Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor β1 Deficiency: Medical and Immunological Implications

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo

Mutations in STAT3 and IL12RB1 impair the development of human IL-17 producing T cells

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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

Evaluation of DiaSorin Liaison® calprotectin fecal assay adapted for pleural effusion

Calprotectin (CP) is a calcium and zinc binding protein that is widely measured on faecal samples but its determination in other biological fluids might be of interest. The aim of this work was to validate the measurement of CP in pleural fluid by chemiluminescence

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

Evaluación de la prueba fecal Liaison® Calprotectin de DiaSorin adaptada al derrame pleural

La calprotectina (CP) es una proteína de unión a calcio y zinc que se suele determinar en muestras fecales, aunque su cuantificación en otros fluidos biológicos podría ser de interés. El objetivo del presente estudio es validar la determinación de CP en líquido pleural mediante quimioluminiscencia

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

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