Germline mutations in CYBB, the human gene encoding the gp91(phox) subunit of the phagocyte NADPH oxidase, impair the respiratory burst of all types of phagocytes and result in X-linked chronic ...granulomatous disease (CGD). We report here two kindreds in which otherwise healthy male adults developed X-linked recessive Mendelian susceptibility to mycobacterial disease (MSMD) syndromes. These patients had previously unknown mutations in CYBB that resulted in an impaired respiratory burst in monocyte-derived macrophages but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation resulted from cell-specific impairment in the assembly of the NADPH oxidase. This 'experiment of nature' indicates that CYBB is associated with MSMD and demonstrates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to tuberculous mycobacteria.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Patients with inborn errors of immunity (IEI) have a compromised or inappropriate immune response. Although they might be considered a high-risk group for severe SARS-CoV-2 infection, ...the reported impact of COVID-19 in these patients has been reassuring, while the differential susceptibility of distinct types of IEI remains unclear.
Objective
We aimed to describe the findings and outcomes of our known patients with IEI who were diagnosed with COVID-19.
Methods
In a retrospective study from March 2020 to February 2021, four centers in Mexico collected clinical, laboratory, and genetic data from pediatric and adult patients with known diagnoses of IEI who presented with COVID-19, based on compatible symptoms and positive SARS-CoV-2 testing or known household exposure.
Results
We report 31 patients with known IEI from Mexico who presented with SARS-CoV-2 infection. Seventy-four percent were male, 52% were pediatric, and 81% survived. Their ages ranged from 5 months to 56 years, with a median of 17 years. Sixty-five percent had predominant antibody deficiencies, 48% were hospitalized, and 26% required ICU. Pediatric patients had a higher hospital admission rate than adults. Inpatient mortality was 40%, and ICU mortality rate was 63%. Forty-eight percent developed pneumonia, while 36% had evidence of hyperinflammation (4 adults and 7 children). Predominant laboratory features were lymphopenia and thrombocytopenia, seen in 70 and 44% of patients, respectively. The serum D-dimer median value was 2.6 (0.5–20.6) μg/mL, and the median highest ferritin value was 1015 (32–10,303) ng/mL. Intravenous immunoglobulin was used in 80% of patients. Other treatments included macrolides (39%) and corticosteroids (29%). Six patients died from secondary infection or uncontrolled systemic inflammation.
Discussion
Although impaired immunity due to IEI may be a predisposing factor for severe COVID-19, most of our patients with IEI who acquired the SARS-CoV-2 infection developed a well-tolerated infection and survived, as have more than 80% of worldwide reported patients to date. An impaired immune or inflammatory response may be a predisposing factor for some and a protective factor for others. A systematic review of the literature could help identify those patients at risk of severe disease and complications. Healthcare-associated infections should be aggressively prevented.
Severe 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.
ABSTRACT
IL‐12Rβ1 deficiency is an autosomal recessive disorder characterized by predisposition to recurrent and/or severe infections caused by otherwise poorly pathogenic mycobacteria and ...salmonella. IL‐12Rβ1 is a receptor chain of both the IL‐12 and the IL‐23 receptor and deficiency of IL‐12Rβ1 thus abolishes both IL‐12 and IL‐23 signaling. IL‐12Rβ1 deficiency is caused by bi‐allelic mutations in the IL12RB1 gene. Mutations resulting in premature stop codons, such as nonsense, frame shift, and splice site mutations, represent the majority of IL‐12Rβ1 deficiency causing mutations (66%; 46/70). Also every other morbid mutation completely inactivates the IL‐12Rβ1 protein. In addition to disease‐causing mutations, rare and common variations with unknown functional effect have been reported in IL12RB1. All these variants have been deposited in the online IL12RB1 variation database (www.LOVD.nl/IL12RB1). In this article, we review the function of IL‐12Rβ1 and molecular genetics of human IL12RB1.
IL‐12Rβ1 deficiency is an autosomal recessive disorder that predisposes to severe infections with otherwise poorly pathogenic mycobacteria and salmonella. Seventy unique IL12RB1 mutations in 198 individuals are known that almost invariably result in the same cellular phenotype: absence of IL‐12Rβ1 expression on the cell surface (in all but one) and absence of IL‐12 and IL‐23 responses (in all). No genotype–phenotype relationship exists. This manuscript reviews the function of IL‐12Rβ1 and molecular genetics of IL12RB1, and introduces the IL12RB1 mutation database.
Introducción: La enfermedad granulomatosa crónica (EGC) es un error innato de la inmunidad, se caracteriza por una susceptibilidad a padecer infecciones bacterianas y fúngicas y a una falta de ...regulación inflamatoria sistémica. Las variantes patogénicas en el gen CYBB se trasmiten con un patrón de herencia ligada al X; mientras que las variantes patogénicas presentes en los genes EROS, NCF1, NCF2, NCF4 o CYBA se trasmiten con un patrón de herencia autosómico recesivo.
Objetivos. Describir las características clínicas, inmunológicas y genéticas de dos pacientes con EGC e infección por BCG.
Métodos: En neutrófilos de sangre periférica se midió la producción de H2O2 y la expresión de las subunidades de la NADPH oxidasa. La detección de las variantes patogénicas fue por secuenciación Sanger del gen NCF2. La información clínica fue extraída de los expedientes por los médicos tratantes.
Resultados: Presentamos a dos lactantes masculinos de dos familias no relacionadas de la etnia maya, con EGC e infección por la vacuna de BCG. Se identificaron tres diferentes variantes patogénicas en el gen NCF2; por un lado, c.304 C>T (p.Arg102*) ya reportada, por otro lado, c.1369 A>T (p.Lys457*) y c.979 G>T (p.Gly327*) no reportadas.
Conclusiones: En pacientes con infección micobacteriana por BCG debemos sospechar en un error innato de la inmunidad, como la EGC. El diagnóstico de EGC se realiza a través de la detección de una falta de producción de radicales libres en los neutrófilos. Los pacientes reportados tuvieron variantes patogénicas en el gen NCF2, dos de ellas no han sido reportadas previamente en la literatura.
La enfermedad granulomatosa crónica (EGC) es un error innato de la inmunidad causado por un defecto en uno de los componentes del complejo NADPH oxidasa, responsable de generar especies reactivas de ...oxígeno (ERO) durante el estallido respiratorio en los fagocitos. La ausencia de ERO producidos por la NADPH oxidasa en los neutrófilos y en los macrófagos produce mayor susceptibilidad a infecciones bacterianas y fúngicas, además de manifestaciones inflamatorias por una respuesta inflamatoria desregulada, lo que sugiere que la capacidad para regular adecuadamente la señalización inflamatoria depende de las ERO derivadas de la NADPH oxidasa. Los pacientes con EGC ligada al cromosoma X tienen un curso de enfermedad más grave con infecciones invasivas recurrentes, a diferencia de los pacientes con EGC no clásica, quienes no presentan infecciones bacterianas o fúngicas invasivas, pero con manifestaciones inflamatorias más prominentes. Las manifestaciones gastrointestinales más frecuentes son estomatitis, gingivitis, diarrea crónica, abscesos hepáticos, similares a las de la enfermedad inflamatoria intestinal (EII) y granulomas, que pueden provocar obstrucción o estenosis en esófago, estómago o intestino. Se ha observado que la deficiencia de p40phox y EROS (EGC no clásica) se asocia a mayor susceptibilidad a colitis y al desarrollo de inflamación severa, por lo que se plantea que estas proteínas participan en la resolución de la inflamación. En general, los hallazgos inflamatorios en la EGC, incluyendo los gastrointestinales, han sido poco descritos. En las cohortes internacionales se reportan manifestaciones similares a EII hasta en 58 % de los pacientes con EGC; en cambio, en la única cohorte mexicana se describe su hallazgo solo en cuatro de 93 pacientes (4.3 %). En esta revisión resumimos los hallazgos clínicos gastrointestinales de la EGC, incluidas las manifestaciones infecciosas e inflamatorias, con énfasis en las últimas.
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