Regulation of human CD4+ T cell differentiation

Naive CD4+ T cells differentiate into specific effector subsets—Th1, Th2, Th17, and T follicular helper (Tfh)—that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4+ T cell differentiation in vitro. IL12Rβ1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10–secreting cells. IL12Rβ1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4+ T cell effector function in the settings of infection, vaccination, or immune dysregulation

Çocukluk çağı astımında serum RANTES düzeylerinin değerlendirilmesi

Giriş: İnflamatuvar hücreler için kemoatraktan bir molekül olan RANTES, değişik allerjik hastalık- larda rol oynar. Bu çalışmanın amacı, çocukluk ça- ğı astımında serum RANTES düzeylerini değerlen- dirmek ve akut astım atağındaki değişimini incele- mektir. Gereç ve Yöntem: Serum RANTES düzeyleri yaş- ları 2-14 yıl arasında olan 16 astımlı çocukta (medi- an yaş: 4.5 yıl) akut astım atağı sırasında ve astım atağından iki hafta sonra ELISA yöntemiyle ölçül- dü. Yaş grubu benzer 10 sağlıklı çocuk da kontrol grubunu oluşturdu. Bulgular: Astımlı çocukların atak sırasında ölçü- len serum RANTES düzeyleri kontrol grubu ile ben- zerken, atak sonrası ikinci haftada kontrol grubun- dan yüksek bulundu (p 0.05). Astımlı hastaların 11inde atak sonrası serum RANTES düzeyleri yük- selirken, dördünde düşme saptandı, birinde ise de- ğişiklik gözlenmedi. Astımlı hastalarda gözlenen bu değişiklik istatistiksel olarak anlamlı bulundu. Sonuç: Akut astım atağı sonrası ikinci haftada göz- lenen serum düzeylerindeki yükselme eğilimi, RAN- TESin çocukluk çağı astımının patogenezinde rol oynayabilen bir molekül olabileceği savını destele- mektedir.Objective: RANTES is considered to play an im- portant role in various allergic disorders since it is a potent chemoattractant for inflammatory cells such as eosinophils, memory T cells and monocy- tes. The aim of this study is to determine serum RANTES levels and to assess whether or not it vari- es in acute attack in the children with asthma. Materials and Methods: Serum RANTES levels were measured in 16 asthmatic children (2 to 14 ye- ars of age, median 4.5 years) longitudinally during asthma attacks and two weeks later by ELISA tech- nique. Ten healthy age-matched children without any atopic and infectious disease served as controls. Results: There was no significant difference in se- rum levels of RANTES between asthmatic patients with acute attacks and controls. Two weeks follo- wing the acute attack, the serum RANTES levels we- re higher than the controls, however the difference was insignificant. When we compared the serum RANTES levels of asthmatic patients during acute attack and two weeks following the acute attack, the serum RANTES levels were elevated in 11 asth- matic patients, decreased in four, and remained unchanged in one. This variation occurring among asthmatic acute attack versus stable asthmatic children was statistically significant (p> 0.05). Conclusion: The up-regulation in the production of RANTES detected in stable asthmatic children two weeks after the acute attack suggests that RANTES is a mediator in the pathogenesis of childhood asthm

Outcome of treosulfan-based reduced-toxicity conditioning regimens for HSCT in high-risk patients with primary immune deficiencies

Introductio

G-CSF-mobilized haploidentical peripheral blood stem cell transplantation in children with poor prognostic nonmalignant disorders

Haploidentical hematopoletic stem cell transplantation (HSCT) is currently one of the alternative curative treatment options for some nonmalignant but also for malignant diseases. However, concerns regarding its safety cause delays in time and a successful outcome. Between 2000 and 2005, twenty-one children with poor prognostic nonmalignant disorders, 13 boys and 8 girls, with a median age of 12 months, underwent 28 haploidentical peripheral HSCT. Immunomagnetic bead depletion device (CliniMACS) was used for indirect T-cell depletion. Indications for transplant were severe combined immunodeficiency (n = 16), osteopetrosis (n = 2), MDS (n = 1), amegakaryocytic thrombocytopenia (n = 1), and aplastic anemia (n = 1). Five patients (24%) had lung infection at the time of transplantation. The patients received a median of 25.67 x 10(6) G-CSF-mobilized peripheral CD34(+) progenitor cells and a median of 4.19 x 10(4) T-lymphocytes per kilogram of body weight with a T-cell depletion rate of median 4.59 logs. The rate of total engraftment was 66.6%. Median times for leukocyte and platelet engraftment were 14 and 16 days, respectively. The 6-year projected survival was 32% for all patients and 29.76% for patients with severe combined immunodeficiency (SCID). The rates of transplant-related mortality, graft failure, and severe GvHD were 14.2, 33.4%, and 8.3%, respectively. Infection was the main cause of death. The poor outcome may be explained with the poor prognostic factors of our patients such as the type of SCID in most cases (T-B-SCID), the median age over 6 months and the presence of lung infection in some children at the time of transplantation

Does the Hyper IgM Phenotype Affect Prognosis in Ataxia Telangiectasia?

Objective: To evaluate the characteristics of the patients who were followed-up with the diagnosis of ataxia telangiectasia (AT) and to assess the relationship between the hyper IgM (HIGM) phenotype and their prognosis

Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations.

Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency