RESUMO
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Assuntos
Feminino , Pessoa de Meia-Idade , Humanos , Plexo Braquial , Bloqueio Nervoso/métodos , Analgésicos/uso terapêutico , Bloqueio Nervoso/efeitos adversos , Ombro , Período Pós-OperatórioRESUMO
HLA-G is expected to play an important role during fetal development. Recently, a healthy individual homozygous for the HLA-G*0105N allele has been described, suggesting that HLA-G expression was not essential for fetal survival. We now report studies of one family with five healthy siblings homozygous for HLA-G*0105N, who had been normally delivered; three of these siblings were females who also had normal deliveries. In addition, HLA-G*0105N cDNA has been fully sequenced, and normal G1 membrane anchored protein cannot be translated since after the codon 130 cytosine deletion (exon 3) a reading frameshift is observed leading to the existence of premature stop codon at position 189 (beginning of exon 4). Other protein isoforms (G2, G3 and G6), all containing the leader peptide and the alpha1 domain, are possible and their messenger mRNAs were found; any of these may undertake the necessary HLA-G functions. Our data show that the membrane anchored HLA-G molecule is not necessary in either mother or fetus for a normal pregnancy and survival. Also, individuals homozygous for HLA-G*0105N are healthy and with no indications of immunodeficiency or autoimmunity.
Assuntos
Antígenos HLA/genética , Antígenos HLA/imunologia , Antígenos HLA/fisiologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/fisiologia , Homozigoto , Alelos , Processamento Alternativo , Sequência de Bases , DNA Complementar , Saúde da Família , Feminino , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígeno HLA-B13 , Antígenos HLA-C/imunologia , Antígenos HLA-G , Haplótipos , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo de Fragmento de Restrição , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , RNA Mensageiro/genética , Alinhamento de Sequência , Deleção de Sequência , Antígenos HLA-ERESUMO
Leucocyte adhesion deficiency (LAD) is an autosomal-recessive genetic disease that is characterized clinically by severe bacterial infections and caused by mutations in the CD18 gene that codes for the beta2 integrin subunit. A patient with a severe LAD phenotype was studied and the molecular basis of the disease was identified as a single homozygous defect in a Herpes virus saimiri (HVS)-transformed T-cell line. The defect identified involves a deletion of 171 bp in the cDNA that encodes part of the proteic extracellular domain. This genetic abnormality was further studied at the genomic DNA level and found to consist of a deletion of 169 bp (from -37 of intron 4 to +132 of exon 5), which abolishes the normal splicing and results in the total skipping of exon 5. The 171-bp shortened 'in-frame' mRNA not only resulted in the absence of CD18 expression on the cell surface but also in its absence in the cytoplasm of HVS T-cell lines. Functionally, the LAD-derived HVS T-cell lines showed a severe, selective T-cell activation impairment in the CD2 (but not in the CD3) pathway. This defect was not reversible when exogenous interleukin-2 (IL-2) was added, suggesting that there is also a functional interaction of the lymphocyte function-associated antigen-1 (LFA-1) protein in the CD2 signal transduction pathway in human T cells, as has been previously reported in mice and in the human Papillon-Lefèvre syndrome. Thus, HVS transformation is not only a suitable model for T-cell immunodeficiency studies and characterization, but is also a good system for investigating the immune system in pathological conditions. It may also be used in the future in cellular models for in vitro gene-therapy trials.
