Objective To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. Study design A ...retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. Results The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations ( P = .015) and speech disorders ( P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. Conclusions Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.
Role of regulatory T cells and FOXP3 in human diseases Bacchetta, Rosa, MD; Gambineri, Eleonora, MD; Roncarolo, Maria-Grazia, MD
Journal of allergy and clinical immunology,
08/2007, Letnik:
120, Številka:
2
Journal Article
Recenzirano
Immune regulation and tolerance are specific functions of the immune system, meaning at prevention or limitation of effector immune responses against inner and external insults. Regulatory T (Treg) ...cells are crucial players in this immune balance network. Research over the last 10 years has significantly contributed to characterizing Treg cell features, their mechanisms of function, and their role in human pathologies. The discovery of FOXP3 as an essential transcription factor not only for differentiation and function of naturally occurring Treg cells but also for regulation of intracellular molecules related to effector T-cell responses has provided new insights into the pathogenesis of immune-mediated diseases. Interestingly, there is increasing evidence that the individual signature of genes relevant for immune regulation definitely influences the final outcome of an immune response.
Background Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3) , a key ...regulator of immune tolerance. Objective We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome. Methods In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data. Results Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity. Conclusion Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome.
Background The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues. Recently, ...HIES has been associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of TH 17 cells. Objective To determine whether there is a correlation between the genotype and the phenotype of patients with HIES and to establish diagnostic criteria to distinguish between STAT3 mutated and STAT3 wild-type patients. Methods We collected clinical data, determined TH 17 cell numbers, and sequenced STAT3 in 100 patients with a strong clinical suspicion of HIES and serum IgE >1000 IU/mL. We explored diagnostic criteria by using a machine-learning approach to identify which features best predict a STAT3 mutation. Results In 64 patients, we identified 31 different STAT3 mutations, 18 of which were novel. These included mutations at splice sites and outside the previously implicated DNA-binding and Src homology 2 domains. A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. TH 17 cells were profoundly reduced in patients harboring STAT3 mutations, whereas 10 of 13 patients without mutations had low (<1%) TH 17 cells but were distinct by markedly reduced IFN-γ–producing CD4+ T cells. Conclusion We propose the following diagnostic guidelines for STAT3-deficient HIES. Possible: IgE >1000IU/mL plus a weighted score of clinical features >30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate. Probable: These characteristics plus lack of TH 17 cells or a family history for definitive HIES. Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.
Background Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a primary immunodeficiency with autoimmunity caused by mutations in forkhead box P3 (FOXP3 ), which encodes a ...transcription factor involved in regulatory T (Treg) cell function. The mechanistic basis for how different mutations in FOXP3 cause distinct manifestations of IPEX remains unclear. Objective To determine whether 3 different point mutants of FOXP3 that cause severe or mild IPEX differ in their ability to reprogram conventional T cells into Treg cells. Methods Human CD4+ T cells were transduced with wild-type or point mutant forms of FOXP3 , and changes in cell surface marker expression, cytokine production, proliferation and suppressive capacity were assessed. Ex vivo TH 17 cells were also transduced with different forms of FOXP3 to monitor changes in IL-17 production. Results The forkhead mutant F373A failed to upregulate CD25 and CCR4, did not suppress cytokine production, and induced suppressive activity less effectively than wild-type FOXP3. In contrast, although the forkhead mutant R347H was also defective in upregulation of CD25, it suppressed the production of cytokines, conferred suppressive capacity on CD4+ T cells, and suppressed IL-17 production. F324L, a mutant outside the forkhead domain associated with mild IPEX, was equivalent to wild-type FOXP3 in all aspects tested. Conclusion Mutations in FOXP3 that cause IPEX do not uniformly abrogate the ability of FOXP3 to regulate transcription and drive the development of Treg cells. These data support the notion that factors in addition to functional changes in Treg cells, such as alterations in conventional T cells, are involved in the pathogenesis of IPEX.
In Vitro Induction of Peanut-Specific Tr1 Cells Pellerin, Laurence, PhD; Jenks, Jennifer Anne; Chinthrajah, R. Sharon, Dr ...
Journal of allergy and clinical immunology,
02/2016, Letnik:
137, Številka:
2
Journal Article
Recenzirano
Peanut allergy is a life-threatening condition with no curative treatment.
PDF