Browsing by Author "Borzutzky, Arturo"
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Item Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease(2019) Dorjbal, Batsukh; Stinson, Jeffrey R.; Ma, Chi A.; Weinreich, Michael A.; Miraghazadeh, Bahar; Hartberger, Julia M.; Frey-Jakobs, Stefanie; Weidinger, Stephan; Moebus, Lena; Franke, Andre; Schäffer, Alejandro; Bulashevska, Alla; Fuchs, Sebastian; Ehl, Stephan; Limaye, Sandhya; Arkwright, Peter D.; Briggs, Tracy A.; Langley, Claire; Bethune, Claire; Whyte, Andrew F; Alachkar, Hana; Nejentsev, Sergey; DiMaggio, Thomas; Nelson, Celeste G.; Stone, Kelly D.; Nason, Martha; Brittain, Erica H.; Oler, Andrew J.; Veltri, Daniel P.; Leahy, T Ronan; Conlon, Niall; Poli, Cecilia; Borzutzky, Arturo; Cohen, Jeffrey I.; Davis, Joie; Lambert, Michele P.; Romberg, Neil; Sullivan, Kathleen E.; Paris, Kenneth; Freeman, Alexandra F.; Lucas, Laura; Chandrakasan, Shanmuganathan; Savic, Sinisa; Hambleton, Sophie; Patel, Smita Y.; Jordan, Michael B.; Theos, Amy; Lebensburger, Jeffrey; Atkinson, Prescott; Torgerson, Troy R.; Chinn, Ivan K.; Milner, Joshua D.; Grimbacher, Bodo; Cook, Matthew C.; Snow, Andrew L.Background: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. Objectives: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. Methods: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. Results: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. Conclusion: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.Item Inmunodeficiencia Combinada Severa, reporte de pacientes chilenos diagnosticados durante el período 1999-2020(2020) Hoyos-Bachiloglu, Rodrigo; Rojas, Jorge; Borzutzky, Arturo; Hernández, Pamela; Vinete, Ana María; Bustos, Paula; Fernández, Fabiola; Lagos, Macarena; Strickler, Alexis; Marinovic, María Angélica; Casado, Cristina; Poli, Cecilia; King, AlejandraLa inmunodeficiencia combinada severa (IDCS) corresponde a una de las formas más graves de inmunodeficiencia primaria, existiendo escasos datos nacionales sobre ésta. Objetivo: describir la epidemiología, complicaciones, pronóstico y uso de la vacuna BCG en pacientes chilenos con IDCS. Pacientes y Método: Estudio retrospectivo de pacientes diagnosticados con IDCS entre los años 1999 y 2020 por médicos inmunólogos a lo largo de Chile. El diagnóstico de IDCS se realizó conforme a los criterios propuestos por Shearer: linfocitos T (CD3+) < 300 células/µL y proliferación 10% del límite de normalidad en respuesta a fitohemaglutinina o presencia de linfocitos T de origen materno. Se obtuvieron de la ficha clínica los datos correspondientes a: sexo, edad al diagnóstico, consanguinidad, región de origen, subpoblaciones linfocitarias, diagnóstico genético, complicaciones infecciosas y no infecciosas, vacunación BCG y sus complicaciones, edad de derivación al centro de TPH y causa de mortalidad no relacionada al TPH. Resultados: se diagnosticaron 25 casos de IDCS en 22 familias entre los años 1999-2020. 78% varones, la edad media a la primera manifestación fue 2.3 meses (0-7), mientras que la edad media al diagnóstico fue de 3.4 meses (0- 7). Un 16% de los casos tenía un antecedente familiar de IDCS. Un 40% de los casos fueron diagnosticados en la Región Metropolitana. El inmunofenotipo más frecuente fue T-B-NK+ (48%). Se realizaron estudios genéticos en 69,5% de los casos, siendo los defectos genéticos en RAG2 (39%) la causa más frecuente. Un 88% de los casos recibió la vacuna Bacillus Calmette-Guerin (BCG) previo al diagnóstico, incluidos 2 pacientes con historia familiar positiva, 36% de los vacunados experimentó complicaciones de la BCG. La edad media a la derivación a trasplante fue de 7,4 meses (5-16). De los 25 pacientes, 11 fallecieron previo a la derivación a un centro de trasplante. Conclusión: En Chile existe un retraso clínicamente significativo entre las primeras manifestaciones y el diagnóstico de IDCS, así como un importante retraso en la derivación a centros de trasplante. La mayoría de los pacientes con IDCS reciben la vacuna BCG, pese a tener antecedentes familiares, y experimentan frecuentemente complicaciones de la vacunaItem Latin American consensus on the supportive management of patients with severe combined immunodeficiency(2019) Bustamante Ogando, Juan Carlos; Partida Gaytán, Armando; Aldave Becerra, Juan Carlos; Álvarez Cardona, Aristóteles; Bezrodnik, Liliana; Borzutzky, Arturo; Blancas Galicia, Lizbeth; Cabanillas, Diana; Condino-Neto, Antonio; Colsa Ranero, Agustín De; Espinosa Padilla, Sara; Folloni Fernandes, Juliana; García Campos, Jorge Alberto; Gómez Tello, Héctor; González Serrano, María Edith; Gutiérrez Hernández, Alonso; Hernández Bautista, Víctor Manuel; Ivankovich Escoto, Gabriele; King, Alejandra; Lessa Mazzucchelli, Juliana; Llamas Guillén, Beatriz Adriana; Lugo Reyes, Saul Oswaldo; Moreno Espinosa, Sarbelio; Oleastro, Matías; Otero Mendoza, Francisco; Poli, Cecilia; Porras, Oscar; Ramirez Uribe, Nideshda; Regairaz, Lorean; Rivas Larrauri, Francisco; Saracho Weber, Federico José; Grumach, Anete S.; Staines Boone, Tamara; Tavares Costa-Carvalho, Beatriz; Yamazaki Nakashimada, Marco Antonio; Espinosa Rosales, Francisco JavierSevere combined immunodeficiency (SCID) represents the most lethal form of primary immunodeficiency, with mortality rates of greater than 90% within the first year of life without treatment. Hematopoietic stem cell transplantation and gene therapy are the only curative treatments available, and the best-known prognostic factors for success are age at diagnosis, age at hematopoietic stem cell transplantation, and the comorbidities that develop in between. There are no evidence-based guidelines for standardized clinical care for patients with SCID during the time between diagnosis and definitive treatment, and we aim to generate a consensus management strategy on the supportive care of patients with SCID. First, we gathered available information about SCID diagnostic and therapeutic guidelines, then we developed a document including diagnostic and therapeutic interventions, and finally we submitted the interventions for expert consensus through a modified Delphi technique. Interventions are grouped in 10 topic domains, including 123 “agreed” and 38 “nonagreed” statements. This document intends to standardize supportive clinical care of patients with SCID from diagnosis to definitive treatment, reduce disease burden, and ultimately improve prognosis, particularly in countries where newborn screening for SCID is not universally available and delayed diagnosis is the rule. Our work intends to provide a tool not only for immunologists but also for primary care physicians and other specialists involved in the care of patients with SCID.Item Prevalence of filaggrin loss-of-function variants in Chilean population with and without atopic dermatitis(2021) Cárdenas, Geovanna; Iturriaga, Carolina; Hernández, Carol; Tejos-Bravo, Macarena; Pérez-Matelina, Guillermo; Cabalin, Carolina; Urzúa, Marcela; Venegas-Salas, Luis; Fraga, Juan P.; Rebolledo-Jaramillo, Boris; Poli, Cecilia; Repetto, Gabriela; Casanello, Paola; Castro-Rodriguez, José; Borzutzky, ArturoBackground Filaggrin (FLG) loss-of-function variants are major genetic risk factors for atopic dermatitis (AD), but these have not been studied in Latin American populations with and without AD. Methods FLG variants R501X and 2282del4 were genotyped in 275 Chilean adults with and without AD from the “Early origins of allergy and asthma” (ARIES) cohort and in 227 patients from an AD cohort based in Santiago, Chile. Results Among adults in the ARIES cohort, 3.3% were carriers of R501X and 2.9% of 2282del4 variants, all heterozygotes. In this cohort, 6.2% were FLG variant carriers: 11.1% of subjects reporting AD were carriers of FLG variants vs. 5.2% in those without AD (P = 0.13). In this first cohort, FLG variants were not significantly associated with asthma, allergic rhinitis, or food allergy. In the AD cohort, the prevalence of FLG variants was 7% for R501X, 2.2% for the 2282del4 variant, and 9.3% for the combined genotype. In this cohort, FLG variants were present in 15.5% of severe AD vs. 7.1% of mild-to-moderate AD subjects (P = 0.056). Evaluation of Chilean population from both cohorts combined (n = 502) revealed that FLG variants were not significantly associated with AD (OR = 1.92 [95% CI 0.95–3.9], P = 0.067) but were associated with asthma (OR = 2.16 [95% CI 1.02– 4.56], P = 0.039). Conclusions This is the first study to evaluate FLG loss-of-function variants R501X and 2282del4 in Latin American population, revealing a similar prevalence of these FLG variant carriers to that of European populations. Among Chileans, FLG variants were significantly associated with asthma but not AD.