RESUMEN
Chronic wounds are a rare complication of X-linked agammaglobulinaemia (XLA). Fastidious organisms such as helicobacter bills have been reported in XLA with chronic wounds but sterile chronic wounds also occur. Hyperbaric Oxygen Therapy has been used in chronic wounds but has not previously been reported in primary antibody deficiencies. We present a case of a chronic wound in a patient with XLA refractory to antimicrobial therapy that made a remarkable recovery following Hyperbaric Oxygen Therapy.
Asunto(s)
Agammaglobulinemia/terapia , Epitelio/efectos de los fármacos , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Oxigenoterapia Hiperbárica , Traumatismos de la Pierna/terapia , Infección de Heridas/terapia , Adulto , Agammaglobulinemia/complicaciones , Agammaglobulinemia/inmunología , Antibacterianos/administración & dosificación , Enfermedad Crónica , Resistencia a Medicamentos , Epitelio/patología , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Lactante , Mediadores de Inflamación/metabolismo , Traumatismos de la Pierna/complicaciones , Traumatismos de la Pierna/inmunología , Recuperación de la Función , Recurrencia , Infección de Heridas/etiología , Infección de Heridas/inmunologíaRESUMEN
Bruton agammaglobulinemia tyrosine kinase (BTK) is a key protein in the B-cell receptor (BCR) signaling pathway and plays an essential role in the differentiation of B lymphocytes. X-linked agammaglobulinemia (XLA) is a primary humoral immunodeficiency caused by mutations in the gene encoding BTK. Previously, we identified two novel variations, L111P and E605G, in BTK; these are localized within the pleckstrin homology and Src homology 1 domains, respectively. In the present study, we evaluated the potential effects of these variations on the structural conformation and the function of BTK. Using in silico methods, we found that the L111P and E650G variations are not located directly in protein-protein interfaces but close to them. They distorted the native structural conformation of the BTK protein, affecting not only its geometry and stability but also its ability for protein recognition and in consequence its functionality. To confirm the results of the in silico assays, WT BTK, L111P, and E650G variants were expressed in the BTK-deficient DT40 cell line. The mutant proteins exhibited an absence of catalytic activity, aberrant redistribution after BCR-crosslinking, and deficient intracellular calcium mobilization. This work demonstrates that L111 and E605 residues are fundamental for the activation and function of BTK.
Asunto(s)
Mutación Missense , Proteínas Tirosina Quinasas/genética , Adolescente , Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia/enzimología , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Linfocitos B/enzimología , Linfocitos B/inmunología , Linfocitos B/patología , Secuencia de Bases , Diferenciación Celular , Línea Celular , ADN Complementario/genética , Estabilidad de Enzimas , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X/enzimología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Humanos , Masculino , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Conformación Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/deficiencia , Proteínas Tirosina Quinasas/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismoRESUMEN
Most polyreactive and antinuclear antibodies are removed from the human antibody repertoire during B cell development. To elucidate how B cell receptor (BCR) signaling may regulate human B cell tolerance, we tested the specificity of recombinant antibodies from single peripheral B cells isolated from patients suffering from X-linked agammaglobulinemia (XLA). These patients carry mutations in the Bruton's tyrosine kinase (BTK) gene that encode an essential BCR signaling component. We find that in the absence of Btk, peripheral B cells show a distinct antibody repertoire consistent with extensive secondary V(D)J recombination. Nevertheless, XLA B cells are enriched in autoreactive clones. Our results demonstrate that Btk is essential in regulating thresholds for human B cell tolerance.