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 arg...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2018 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/463008 |
| Acceso en línea: | http://hdl.handle.net/10803/463008 |
| Access Level: | acceso abierto |
| Palabra clave: | Malalties rares Enfermedades raras Rare diseases Aminoàcids Aminoácidos Amino acids Immunitat Inmunidad Immunity Metabolisme mineral Metabolismo mineral Mineral metabolism Ferro Hierro Iron Ciències de la Salut 577 |
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España |
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Pathophysiology of immune-related complications in Lysinuric Protein Intolerance |
| title |
Pathophysiology of immune-related complications in Lysinuric Protein Intolerance |
| spellingShingle |
Pathophysiology of immune-related complications in Lysinuric Protein Intolerance Sotillo Rodríguez, Fernando Malalties rares Enfermedades raras Rare diseases Aminoàcids Aminoácidos Amino acids Immunitat Inmunidad Immunity Metabolisme mineral Metabolismo mineral Mineral metabolism Ferro Hierro Iron Ciències de la Salut 577 |
| title_short |
Pathophysiology of immune-related complications in Lysinuric Protein Intolerance |
| title_full |
Pathophysiology of immune-related complications in Lysinuric Protein Intolerance |
| title_fullStr |
Pathophysiology of immune-related complications in Lysinuric Protein Intolerance |
| title_full_unstemmed |
Pathophysiology of immune-related complications in Lysinuric Protein Intolerance |
| title_sort |
Pathophysiology of immune-related complications in Lysinuric Protein Intolerance |
| dc.creator.none.fl_str_mv |
Sotillo Rodríguez, Fernando |
| author |
Sotillo Rodríguez, Fernando |
| author_facet |
Sotillo Rodríguez, Fernando |
| author_role |
author |
| dc.contributor.none.fl_str_mv |
Palacín Prieto, Manuel Bodoy i Salvans, Susanna Palacín Prieto, Manuel Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació |
| dc.subject.none.fl_str_mv |
Malalties rares Enfermedades raras Rare diseases Aminoàcids Aminoácidos Amino acids Immunitat Inmunidad Immunity Metabolisme mineral Metabolismo mineral Mineral metabolism Ferro Hierro Iron Ciències de la Salut 577 |
| topic |
Malalties rares Enfermedades raras Rare diseases Aminoàcids Aminoácidos Amino acids Immunitat Inmunidad Immunity Metabolisme mineral Metabolismo mineral Mineral metabolism Ferro Hierro Iron Ciències de la Salut 577 |
| description |
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. |
| publishDate |
2018 |
| dc.date.none.fl_str_mv |
2018 2018 2019 |
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info:eu-repo/semantics/doctoralThesis info:eu-repo/semantics/publishedVersion |
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doctoralThesis |
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publishedVersion |
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http://hdl.handle.net/10803/463008 |
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http://hdl.handle.net/10803/463008 |
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Inglés |
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Inglés |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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163 p. application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Universitat de Barcelona |
| publisher.none.fl_str_mv |
Universitat de Barcelona |
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TDX (Tesis Doctorals en Xarxa) reponame:TDR. Tesis Doctorales en Red instname:CBUC, CESCA |
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CBUC, CESCA |
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TDR. Tesis Doctorales en Red |
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TDR. Tesis Doctorales en Red |
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1869411903512510464 |
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Pathophysiology of immune-related complications in Lysinuric Protein IntoleranceSotillo Rodríguez, FernandoMalalties raresEnfermedades rarasRare diseasesAminoàcidsAminoácidosAmino acidsImmunitatInmunidadImmunityMetabolisme mineralMetabolismo mineralMineral metabolismFerroHierroIronCiències de la Salut577Lysinuric 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.La Lisinúria amb intolerància a proteïnes (LPI, MIM #222700) és una malaltia rara causada per mutacions al gen SLC7A7. Els símptomes que caracteritzen la LPI són malabsorció intestinal i reabsorció deficient d'aminoàcids catiònics, que generen un defecte al funcionament del cicle de la urea. Els pacients de LPI, a més, desenvolupen una sèrie de complicacions immunològiques i hematològiques tals com la proteïnosis alveolar pulmonar, anèmia o hemofagocitosis amb limfohistiocitosis. El(s) mecanisme(s) moleculars que desencadenen aquestes complicacions, alguna d'elles letals, és totalment desconegut. A la literatura es descriu l’arginina com un factor regulador de la resposta immune. Per això, la nostra hipòtesi de treball va ser que la deficiència metabòlica afecta al cicle de la urea, però també pot contribuir en les complicacions immunològiques de la LPI. Degut a què l’ablació total del gen Slc7a7 a ratolí causa la mort de l’animal pocs dies després del part, el nostre grup ha generat el primer model de ratolí induïble per tamoxifè per eliminar Slc7a7 i estudiar la LPI humana (Slc7a7-/-). Aquests animals desenvolupen els símptomes metabòlics característics de la LPI humana: malabsorció intestinal i reabsorció renal deficient d'amino àcids catiònics, i conseqüentment problemes derivats al cicle de la urea. A més a més, manifesten diferents símptomes característics de les complicacions immuno i hematològiques descrites a la LPI humana, com són l’anèmia, la proteïnosis alveolar pulmonar, la hiperferritinemia i un augment de l'eritrofagocitosi. Així mateix, s'han descrit dos nous símptomes de la LPI: una acumulació excessiva de ferro als macròfags de diferents teixits i un defecte a la eritropoesis. També es va comprovar com l’addició de citrul·lina a la dieta dels ratolins va millorar tant els símptomes metabòlics com les complicacions de caràcter immune, i que només amb la pèrdua de Slc7a7 a cèl·lules mieloides no és suficient per desenvolupar les complicacions immunològiques. Així, per primera vegada, s’estableix una relació directa entre la deficiència metabòlica i les complicacions immunes a la LPI.Universitat de BarcelonaPalacín Prieto, ManuelBodoy i Salvans, SusannaPalacín Prieto, ManuelUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació201820192018info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion163 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/463008TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-nd/4.0/http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/4630082026-06-14T12:46:07Z |
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15,300719 |