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Memory CD4⁺ T cells. (A) Absolute T cell numbers and (B) absolute memory CD4⁺ T cell numbers in patients with DiGeorge syndrome, compared to published healthy reference values (20), shown as mean and 90% range. (C) Proportion of memory CD4⁺ T cells of all CD4⁺ T cells compared to age, shown with linear regression trendlines and (D) divided into several age groups.
Source publication
DiGeorge syndrome is an immunodeficiency characterized by thymic dysplasia resulting in T cell lymphopenia. Most patients suffer from increased susceptibility to infections and heightened prevalence of autoimmune disorders, such as autoimmune thrombocytopenia. B cells in DiGeorge syndrome show impaired maturation, with low switched-memory B cells a...
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Citations
... Our (86) or subjects with HIV-acquired T cell immunodeficiency (87). It would also account for the ability of T cell-incompetent children and young adults to cope with many bacterial infections, as in subjects with partial DiGeorge syndrome (thymic hypoplasia), in whom no correlation occurs between serum IgG levels and numbers of circulating T FH cells (88). CD154-and CD40-deficient patients display mainly defects in T cell-mediated immunity to viruses and fungi, particularly Pneumocystis carinii and Cryptosporidium parvum (89). ...
Maturation of antibody responses entails somatic hypermutation (SHM), class-switch DNA recombination (CSR), plasma cell differentiation, and generation of memory B cells, and it is thought to require T cell help. We showed that B cell Toll-like receptor 4 (TLR4)-B cell receptor (BCR) (receptor for antigen) coengagement by 4-hydroxy-3-nitrophenyl acetyl (NP)-lipopolysaccharide (LPS) (Escherichia coli lipid A polysaccharide O-antigen) or TLR5-BCR coengagement by Salmonella flagellin induces mature antibody responses to NP and flagellin in Tcrβ-/-Tcrδ-/- and NSG/B mice. TLR-BCR coengagement required linkage of TLR and BCR ligands, "linked coengagement." This induced B cell CSR/SHM, germinal center-like differentiation, clonal expansion, intraconal diversification, plasma cell differentiation, and an anamnestic antibody response. In Tcrβ-/-Tcrδ-/- mice, linked coengagement of TLR4-BCR by LPS or TLR5-BCR by flagellin induced protective antibodies against E. coli or Salmonella Typhimurium. Our findings unveiled a critical role of B cell TLRs in inducing neutralizing antibody responses, including those to microbial pathogens, without T cell help.
... Moreover, child activity and discomfort with the gastrostomy tube can cause accidental pulling of the tube leading to skin manifestations due to scratching, which causes erythema, excoriation, and irritation around the site of the stoma. In addition, patients' existing comorbid conditions could predispose them to certain complications; for example, patients with DiGeorge syndrome, a primary immunodeficiency disease, are at higher risk of infections compared to immunocompetent individuals [20]. It is established that congenital heart defects in addition to neurological disorders, whether acute or chronic, can cause malnutrition [21][22][23]. ...
Background and objective
Gastrostomy is a procedure that involves placing a feeding tube through the abdominal wall into the stomach to provide nutritional support. There are several modes of gastrostomy tube insertion including laparoscopic-assisted gastrostomy (LAG), percutaneous endoscopic gastrostomy (PEG), and open gastrostomy (OG) procedure, among others. Although it is a widely performed procedure, limited data is available regarding gastrostomy in Saudi Arabia, specifically among the pediatric population. This study aimed to shed more light on different aspects of surgical gastrostomy procedures among pediatric patients at the King Abdullah Specialist Children’s Hospital (KASCH) in Riyadh, Saudi Arabia. The main objective of our study was to report the indications and complications of both LAG and OG insertions in the pediatric population.
Methods
A retrospective cross-sectional study was conducted at KASCH to analyze the different parameters related to LAG and OG insertions, and to evaluate for any association between these modes of insertion and their complications. Pertinent data on children from birth to 14 years of age were collected through consecutive sampling using a chart review. A total of 107 pediatric patients who underwent the procedure from 2016 to 2020 were evaluated.
Results
Demographically, the majority (58%) of gastrostomies were performed in infants (less than a year old). Additionally, our study showed a significantly increased association between LAG and complications such as discharge, (27.12%), skin manifestations (27.12%), and bleeding (10.17%) when compared to OG.
Conclusion
Based on our findings, LAG showed less favorable outcomes in contrast to OG. Further studies should be conducted to validate our findings and ensure consistent results and outcomes among different methods of gastrostomy tube insertion.
... We and others have previously shown that the decreased thymic output results in early maturation of those T cells which do develop, leading to reduced number of recent thymic emigrants (RTE), non-memory T cells [13,15,19,20] and low detectable T cell receptor excision circles (TRECs) [15,21]. These cells divide through homeostatic proliferation, which together with the natural involution of thymic function over time leads to gradual normalization of T cell counts in older 22q11.2DS ...
... We have previously shown altered temporal changes in the expression pattern of PD1, one of the major T cell exhaustion markers [26], on 22q11.2DS T cells [20]; however, the principal focus of that study was follicular helper T cells, where PD1 may play a different role. To our knowledge, no publications describe exhaustion of T cells in patients with primary immunodeficiency caused by a thymic pathology, as most studies on this topic focus on chronic viral infections such as hepatitis C, HIV [27,28] or intrinsic T cell defects [29]. ...
... PBMCs were stained by fluorescent conjugated monoclonal antibodies against surface membrane markers. After fixation and permeabilization with eBioscience™ Foxp3/Transcription Factor Fixation/Permeabilization kit (Thermo Fisher Scientific, Waltham, CA, USA), cells were stained for intracellular markers according to previously published protocol [20]. The list of used antibody-fluorochrome conjugates is shown in Supplementary Table S1. ...
Purpose22q11.2 deletion syndrome (22q11.2DS) is a primary immunodeficiency characterized chiefly by the hypoplasia of the thymus resulting in T cell lymphopenia, increased susceptibility to infections, and higher risk of autoimmune diseases. The irregular thymic niche of T cell development may contribute to autoimmune and atopic complications, whereas the compensatory mechanism of homeostatic T cell proliferation and continuous immune stimulation may result in T cell senescence and exhaustion, further aggravating the immune system dysregulation.Methods
We used flow cytometry to investigate T cell maturation, delineation, proliferation, activation, and expression of senescence and exhaustion-associated markers (PD1, KLRG1, CD57) in 17 pediatric and adolescent patients with 22q11.2DS and age-matched healthy donors.Results22q11.2DS patients aged 0–5 years had fewer naïve but more effector memory T cells with a tendency to approach normal values with increasing age. Young patients in particular had a higher percentage of proliferating T cells and increased expression of PD1, KLRG1, and CD57, as well as cells co-expressing several exhaustion-associated molecules (PD1, KLRG1, Tbet, Eomes, Helios). Additionally, high-risk 22q11.2DS patients with very low numbers of CD4 T cells had significantly higher percentage of Th1 and Th17 T cells, driven in part by higher proportion of mature T cell forms.Conclusion
The low thymic output and accelerated T cell differentiation remain the principal features of 22q11.2DS patient immunity, especially in young patients of < 5 years. Later in life, homeostatic proliferation drives expression of T cell exhaustion and senescence-associated markers, suggesting functional aberrations in addition to numeric T cell deficiency.
... Autoimmunity and atopy affect a significant number of patients ranging from 8 to 24% [7,8,29]. Various mechanisms have been hypothesized to account for this association including homeostatic expansion, diminished regulatory T cells, altered TFH cells, and a specific effect of the deletion on T cell tolerance [3,15,30,31]. Murine models of thymic hypoplasia are also associated with autoimmunity suggesting that the deletion itself is not critical for the evolution of autoimmunity [32]. In a large study of serum cytokines, patients with 22q11.2del ...
PurposeChromosome 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.MethodsCD4 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.ResultsHistone 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.
... 8 Furthermore, patients with 22q11.2DS may exhibit hypogammaglobulinemia with defective response to pneumococcal polysaccharide, 9,10 decreased CD27þ memory B cells, 11,12 increased CXCR4þ circulating follicular helper T cells (cTFHs), 12,13 low natural regulatory T cells (Tregs), 7,14 and deficient natural killer (NK) cytotoxic activity. 15 Another hallmark of patients with 22q11DS is the increased risk of autoimmune diseases such as thrombocytopenic purpura (ITP), hemolytic anemia (AIHA), thyroiditis, and arthritis. ...
... exhibit a reduction of SMB and a decrease rate of somatic hypermutation, whereas cTFHs are present at higher percentages at all ages and display a more activated phenotype. 12,13 Indeed, in our cohort, both HA and non-HA patients have increased percentages of circulating T follicular helper cells (cTFH), and the subjects with higher cTFH values have more severe autoimmune manifestations (ITPþAIHA) (data not shown). Nevertheless, the overall difference between cTFH in HA and non-HA does not reach the statistical significance. ...
Background:
Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients.
Objective:
To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA.
Methods:
We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes.
Results:
Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naïve CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naïve ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002.
Conclusions:
Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.
Aim
The study aimed to offer better genetic evaluation and consultation for DiGeorge syndrome (DGS) patients by combining screening of 22q11.2 and immunologic studies. A basic immune profile including the basic CD panel and immunoglobulins estimation was performed. TRECS and KRECS expression were studied in addition to measuring serum IL33, Obestatin, HLA-G, and Procalcitonin serum levels.
Methods
All investigations were performed for DGS patients (n = 33) and the matched control group (n = 45). Polymorphic 22q11.2 markers mapping was performed by PCR-STR technique. Lymphocyte subsets immunophenotyping was done using flow cytometry, while measurement of serum immunoglobulins was estimated using nephelometry. Real-time PCR was the method used for TRECs and KRECs measurement. Serum IL33, Obestatin, HLA-G, and Procalcitonin levels were determined using an Enzyme-linked immunosorbent assay (ELISA). Data was coded, tabulated, and statistically analyzed using SPSS version 19.0 software.
Results
In our case–control study, KREC expression was significantly elevated in DGS compared to healthy controls (P = 0.0008). There was also a significant increase in immunoglobulin levels in DGS. CD8% as well as CD8 absolute count in the patients with DGS were significantly lower than in the healthy control (P = 0.01273 and 0.05358 respectively). There were no significant differences in IL33, Obestatin, HLA-G, and Procalcitonin levels between DGS patients compared to the control group. Our results concerning the distinct segment of 22q11.2 as a DGS susceptibility region revealed an informative novel atypical interstitial homozygous deletion. This deletion included D22S944 and COMT absence, and D22S941 and D22S264 presence. Out of 33 DGS patients, three patients showed deletion in the D22S944 marker only in the presence of D22S941, and D22S264 markers. Therefore, we could assume that D22S944 is a common deleted marker in non-isolated DGS patients.
Conclusion
Combining 22q11.2 region screening, immune profile studies, and TRECS and KRECS expression offers a new comprehensive approach for DGS patients. This approach provides a better strategy for genetic consultation for DGS patients. Moreover, this study may be the first to show a small interstitial 22q11.2 deletion stereotype in a DGS patient and also showed that the smallest deletion at the 22q11.2 region is enough to confer the DGS phenotype.
The abnormal immune response mediated by malignant melanoma is related to PD1. Paeonol has pharmacological antitumor activity. Previous studies have indicated that paeonol induces tumor cell apoptosis, but its underlying mechanism in tumor immunity remains unknown. In this study, malignant melanoma was established in normal and thymectomized mice to determine the important role of the thymus in the antitumor effects of paeonol. Paeonol-treated thymocytes were cocultured with melanoma cell spheres to further evaluate the regulatory role of thymocytes in tumor immune dysfunction. Studies have shown that PD1 may be targeted by miR-139-5p. Our results revealed that tumor-induced thymic atrophy was significantly accompanied by high PD1 expression and low miR-139-5p expression. Interestingly, paeonol significantly reversed thymic atrophy and largely protected thymocytes against low PD1 expression and high miR-139-5p expression. Dual-luciferase assays indicated that miR-139-5p interacted with the 3' untranslated region (3'-UTR) of PD1. These results showed that paeonol alleviates PD1-mediated antitumor immunity by reducing miR-139-5p expression and demonstrated a novel mechanism for melanoma immunotherapy.
The immune system percolating throughout the body can impact the function of other organs by contributing to allergy or autoimmune disease. Thymic hypoplasia is one of the central features of this condition, and its main consequence is to restrict T-cell production. Children typically have low T cells with preserved antibody production, while adults more often have adequate T-cell counts, and a subset have impaired antibody production. Homeostatic proliferation is invoked by the body to try to correct the low T-cell counts, but it is associated with Th2 polarization, which contributes to atopic risk in this population. Low regulatory T cells are seen and may be part of the autoimmune predisposition. The effects are complex and often age dependent, consistent with other features of the syndrome. Careful monitoring is crucial for the management of the immunodeficiency.
