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J Allergy Clin Immunol ; 142(4): 1285-1296, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29477724


BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

J Clin Pathol ; 71(1): 12-19, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28663326


AIMS: Autoantibodies targeting Ro52 and Ro60 antigens are historically reported as anti SSA/Ro. In general anti SSA/Ro results are either anti Ro52+Ro60+ or anti Ro52-Ro60+ antibodies. Anti Ro52 without anti Ro60 (Ro52+ Ro60-) antibodies are often not reported routinely. This study intends to review the potential significance of these autoantibodies in the management of connective tissue diseases. METHOD: A retrospective survey of Ro52+Ro60- was carried out as part of the service evaluation of extractable nuclear antigen antibodies (ENA) reporting from the immunology laboratory, the NHS Greater Glasgow and Clyde (GGC), UK. The clinical documents and laboratory results of 97 patients with Ro52+Ro60- and 100 patients with Ro52+Ro60+ were reviewed. RESULTS: Seventy-one patients (73%) with anti Ro52+Ro60- antibodies have been diagnosed with autoimmune conditions including undifferentiated connective tissue diseases (n=14, 14%), systemic lupus erythematosus (n=10, 10%), Sjögren's syndrome (n=10, 10%) and rheumatoid arthritis (n=13, 13%). Twenty-three patients (24%) with anti Ro52+Ro60- antibodies have no autoimmune features but were found to have significant clinical conditions including malignancies. In contrast, 87 patients (87%) with anti Ro52+Ro60+ antibodies have autoimmune conditions including Sjögren's syndrome (n=34, 34%), systemic lupus erythematosus (SLE; n=23, 23%), undifferentiated connective tissue diseases (n=12, 12%) and rheumatoid arthritis (n=6, 6%). CONCLUSION: Anti Ro52 without anti Ro60 (Ro52+Ro60-) antibodies should be reported. In the majority of patients these autoantibodies were associated with various autoimmune diseases. Anti Ro52+Ro60- antibodies were also found in patients with significant clinical conditions including malignancies even though there was no suggestion of autoimmunity at the time of testing.

Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Ribonucleoproteínas/imunologia , Síndrome de Sjogren/imunologia , Doenças do Tecido Conjuntivo Indiferenciado/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
Biol Neonate ; 81(2): 105-8, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11844879


Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) in 46 samples from 46 infants undergoing intensive care were studied. Residual serum remaining after routine electrolyte analysis was utilised. sICAM-1 levels were determined by ELISA. Blind retrospective chart review was employed to determine whether infants were infected. Serum levels were significantly elevated in infants with proven and probable infection, compared with non-infected infants (p < 0.001). sICAM-1 levels in serum were comparable to levels previously established in plasma samples. The results suggest that serum sICAM-1 measurement is a simple and robust test that differentiates infected from non-infected infants and that a low level of serum sICAM-1 may particularly assist in the exclusion of infection.

Infecções Bacterianas/sangue , Recém-Nascido Prematuro/sangue , Molécula 1 de Adesão Intercelular/sangue , Infecções Bacterianas/diagnóstico , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos