The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008

Primary immunodeficiencies (PID) are rare diseases; therefore transnational studies are essential to maximize the scientific outcome and to improve diagnosis and therapy. In order to estimate the prevalence of PID in Europe as well as to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Within 4 years, 7430 patients from 39 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity, with 1540 patients or 20.7% of all entries, followed by isolated immunoglobulin (Ig)G subclass deficiency (546 patients, 7.4%). Evaluations show that the average life expectancy for PID patients varies from 1 to 49 years (median), depending on the type of PID. The prevalence and incidence of PID remains a key question to be answered. As the registration progress is far from finished we can only calculate minimum values for PID, with e.g. France currently showing a minimum prevalence of 3.72 patients per 100,000 inhabitants. The most frequently documented permanent treatment is immunoglobulin replacement; 2819 patients (42% of all patients alive) currently receive this form of treatment

IL-12 RB1 Genetic Variants Contribute to Human Susceptibility to Severe Acute Respiratory Syndrome Infection among Chinese

BACKGROUND: Cytokines play important roles in antiviral action. We examined whether polymorphisms of interleukin (IL)-12 receptor B1 (IL-12RB1) affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS). METHODS: A case-control study was carried out in Chinese SARS patients and healthy controls. The genotypes of 4SNPs on IL-12 RB1 gene, +705A/G,+1158T/C, +1196G/C and +1664 C/T, were determined by PCR-RFLP. Haplotypes were estimated from the genotype data using the expectation-maximisation algorithm. RESULTS: Comparison between patients and close contacts showed that individuals with the +1664 C/T (CT and TT) genotype had a 2.09-fold (95% confidence interval [CI], 1.90-7.16) and 2.34-fold (95% CI, 1.79-13.37) increased risk of developing SARS, respectively. For any of the other three polymorphisms, however, no significant difference can be detected in allele or genotype frequencies between patients and controls. Additionally, estimation of the frequencies of multiple-locus haplotypes revealed potential risk haplotypes (GCCT) for SARS infection. CONCLUSIONS: Our data indicate that genetic variants of IL12RB1confer genetic susceptibility to SARS infection, but not necessary associated with the progression of the disease in Chinese population

IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

RANTES levels in pre-and-post 3 years of HAART and CCR5 expression in HIV-1 infected children.

Las quimiocinas son citocinas proinflamatorias que atraen y activan subpoblaciones leucocitarias específicas cuyos receptores son empleados como coreceptores por algunas cepas virales. El papel de las quimiocinas durante la infección por el VIH-1 ha sido poco estudiado y en casos particulares los niveles elevados en plasma de algunas, como RANTES (regulated on activation, normal T cell expressed and secreted), han sido asociados en los individuos infectados a un buen pronóstico, para su recuperación inmunológica. El presente trabajo evaluó el papel de RANTES y su receptor CCR5 en la reconstitución inmunológica de niños infectados por transmisión vertical con VIH-1 y bajo triple terapia antirretroviral de alta eficacia (TAEE). Se estudió un grupo de 32 niños infectados entre 4 y 12 años de edad y un grupo control de la misma edad. En ambos grupos se analizaron las subpoblaciones linfocitarias por citometría de flujo (CMF), para determinar la expresión de CCR5 en células T CD4+, y la producción intracelular de interleucina (IL)-2 e interferón (IFN)-?, y mediante un ensayo inmunoenzimático (ELISA) los niveles de RANTES en plasma y sobrenadantes de cultivos linfocitarios. En los niños infectados, los niveles plasmáticos pre y post TAAE de RANTES fueron 886 y 1025 pg/ml, respectivamente, y la expresión media de CCR5 en CD4+ fue 18%, siendo más baja en 3 casos heterocigotos para la mutación CCR5D32. En el grupo control, la expresión media de CCR5 en CD4+ fue de 38% y los niveles de RANTES de 687 pg/ml. En relación a la edad, en ambos grupos los niveles de RANTES y la expresión de CCR5 no arrojaron diferencias significativas. En los niños infectados, los niveles de IL-2 e IFN-? no fueron significativamente diferentes a los del grupo control, aunque la relación CD4+/CD8+ fue más baja en los primeros, aún después de la terapia. La expresión disminuida de CCR5 en CD4+, con respecto a los controles y el incremento de los niveles de RANTES post TAAE, se correlacionaron al mejoramiento del número total de linfocitos T CD4+, las condiciones clínicas y la disminución de la carga viral, lo cual establece que los niveles de RANTES pueden ser un marcador muy útil para evaluar la recuperación inmunológica en individuos infectados por el VIH-1.53-62bimestralChemokines are pro-inflammatory cytokines that attract and activate specific leukocyte subsets whose receptors are used as co-receptors by some viral strains. The role of chemokines have been barely assessed and increased plasma levels, particularly RANTES (regulated on activation, normal T cell expressed and secreted), have been associated with better prognosis to immune recovery. To evaluate the role of RANTES and its receptor CCR5 in immunological reconstitution in HIV vertically infected children, after highly active antiretroviral therapy (HAART), lymphocytes subsets, CCR5 expression on CD4+ T cells and intracellular production of interleukin (IL)-2 and interferon (IFN)- ? were determined by flow cytometry (FCM). RANTES levels were assessed by ELISA in plasma and lymphocyte culture supernatants. Thirty-two infected children (4-12-years old) and an age-matched control group were studied. RANTES plasma levels were 886 and 1025 pg/ml pre and post HAART, respectively. Mean CCR5 expression on CD4+ cells was 18% and lower in 3 cases, heterozygous for CCR5D32 mutation. In the control group the mean CCR5 expression on CD4+ cells was 38% and plasma RANTES levels were 687 pg/ml. RANTES levels and CCR5 expression were also analyzed in relation to age and no significant differences were observed. Intracellular IL-2 and IFN- ? values were not significantly different from controls, although CD4+/CD8+ ratio was much lower in infected patients even after therapy. Lower CCR5 expression than controls and increased RANTES levels post therapy correlate with the improvement in total CD4+ cells, clinical conditions and decreased viral load in the post HAART period, and could be a reliable marker of immune recovery

High-content cytometry and transcriptomic biomarker profiling of human B-cell activation

BACKGROUND:Primary antibody deficiencies represent the most prevalent, although very heterogeneous, group of inborn immunodeficiencies, with a puzzling complexity of cellular and molecular processes involved in disease pathogenesis. OBJECTIVE:We aimed to study in detail the kinetics of CD40 ligand/IL-21-induced B-cell differentiation to define new biomarker sets for further research into primary antibody deficiencies. METHODS:We applied high-content screening methods to monitor B-cell activation on the cellular (chip cytometry) and transcriptomic (RNA microarray) levels. RESULTS:The complete activation process, including stepwise changes in protein and RNA expression patterns, entry into the cell cycle, proliferation and expression of activation-induced cytidine deaminase (AID), DNA repair enzymes, and post-class-switch expression of IgA and IgG, was successfully monitored during in vitro differentiation. We identified a number of unknown pathways engaged during B-cell activation, such as CXCL9/CXCL10 secretion by B cells. Finally, we evaluated a deduced set of biomarkers on a group of 18 patients with putative or proved intrinsic B-cell defects recruited from the European Society for Immunodeficiencies database and successfully predicted 2 AID defects and 1 DNA repair defect. Complete absence of class-switched B cells was a sensitive predictor of AID deficiency and should be further evaluated as a diagnostic biomarker. CONCLUSION:The biomarkers found in this study could be used to further study the complex process of B-cell activation and to understand conditions that lead to the development of primary antibody deficiencies