138 research outputs found
Primary Immune Regulatory Disorders With an Autoimmune Lymphoproliferative Syndrome-Like Phenotype: Immunologic Evaluation, Early Diagnosis and Management
Primary immune regulatory disorders (PIRD) are associated with autoimmunity, autoinflammation and/or dysregulation of lymphocyte homeostasis. Autoimmune lymphoproliferative syndrome (ALPS) is a PIRD due to an apoptotic defect in Fas-FasL pathway and characterized by benign and chronic lymphoproliferation, autoimmunity and increased risk of lymphoma. Clinical manifestations and typical laboratory biomarkers of ALPS have also been found in patients with a gene defect out of the Fas-FasL pathway (ALPS-like disorders). Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA), we identified more than 600 patients suffering from 24 distinct genetic defects described in the literature with an autoimmune lymphoproliferative phenotype (ALPS-like syndromes) corresponding to phenocopies of primary immunodeficiency (PID) (NRAS, KRAS), susceptibility to EBV (MAGT1, PRKCD, XIAP,
SH2D1A, RASGRP1, TNFRSF9), antibody deficiency (PIK3CD gain of function (GOF), PIK3R1 loss of function (LOF), CARD11 GOF), regulatory T-cells defects (CTLA4, LRBA, STAT3 GOF, IL2RA, IL2RB, DEF6), combined immunodeficiencies (ITK, STK4), defects in intrinsic and innate immunity and predisposition to infection (STAT1 GOF, IL12RB1) and autoimmunity/autoinflammation (ADA2, TNFAIP3,TPP2, TET2). CTLA4 and LRBA patients correspond around to 50% of total ALPS-like cases. However, only 100% of CTLA4, PRKCD, TET2 and NRAS/KRAS reported patients had an ALPS-like presentation, while the autoimmunity and lymphoproliferation combination resulted rare n other genetic defects. Recurrent infections, skin lesions, enteropathy and malignancy
are the most common clinical manifestations. Some approaches available for the immunological study and identification of ALPS-like patients through flow cytometry and ALPS biomarkers are provided in this work. Protein expression assays for NKG2D, XIAP, SAP, CTLA4 and LRBA deficiencies and functional studies of AKT, STAT1 and STAT3 phosphorylation, are showed as useful tests. Patients suspected to suffer from one of these disorders require rapid and correct diagnosis allowing initiation of tailored specific therapeutic strategies and monitoring thereby improving the prognosis and their quality of life
Tenodermodesis para el tratamiento del dedo en martillo tendinoso de presentación tardía en niños y adolescentes
Introducción: El diagnóstico del dedo en martillo tendinoso puede pasar desapercibido inicialmente en niños y adolescentes, esto limita las posibilidades del tratamiento conservador. El objetivo fue evaluar los resultados del tratamiento quirúrgico con la técnica de tenodermodesis en lesiones de presentación tardía.
Materiales y Métodos: Se evaluó retrospectivamente a 9 pacientes (8 niños) con una edad promedio de 8.6 ± 6 años (rango 1-15). Los días promedio de evolución de la lesión eran 27±11.4 (rango 15-45). El mecanismo de lesión fue una herida cortante (4 casos) y un traumatismo indirecto (5 casos). El tratamiento consistió en tenodermodesis e inmovilización transitoria con clavija transarticular. El seguimiento promedio fue de 61 ± 34.7 meses (rango 12-106). Se evaluaron la movilidad activa y pasiva de la articulación interfalángica distal, la presencia de dolor o deformidad, la limitación de actividades de la vida diaria y la necesidad de tratamientos adicionales. Se clasificaron los resultados con los criterios de evaluación de Crawford.
Resultados: En 8 pacientes, el resultado fue excelente y, en uno, regular según Crawford. Un paciente poco colaborador requirió una segunda intervención por re-rotura. En dos casos, hubo una complicación (granuloma) y requirió resección. Ningún paciente refirió dolor al final del seguimiento, ni limitaciones para las actividades de la vida diaria. Ocho presentaron extensión activa completa y uno, una deformidad residual de 20°.
Conclusión: La tenodermodesis permite la reconstrucción anatómica del mecanismo extensor en niños y adolescentes. Los resultados clínicos de este estudio son alentadores en lesiones no diagnosticadas en forma temprana.
Nivel de Evidencia: I
γδ T lymphocytes in the diagnosis of human T cell receptor immunodeficiencies
Supported by grants from MINECO (SAF 2011-24235, BES-2012-055054, SAF2014- 54708-R, and SAF2014-53563-REDT) CAM (S2010/BMD-2316) ISCIII (RD08- 0075-0002 and PI12/02761)Peer Reviewe
Generation, establishment and characterization of a pluripotent stem cell line (CVTTHi001-A) from primary fibroblasts isolated from a patient with activated PI3 kinase delta syndrome (APDS2)
APDS2 is caused by mutations in PIK3R1 gene resulting in constitutive PI3Kδ activation. PI3Kδ is predominantly expressed in leukocytes and plays critical roles in regulating immune responses. Here we first derived fibroblast primary cells from a skin biopsy of a patient carrying a heterozygous single T deletion in intron 11 of the PIK3R1 gene. We next present the derivation of an induced pluripotent stem cell (iPS) line using a non-integrative reprogramming technology. Pluripotent-related hallmarks are further shown, including: iPSCs self-renewal and expression of pluripotent and differentiation markers after in vitro differentiation towards embryonic germ layers, assessed by RT-PCR and immunofluorescence
Newborn screening for presymptomatic diagnosis of complement and phagocyte deficiencies
The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by
accurate diagnosis early in life. However, it is not common to consider PIDs before
the manifestation of severe clinical symptoms. Including PIDs in the nation-wide
newborn screening programs will potentially improve survival and provide better disease
management and preventive care in PID patients. This calls for the detection of
disease biomarkers in blood and the use of dried blood spot samples, which is a part
of routine newborn screening programs worldwide. Here, we developed a newborn
screening method based on multiplex protein profiling for parallel diagnosis of 22 innate
immunodeficiencies affecting the complement system and respiratory burst function in
phagocytosis. The proposed method uses a small fraction of eluted blood from dried
blood spots and is applicable for population-scale performance. The diagnosis method
is validated through a retrospective screening of immunodeficient patient samples. This
diagnostic approach can pave the way for an earlier, more comprehensive and accurate
diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy
and active life for the PID patientsThis work was supported by the Swedish Research Council
(VR) and grants provided by the Stockholm County
Council (ALF)
Longitudinal dynamics of SARS-CoV-2-specific cellular and humoral immunity after natural infection or BNT162b2 vaccination
The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations
Acquired and Innate Immunity Impairment and Severe Disseminated Mycobacterium genavense Infection in a Patient With a NF-κB1 Deficiency
Background: NF-κB1 is a master regulator of both acquired and innate responses. NFKB1 loss-of-function mutations elicit a wide clinical phenotype with asymptomatic individuals at one end of the spectrum and patients with common variable immunodeficiency, combined immunodeficiency or autoinflammation at the other. Impairment of acquired and innate immunity and disseminated Mycobacterium genavense infection expands the clinical and immunological phenotype of NF-κB1 deficiency.Objective: Functional and molecular characterization of a patient with a novel phenotype of NF-κB1 deficiency.Methods: Circulating T, B, dendritic cell subsets and innate or unconventional T-cells were quantified. The cytokine production in stimulated whole blood samples was assessed and molecular characterization by next generation sequencing and gene expression assays were also performed.Results: We report a patient presenting with features of combined immunodeficiency (CID) and disseminated Mycobacterium genavense infection. Sequencing of genomic DNA identified a novel synonymous mutation (c.705G > A) in NFKB1 gene which resulted in exon 8 skipping and haploinsufficiency of the NF-κB1 subunit p50. The susceptibility to atypical mycobacterial infection has not been previously reported and may be the result of a dendritic cell deficiency. A selective deficiency of circulating follicular helper T (cTFH) cells responsible for mediating the differentiation of naive B cells into memory and plasma cells was also present in the patient. It could affect the maturation of innate or unconventional T cells where NF-κB1 could also be involved.Conclusion: These findings showed that the role of NF-κB1 in humans could be critical for the development of acquired and innate immunity and further highlights the role of human T cells in anti-mycobacterial immunity
Extreme Phenotypes With Identical Mutations: Two Patients With Same Non-sense NHEJ1 Homozygous Mutation
Cernunnos/XLF deficiency is a rare primary immunodeficiency classified within the DNA repair defects. Patients present with severe growth retardation, microcephaly, lymphopenia and increased cellular sensitivity to ionizing radiation. Here, we describe two unrelated cases with the same non-sense mutation in the NHEJ1 gene showing significant differences in clinical presentation and immunological profile but a similar DNA repair defect
The Seventh Data Release of the Sloan Digital Sky Survey
This paper describes the Seventh Data Release of the Sloan Digital Sky Survey
(SDSS), marking the completion of the original goals of the SDSS and the end of
the phase known as SDSS-II. It includes 11663 deg^2 of imaging data, with most
of the roughly 2000 deg^2 increment over the previous data release lying in
regions of low Galactic latitude. The catalog contains five-band photometry for
357 million distinct objects. The survey also includes repeat photometry over
250 deg^2 along the Celestial Equator in the Southern Galactic Cap. A
coaddition of these data goes roughly two magnitudes fainter than the main
survey. The spectroscopy is now complete over a contiguous area of 7500 deg^2
in the Northern Galactic Cap, closing the gap that was present in previous data
releases. There are over 1.6 million spectra in total, including 930,000
galaxies, 120,000 quasars, and 460,000 stars. The data release includes
improved stellar photometry at low Galactic latitude. The astrometry has all
been recalibrated with the second version of the USNO CCD Astrograph Catalog
(UCAC-2), reducing the rms statistical errors at the bright end to 45
milli-arcseconds per coordinate. A systematic error in bright galaxy photometr
is less severe than previously reported for the majority of galaxies. Finally,
we describe a series of improvements to the spectroscopic reductions, including
better flat-fielding and improved wavelength calibration at the blue end,
better processing of objects with extremely strong narrow emission lines, and
an improved determination of stellar metallicities. (Abridged)Comment: 20 pages, 10 embedded figures. Accepted to ApJS after minor
correction
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