RESUMEN
Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, a defective class switch indicated by low numbers of IgM- and IgG-memory B cells, as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase δ (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity.
Asunto(s)
Autoinmunidad , Linfocitos B/patología , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/patología , Mutación , Proteína Quinasa C-delta/genética , Adulto , Antígenos CD19/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Niño , Femenino , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/terapia , Inmunofenotipificación , Masculino , Linaje , Polimorfismo de Nucleótido Simple , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Proteína Quinasa C-delta/inmunologíaRESUMEN
AIM: We analyzed data from 71 patients with chronic granulomatous disease (CGD) with a confirmed genetic diagnosis, registered in the online Latin American Society of Primary Immunodeficiencies (LASID) database. RESULTS: Latin American CGD patients presented with recurrent and severe infections caused by several organisms. The mean age at disease onset was 23.9 months, and the mean age at CGD diagnosis was 52.7 months. Recurrent pneumonia was the most frequent clinical condition (76.8%), followed by lymphadenopathy (59.4%), granulomata (49.3%), skin infections (42%), chronic diarrhea (41.9%), otitis (29%), sepsis (23.2%), abscesses (21.7%), recurrent urinary tract infection (20.3%), and osteomyelitis (15.9%). Adverse reactions to bacillus Calmette-Guérin (BCG) vaccination were identified in 30% of the studied Latin American CGD cases. The genetic diagnoses of the 71 patients revealed 53 patients from 47 families with heterogeneous mutations in the CYBB gene (five novel mutations: p.W361G, p.C282X, p.W483R, p.R226X, and p.Q93X), 16 patients with the common deletion c.75_76 del.GT in exon 2 of NCF1 gene, and two patients with mutations in the CYBA gene. CONCLUSION: The majority of Latin American CGD patients carry a hemizygous mutation in the CYBB gene. They also presented a wide range of clinical manifestations most frequently bacterial and fungal infections of the respiratory tract, skin, and lymph nodes. Thirty percent of the Latin American CGD patients presented adverse reactions to BCG, indicating that this vaccine should be avoided in these patients.
Asunto(s)
Enfermedad Granulomatosa Crónica , Glicoproteínas de Membrana/genética , Mutación , NADPH Oxidasas/genética , Sistema de Registros , Absceso/epidemiología , Absceso/etiología , Absceso/genética , Adolescente , Edad de Inicio , Niño , Preescolar , Diarrea/epidemiología , Diarrea/etiología , Diarrea/genética , Femenino , Enfermedad Granulomatosa Crónica/complicaciones , Enfermedad Granulomatosa Crónica/epidemiología , Enfermedad Granulomatosa Crónica/genética , Hispánicos o Latinos , Humanos , Lactante , Recién Nacido , Enfermedades Linfáticas/epidemiología , Enfermedades Linfáticas/etiología , Enfermedades Linfáticas/genética , Masculino , NADPH Oxidasa 2 , Osteomielitis/epidemiología , Osteomielitis/etiología , Osteomielitis/genética , Otitis/epidemiología , Otitis/etiología , Otitis/genética , Neumonía/epidemiología , Neumonía/etiología , Neumonía/genética , Sepsis/epidemiología , Sepsis/etiología , Sepsis/genética , Enfermedades de la Piel/epidemiología , Enfermedades de la Piel/etiología , Enfermedades de la Piel/genética , Infecciones Urinarias/epidemiología , Infecciones Urinarias/etiología , Infecciones Urinarias/genéticaRESUMEN
Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.
Asunto(s)
Síndrome de Inmunodeficiencia con Hiper-IgM/epidemiología , Ligando de CD40/deficiencia , Ligando de CD40/genética , Preescolar , Comorbilidad , Citidina Desaminasa/deficiencia , Citidina Desaminasa/genética , Femenino , Hispánicos o Latinos , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/complicaciones , Síndrome de Inmunodeficiencia con Hiper-IgM/diagnóstico , Síndrome de Inmunodeficiencia con Hiper-IgM/terapia , Lactante , Recién Nacido , Infecciones/diagnóstico , Infecciones/etiología , Pulmón/patología , Masculino , Sistema de Registros , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity.