Pathophysiology of immune-related complications in lysinuric protein intolerance

• Autores: Fernando Sotillo Rodriguez
• Directores de la Tesis: Manuel Palacín Prieto (dir. tes.), Susanna Bodoy Salvans (codir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2018
• Idioma: español
• Tribunal Calificador de la Tesis: Annabel Fernández Valledor (presid.), M. Carmen Sanchez Fernández de Sentle (secret.), Meritxell Espino Guarch (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad de Barcelona
• Materias:
  • Ciencias de la vida
    • Biología animal (zoología)
      • Patología animal
    • Fisiología humana
      • Metabolismo humano
  • Ciencias médicas
    • Medicina interna
      • Hematología
    • Patología
      • Inmunopatología
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • Pathophysiology of immune-related complications in Lysinuric Protein Intolerance Lysinuric Protein Intolerance (LPI, MIM #222700) is a rare autosomic disease caused by mutations in SLC7A7 gene. Hallmarks of LPI are malabsorption and deficient renal reabsorption of cationic amino acids, which drives a deficit in the functioning of the urea cycle due to the reduction levels of arginine and ornithine in plasma. Nevertheless LPI patients also develop immune and hematologic complications such as anemia, pulmonary alveolar proteinosis or hemophagocytic lymphohistiocytosis. However the molecular mechanism(s) and/or the initiation events that trigger the development of LPI immune and hematologic complications still remain unknown.

    Arginine has been demonstrated to be crucial for a correct immunity, and specifically, for a proper macrophage functioning. Then, we hypothesize that primary metabolic condition may be also contributing to the development of LPI immune and hematologic complications. Due to ablation of Slc7a7 is perinatally lethal in mouse; our group has generated the first tamoxifen-inducible KO mouse model (Slc7a7-/-) for the study of human LPI. Slc7a7-/- mouse model fulfilled human LPI metabolic disease: impaired renal reabsorption and intestinal malabsorption of cationic amino acids with consequent deficient functioning of the urea cycle. Urea cycle defect presented with increased levels of ammonia and glutamine in plasma and increased concentration of orotic acid in urine.

    In addition, Slc7a7-/- mice developed some of the immune-related complications reported in LPI patients: anemia, hyperferritinemia, pulmonary alveolar proteinosis and increased erythrophagocytosis. Furthermore we have characterized two novel traits in LPI; aberrant iron accumulation in macrophages, and defective erythropoiesis, which may be a plausible explanation for some of the LPI complications such as anemia, hyperferritinemia and increased erythrophagocytosis.

    Citrulline supplementation is commonly used to mitigate the defect in the urea cycle of LPI patients, and we corroborated that citrulline supplementation in the water drink improved the metabolic condition also in Slc7a7-/- animals. However, we also observed that by treating the metabolic disease, the immune and hematologic symptoms in Slc7a7-/- mice were improved as well. Moreover, Slc7a7-/- myeloid-specific ablated animals did not show any of the symptoms found in Slc7a7-/- mice, confirming the necessity of the metabolic condition for the development of the LPI immune-related complications. Thus, for the first time, we are describing a direct relationship between the primary metabolic dysfunction and the immune and hematologic complications in LPI.