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Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0)  and 5.0 (3.0-8.0) years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT.

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Los errores innatos de la inmunidad (EII), antes llamados inmunodeficiencias primarias (IDP), son un grupo heterogéneo de trastornos genéticos con defectos en uno o más componentes del sistema inmune. Los pacientes afectados por EII presentan aumentada susceptibilidad a microorganismos únicos o múltiples que se manifestará con infecciones recurrentes de diferente tipo y gravedad dependiendo del tipo de la localización del defecto. La prevención de infecciones es uno de los pilares fundamentales en el abordaje integral de los pacientes con EII. En este trabajo se resumen las conclusiones consensuadas en el Grupo de Trabajo de Inmunología Pediátrica de la Sociedad Argentina de Pediatría, sobre la base de la revisión de la evidencia disponible, respecto a los principios esenciales para el cuidado, la prevención de infecciones y la quimioprofilaxis en los errores innatos de la inmunidad para la orientación del pediatra y especialista dedicados al seguimiento de estas enfermedades.

Inborn errors of immunity, previously named primary immunodeficiency are a heterogeneous group of genetic defects of different components of the immune system. Patients present high susceptibility to an only or several microorganisms, developing recurrent infections; the severity is related to the specific genetic type of immunity defect. The main strategy on the management of these illness is the prevention of infections. These consensus guidelines made by the Pediatric Immunology Work Group of Sociedad Argentina de Pediatría, givese main approaches of infection prevention in order to provide a useful tool for all practitioners who are involved in the management of these patients, based on scientific evidence and broad consensus of a specialized panel expert.

Assuntos

RESUMO

Inborn errors of immunity, previously named primary immunodeficiency are a heterogeneous group of genetic defects of different components of the immune system. Patients present high susceptibility to an only or several microorganisms, developing recurrent infections; the severity is related to the specific genetic type of immunity defect. The main strategy on the management of these illness is the prevention of infections. These consensus guidelines made by the Pediatric Immunology Work Group of Sociedad Argentina de Pediatría, givese main approaches of infection prevention in order to provide a useful tool for all practitioners who are involved in the management of these patients, based on scientific evidence and broad consensus of a specialized panel expert..

Los errores innatos de la inmunidad (EII), antes llamados inmunodeficiencias primarias (IDP), son un grupo heterogéneo de trastornos genéticos con defectos en uno o más componentes del sistema inmune. Los pacientes afectados por EII presentan aumentada susceptibilidad a microorganismos únicos o múltiples que se manifestará con infecciones recurrentes de diferente tipo y gravedad dependiendo del tipo de la localización del defecto. La prevención de infecciones es uno de los pilares fundamentales en el abordaje integral de los pacientes con EII. En este trabajo se resumen las conclusiones consensuadas en el Grupo de Trabajo de Inmunología Pediátrica de la Sociedad Argentina de Pediatría, sobre la base de la revisión de la evidencia disponible, respecto a los principios esenciales para el cuidado, la prevención de infecciones y la quimioprofilaxis en los errores innatos de la inmunidad para la orientación del pediatra y especialista dedicados al seguimiento de estas enfermedades.

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Patients with inborn errors of immunity (IEI) in Argentina were encouraged to receive licensed Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer vaccines, even though most of the data of humoral and cellular responses combination on available vaccines comes from trials conducted in healthy individuals. We aimed to evaluate the safety and immunogenicity of the different vaccines in IEI patients in Argentina. The study cohort included adults and pediatric IEI patients (n = 118) and age-matched healthy controls (HC) (n = 37). B cell response was evaluated by measuring IgG anti-spike/receptor binding domain (S/RBD) and anti-nucleocapsid(N) antibodies by ELISA. Neutralization antibodies were also assessed with an alpha-S protein-expressing pseudo-virus assay. The T cell response was analyzed by IFN-γ secretion on S- or N-stimulated PBMC by ELISPOT and the frequency of S-specific circulating T follicular-helper cells (TFH) was evaluated by flow cytometry.No moderate/severe vaccine-associated adverse events were observed. Anti-S/RBD titers showed significant differences in both pediatric and adult IEI patients versus the age-matched HC cohort (p < 0.05). Neutralizing antibodies were also significantly lower in the patient cohort than in age-matched HC (p < 0.01). Positive S-specific IFN-γ response was observed in 84.5% of IEI patients and 82.1% presented S-specific TFH cells. Moderna vaccines, which were mainly administered in the pediatric population, elicited a stronger humoral response in IEI patients, both in antibody titer and neutralization capacity, but the cellular immune response was similar between vaccine platforms. No difference in humoral response was observed between vaccinated patients with and without previous SARS-CoV-2 infection.In conclusion, COVID-19 vaccines showed safety in IEI patients and, although immunogenicity was lower than HC, they showed specific anti-S/RBD IgG, neutralizing antibody titers, and T cell-dependent cellular immunity with IFN-γ secreting cells. These findings may guide the recommendation for a vaccination with all the available vaccines in IEI patients to prevent COVID-19 disease.

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CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.

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The phenolic profile of skin and flesh from Manifera indica main commercial cultivars (Keitt and Tommy Atkins) in Costa Rica was studied using ultra performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-ESI-MS) on enriched phenolic extracts. A total of 71 different compounds were identified, including 32 gallates and gallotannins (of different polymerization degree, from galloyl hexose monomer up to decagalloyl hexoses and undecagalloyl hexoses); seven hydroxybenzophenone (maclurin and iriflophenone) derivatives, six xanthonoids (including isomangiferin and mangiferin derivatives); 11 phenolic acids (hydroxybenzoic and hydroxycinnamic acid derivatives); and eight flavonoids (rhamnetin and quercetin derivatives). The findings for T. Atkins skin constitute the first report of such a high number and diversity of compounds. Also, it is the first time that the presence of gallotannin decamers and undecamers are reported in the skin and flesh of Keitt cultivar and in T. Atkins skins. In addition, total phenolic content (TPC) was measured with high values especially for fruits' skins, with a TPC of 698.65 and 644.17 mg gallic acid equivalents/g extract, respectively, for Keitt and T. Atkins cultivars. Antioxidant potential using 2,2-diphenyl-1-picrylhidrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) methods were evaluated, with T. Atkins skin showing the best values for both DPPH (IC50 = 9.97 µg/mL) and ORAC (11.02 mmol TE/g extract). A significant negative correlation was found for samples between TPC and DPPH antioxidant values (r = -0.960, p < 0.05), as well as a significant positive correlation between TPC and ORAC (r = 0.910, p < 0.05) and between DPPH and ORAC antioxidant methods (r = 0.989, p < 0.05). Also, cytotoxicity was evaluated in gastric adenocarcinoma (AGS), hepatocarcinoma (HepG2), and colon adenocarcinoma (SW620), with T. Atkins skin showing the best results (IC50 = 138-175 µg/mL). Finally, for AGS and SW 620 cell lines particularly, a high significant negative correlation was found between cytotoxic activity and gallotannins (r = -0.977 and r = -0.940, respectively) while for the HepG2 cell line, the highest significant negative correlation was found with xanthonoids compounds (r = -0.921).

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Uncaria tomentosa, which is widely commercialized as an herbal medicine, constitutes an important source of secondary metabolites with diverse biological activities. For instance, we have previously reported, for the first time, of a polyphenolic profile rich in proanthocyanidins from extracts of U. tomentosa plants, as well as their antioxidant capacity, antimicrobial activity on aerial bacteria, and cytotoxicity on cancer cell lines. These promising results prompted this research to evaluate the polyphenolic contents of U. tomentosa commercial products. We report a detailed study on the polyphenolic composition of extracts from U. tomentosa bark products (n = 18) commercialized in Costa Rica and Spain. Using HPLC-DAD/TQ-ESI-MS, a total of 25 polyphenolic compounds were identified, including hydroxybenzoic and hydroxycinnamic acids, flavan-3-ol monomers, procyanidin dimers, procyanidin trimers, as well as propelargonidin dimers. Our findings on the polyphenolic profile for all commercial samples show analogous composition to previous reports on U. tomentosa bark material, for instance a 41-49% content of procyanidin dimers and the presence of propelargonidin dimers (8-15%). However, most of the 18 commercial samples exhibit low proanthocyanidin contents (254.8-602.8 µg/g), more similar to previous U. tomentosa inner bark reports, while some exhibit better results, with one sample (SP-2) showing the highest contents (2386.5 µg/g) representing twice the average value of all 18 commercial products. This sample also exhibits the highest total phenolics (TP) and total proanthocyanidins (PRO) contents, as well as the highest Oxygen Radical Absorbance Capacity (ORAC) value (1.31 µg TE/g). One-way Analysis of Variance (ANOVA) with a Tukey post hoc test indicated significant difference (p < 0.05) between products from Costa Rica and Spain for TP and PRO findings, with samples from Spain exhibiting a higher average value. In addition, Pearson correlation analysis results showed a positive correlation (p < 0.05) between TP, PRO, and ORAC results, and an especially important correlation between ORAC antioxidant values and procyanidin dimers (r = 0.843, p < 0.05), procyanidin trimers (r = 0.847, p < 0.05), and propelargonidin dimers (r = 0.851, p < 0.05) contents. Finally, Principal Component Analysis (PCA) results indicated some variability in the composition regardless of their origin. However, only one sample (SP-2) stands out significatively, showing the highest PC1 because of its particularly high proanthocyanidins contents, which could be attributed to the 15% bark polyphenolic extract labeled in this commercial product, which differentiate this sample from all other 17 commercial samples. Therefore, our findings confirmed previous results on the value of extracts in the elaboration of potential commercial products from U. tomentosa, rich in proanthocyanidins and exhibiting high antioxidant activity.

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The phenolic composition of skin and flesh from Malus domestica apples (Anna cultivar) and Prunus domestica plums (satsuma cultivar) commercial cultivars in Costa Rica, was studied using Ultra Performance Liquid Chromatography coupled with High Resolution Mass Spectrometry (UPLC-DAD-ESI-MS) on enriched-phenolic extracts, with particular emphasis in proanthocyanidin and flavonoids characterization. A total of 52 compounds were identified, including 21 proanthocyanidins ([(+)-catechin and (-)-epicatechin]) flavan-3-ols monomers, five procyanidin B-type dimers and two procyanidin A-type dimers, five procyanidin B-type trimers and two procyanidin A-type trimers, as well as one procyanidin B-type tetramer, two procyanidin B-type pentamers, and two flavan-3-ol gallates); 15 flavonoids (kaempferol, quercetin and naringenin derivatives); nine phenolic acids (protochatechuic, caffeoylquinic, and hydroxycinnamic acid derivatives); five hydroxychalcones (phloretin and 3-hydroxyphloretin derivatives); and two isoprenoid glycosides (vomifoliol derivatives). These findings constitute the first report of such a high number and diversity of compounds in skins of one single plum cultivar and of the presence of proanthocyanidin pentamers in apple skins. Also, it is the first time that such a large number of glycosylated flavonoids and proanthocyanidins are reported in skins and flesh of a single plum cultivar. In addition, total phenolic content (TPC) was measured with high values observed for all samples, especially for fruits skins with a TPC of 619.6 and 640.3 mg gallic acid equivalents/g extract respectively for apple and plum. Antioxidant potential using 2,2-diphenyl-1-picrylhidrazyl (DPPH) and oxygen radical absorbance capacity (ORAC) methods were evaluated, with results showing also high values for all samples, especially again for fruit skins with IC50 of 4.54 and 5.19 µg/mL (DPPH) and 16.8 and 14.6 mmol TE/g (ORAC) respectively for apple and plum, indicating the potential value of these extracts. Significant negative correlation was found for both apple and plum samples between TPC and DPPH antioxidant values, especially for plum fruits (R = -0.981, p < 0.05) as well as significant positive correlation between TPC and ORAC, also especially for plum fruits (R = 0.993, p < 0.05) and between both, DPPH and ORAC antioxidant methods (R = 0.994, p < 0.05).

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The phenolic composition of leaves from Phyllanthus acuminatus L., a plant commonly used in Costa Rica as traditional medicine, was studied using UPLC-ESI-MS on an enriched phenolic extract. A total of 20 phenolic compounds were identified, comprising eight flavonoids (two flavanones-pinocembrin isomers and six derivatives from apigenin, chrysin, quercetin, and kaempferol); seven ellagitannins, two flavan-3-ols (prodelphinidin B dimer and (epi)gallocatechin); and three phenolic acids (ellagic acid, trimethylellagic acid, and ferulic acid). All of these compounds are reported for the first time in P. acuminatus, while previously reported in the genus Phyllanthus. Antioxidant evaluation was performed for P. acuminatus phenolic extract obtaining DPPH results with a remarkably low IC50 value of 0.15 µg/mL. Also, cytotoxicity on gastric AGS and colon SW20 adenocarcinoma cell lines was evaluated, and highly promising results were obtained, with IC50 values of 11.3 µg/mL and 10.5 µg/mL, respectively. Furthermore, selectivity index values obtained when comparing cytotoxicity on normal Vero cells was SI > 20 for both cancer cell lines, indicating a particularly high selectivity. Additionally, Justicidin B, a metabolite extensively studied for its antitumoral activity, was isolated from a non-polar extract of P. acuminatus, and comparatively evaluated for both bioactivities. The DPPH value obtained for Justicidin B was moderate (IC50 = 14.28 µg/mL), while cytotoxicity values for both AGS (IC50 = 19.5 µg/mL) and SW620 (IC50 = 24.8 µg/mL) cell lines, as well as selectivity when compared with normal Vero cells (SI = 5.4 and 4.2 respectively), was good, but lower than P. acuminatus extract. These preliminary results suggest that P. acuminatus enriched phenolic extract containing flavonoids, ellagitannins, flavan-3-ols, and phenolic acids, reported for the first time in this plant, could be of interest for further cancer cytotoxicity studies to elucidate structure-bioactivity relationships, and the molecular mechanisms and pathways.