeorge syndrome in the USIDNET registry as of September 2016, and to correlate IGRT use with prior infections and laboratory evidence of immune deficiency. METHODS: Current patients in the USIDNET registry with DGS were identified. Patients who were treated with immune globulin replacement therapy (IGRT) were compared with those who were untreated with respect to their laboratory findings and clinical history. RESULTS: Four hundred seventy-three patients were identified. The use of IGRT in patients with DGS has increased over time from 3 to 6.6%. IGRT was more common in patients with humoral immune deficiency (18.2% of those with hypogammaglobulinemia, 39.1% of those with documented low vaccine titers), but most patients with evidence of humoral immune deficiency remain untreated with IGRT. Patients treated with IGRT were more likely to have experienced episodes of pneumonia, sepsis, and bacterial skin infections (p < 0.01 for all). CONCLUSIONS: Humoral immune deficiencies were more common among patients with DGS than previously reported. IGRT was used most commonly in patients with DGS who demonstrated frequent or severe bacterial infections. There is still a significant deficit between those with DGS who have laboratory evidence of a humoral immune deficiency and those being treated for it.

22q11.2 deletion syndrome: 20 years of experience from two pediatric immunology units and review of clues for diagnosis and disease management.

INTRODUCTION AND OBJECTIVES: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease. MATERIAL AND METHODS: Thirty-three pediatric patients with 22q11.2 deletion syndrome diagnosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children's Education and Research Hospital were evaluated. RESULTS: This study includes the largest case series reported from Turkey. Congenital cardiac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syndrome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogammaglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up. CONCLUSIONS: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any difference in terms of numbers and severity of infections and autoimmunity.

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.

Vitamin D status and the immune assessment in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is characterized by a heterogeneous phenotype, including alterations in phospho-calcium metabolism and immunodeficiency. We analyzed vitamin D status and the immune assessment, focusing on T cell subpopulations and dendritic cells (DCs) in a cohort of 17 pediatric 22q11.2DS patients and 17 age-matched healthy subjects. As antigen-presenting cells, DCs are the main target of vitamin D, promoting a tolerogenic T cell response. Patients were subdivided into three groups according to the parameters of phospho-calcium metabolism and serum levels of 25OHD: normal values, vitamin D deficiency and hypoparathyroidism. Different degrees of T cell deficiency, ranging from normal to partial T cell numbers, were observed in the cohort of patients. The group with vitamin D deficiency showed a significant reduction of naive T cells and a significant increase of central memory T cells compared to controls. In this group the number of circulating DCs was significantly reduced. DC decrease affected both myeloid and plasmacytoid DC subsets (mDCs and pDCs), with the most relevant reduction involving pDCs. A direct correlation between 25OHD levels and recent thymic emigrant (RTE) and DC number was identified. Despite the limited cohort analyzed, our results show that deficiency of the pDC subset in patients with 22q11.2DS may be included among the causative factors of the progressive increase of risk of autoimmune diseases in these patients. As most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, we suggest a potential role of vitamin D supplementation in preventing autoimmune or proinflammatory diseases in 22q11.2DS.

Complement Activation in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.

Unexpected combination: DiGeorge syndrome and myeloperoxidase deficiency.

We report a case of a 3-year-old boy who presented with recurrent bacterial and fungal infections and a known diagnosis of partial DiGeorge (22q11.2 deletion) syndrome. The nature and severity of his infections were more than normally expected in partial DiGeorge syndrome with normal T-cell counts and T-cell proliferative response to phytohaemagglutinin. This prompted further investigation of the immune system. An abnormal neutrophil respiratory oxidative burst, but normal protein expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, led to the identification of myeloperoxidase deficiency. DiGeorge syndrome has a heterogeneous clinical phenotype and may not be an isolated diagnosis. It raises awareness of the possibility of two rare diseases occurring in a single patient and emphasises that even when a rare diagnosis is confirmed, if the clinical features remain atypical or unresponsive, then further investigation for additional cofactors is warranted.

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

BACKGROUND: 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). OBJECTIVE: We sought to determine the cause of selective T-cell lymphopenia with inverted kappa/lambda ratio in several kindreds. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Risk factors of clinical dysimmune manifestations in a cohort of 86 children with 22q11.2 deletion syndrome: A retrospective study in France.

In this study, we describe the biological immune profiles and clinical dysimmune manifestations (infections, autoimmune diseases, and allergies) of patients with 22q11.2 deletion syndrome with the aim of determining risk factors for clinical events. This retrospective study concerned all the patients with 22q11 deletion syndrome attending the Montpellier University Hospital from January 1, 1992, to December 31, 2014 who had at least one immune investigation before the age of 18. We analyzed the clinical features, biological tests and the course of infections, autoimmunity, and allergy of 86 children. Among these 86 children, 48 (59%) had a low T lymphocyte level. Twenty-nine patients (34%) had a severe infection. The only risk factor for severe infection was the low level of CD4+ T-cells (OR: 3.3; 95% confidence interval (CI) [1.020-11.108]). Eleven patients (13%) developed an autoimmune disease; the only risk factor was an antecedent of severe infection (OR: 4.1; 95% CI [1.099-15.573]). Twenty-three patients (27%) had allergic episodes. A low level of CD8+ T-cells (OR: 3.2; 95% CI [1.07-9.409]) was significantly associated with allergy manifestations. Patients with 22q11 deletion syndrome have a high rate of dysimmune manifestations. We found statistic correlations among CD4+ T-cell count, infectious manifestations, and autoimmunity.

[Live Vaccine in Children with DiGeorge/22q11.2 Deletion Syndrome]. / Vacinas Vivas em Crianças com Síndrome de DiGeorge/ Deleção 22q11.2.

INTRODUCTION: Children with DiGeorge syndrome/chromosome 22q11.2 deletion syndrome might have a variable degree of immunodeficiency, which may limit the use of live vaccines. The aim of this study was to review the adverse effects of live vaccines and possible relation with immune status in patients with DiGeorge Syndrome/partial 22q11.2 deletion syndrome. MATERIAL AND METHODS: Retrospective study with analysis of the clinical records of children with chromosome 22q11.2 deletion syndrome and DiGeorge syndrome phenotype, followed in a Primary Immunodeficiency center. Data were collected on: demographic characteristics; medical and vaccination history with live vaccines; T-CD4+ lymphocyte counts and lymphocyte proliferative responses to antigens and mitogens; adverse reactions; vaccine failure. RESULTS: Twenty three children with DiGeorge syndrome/22q11.2 deletion syndrome were included, 65.2% male, with average age at diagnosis of 11.3 months. Eighteen children (78%) received bacillus Calmette-Guérin vaccine: all with evidence of thymic activity; three presented moderate T-CD4+ lymphopenia and abnormal lymphocyte proliferative responses; one had abnormal lymphocyte proliferative responses for mitogens, four for purified protein derivative and one for tetanus toxoid. Measles, mumps and rubella vaccine was administered to 15 children, three of them with moderate immunosuppression and abnormal lymphocyte proliferative responses. Live attenuated polio vaccine was administered to 4 children without immunosuppression and the rotavirus vaccine to three children, one with moderate immunosuppression. No significant adverse reactions were reported. DISCUSSION: These data are in line with the findings of other international studies. CONCLUSION: In our sample, live vaccines were well-tolerated, even in children with moderate T-CD4+ lymphopenia and abnormal lymphocyte proliferative responses to antigens/mitogens.

Introdução: A síndrome de DiGeorge/deleção 22q11.2 pode apresentar um grau variável de imunodeficiência, condicionando a utilização de vacinas vivas. Este estudo teve como objetivo documentar os efeitos adversos de vacinas vivas e possível relação com alterações imunitárias em crianças com síndrome de DiGeorge/deleção 22q11.2 parcial. Material e Métodos: Foi realizado um estudo retrospetivo por revisão dos processos clínicos das crianças com deleção do cromossoma 22q11.2 e fenótipo de síndrome de DiGeorge, seguidos num centro de referência de imunodeficiências primárias. Foi realizada colheita de dados, incluindo: características demográficas; história médica; historial de vacinação com vacinas vivas; contagem de linfócitos T-CD4+ e respostas proliferativas linfocitárias a antigénios e mitogénios; reações adversas; falências vacinais. Resultados: Foram incluídas 23 crianças com síndrome de DiGeorge/deleção 22q11.2, 65,2% do sexo masculino e idade média de diagnóstico de 11,3 meses. Destas, 18 crianças (78%) receberam a vacina bacillus Calmette-Guérin: todas com evidência de atividade tímica; três apresentaram linfopénia T-CD4+ moderada e respostas proliferativas linfocitárias anormais; uma com respostas proliferativas linfocitárias anormais para mitogénios, quatro para derivado de proteína purificada e uma para toxóide tetânico. A vacina tríplice contra o sarampo, parotidite e rubéola foi administrada a 15 crianças, três com imunossupressão moderada e respostas proliferativas linfocitárias anormais. A vacina viva atenuada contra poliomielite foi administrada a quatro crianças sem imunossupressão e a vacina contra o rotavírus a três crianças, uma com imunossupressão moderada. Não foram reportadas reações adversas. Discussão: Estes dados estão de acordo com as conclusões de outros estudos internacionais. Conclusão: Na nossa amostra, as vacinas vivas atenuadas foram bem toleradas, incluindo em crianças com linfopénia T-CD4+ moderada e com respostas proliferativas linfocitárias a antigénios/mitogénios anormais.

Immune system defects in DiGeorge syndrome and association with clinical course.

We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4+ T and CD8+ T cells were defined as high-risk (HR) patients, whereas patients with normal numbers of naive CD4+ and CD8+ T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3+ T cell counts and percentages of class-switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class-switched B cells had earlier onset of infection, lower blood IgM, lower CD4+ and CD8+ T counts than patients with normal class-switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4+ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.

Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development.

The thymus plays a fundamental role in establishing and maintaining central and peripheral tolerance and defects in thymic architecture or AIRE expression result in the development of autoreactive lymphocytes. Patients with partial DiGeorge Syndrome (pDGS) and Down Syndrome (DS) present alterations in size and architecture of the thymus and higher risk to develop autoimmunity. We sought to evaluate thymic architecture and thymocyte development in DGS and DS patients and to determine the extent to which thymic defects result in immune dysregulation and T cell homeostasis perturbation in these patients. Thymi from pediatric patients and age-matched controls were obtained to evaluate cortex and medullary compartments, AIRE expression and thymocyte development. In the same patients we also characterized immunophenotype of peripheral T cells. Phenotypic and functional characterization of thymic and peripheral regulatory T (Treg) cells was finally assessed. Histologic analysis revealed peculiar alterations in thymic medulla size and maturation in DGS and DS patients. Perturbed distribution of thymocytes and altered thymic output was also observed. DGS patients showed lower mature CD4+ and CD8+ T cell frequency, associated with reduced proportion and function of Tregs both in thymus and peripheral blood. DS patients showed increased frequency of single positive (SP) thymocytes and thymic Treg cells. However, Tregs isolated both from thymus and peripheral blood of DS patients showed reduced suppressive ability. Our results provide novel insights on thymic defects associated with DGS and DS and their impact on peripheral immune dysregulation. Indeed, thymic abnormalities and defect in thymocyte development, in particular in Treg cell number and function could contribute in the pathogenesis of the immunodysregulation present in pDGS and in DS patients.

Clinical and immunological features in a cohort of patients with partial DiGeorge syndrome followed at a single center.

DiGeorge syndrome (DGS) is a primary immunodeficiency characterized by various degrees of T-cell deficiency. In partial DGS (pDGS), other risk factors could predispose to recurrent infections, autoimmunity, and allergy. The aim of this study was to assess the effect of different factors in the development of infections, autoimmunity, and/or allergy in patients with pDGS. We studied 467 pDGS patients in follow-up at Great Ormond Street Hospital. Using a multivariate approach, we observed that palatal anomalies represent a risk factor for the development of recurrent otitis media with effusion. Gastroesophageal reflux/dysphagia and asthma/rhinitis represent a risk factor for the development of recurrent upper respiratory tract infections. Allergy and autoimmunity were associated with persistently low immunoglobulin M levels and lymphopenia, respectively. Patients with autoimmunity showed lower levels of CD3+, CD3+CD4+, and naïve CD4+CD45RA+CD27+ T lymphocytes compared with pDGS patients without autoimmunity. We also observed that the physiological age-related decline of the T-cell number was slower in pDGS patients compared with age-matched controls. The age-related recovery of the T-cell number depended on a homeostatic peripheral proliferation of T cells, as suggested by an accelerated decline of the naïve T lymphocytes in pDGS as well as a more skewed T-cell repertoire in older pDGS patients. These evidences suggest that premature CD4+ T-cell aging and lymphopenia induced spontaneous peripheral T-cell proliferation might contribute to the pathogenesis of autoimmunity in patients with pDGS. Infections in these patients represent, in most of the cases, a complication of anatomical or gastroenterological anomalies rather than a feature of the underlying immunodeficiency.