RESUMO
Gene correction of induced pluripotent stem cells (iPSCs) has therapeutic potential for treating homozygous familial hypercholesterolemia (HoFH) associated with low-density lipoprotein (LDL) receptor (LDLR) dysfunction. However, few data exist regarding the functional recovery and immunogenicity of LDLR gene-corrected iPSC-derived hepatocyte-like cells (HLCs) obtained from an HoFH patient. Therefore, we generated iPSC-derived HLCs from an HoFH patient harbouring a point mutation (NM_000527.4:c.901 G > T) in exon 6 of LDLR, and examined their function and immunogenicity. From the patient's iPSCs, one homozygous gene-corrected HoFH-iPSC clone and two heterozygous clones were generated using the CRISPR/Cas9 method. Both types of iPSC-derived HLCs showed recovery of the function of LDL uptake in immunofluorescence staining analysis. Furthermore, these gene-corrected iPSC-derived HLCs showed little immunogenicity against the patient's peripheral blood mononuclear cells in a cell-mediated cytotoxicity assay. These results demonstrate that LDL uptake of iPSC-derived HLCs from HoFH can be restored by gene correction without the appearance of further immunogenicity, suggesting that gene-corrected iPSC-derived HLCs are applicable to the treatment of HoFH.
Assuntos
Terapia Biológica/métodos , Terapia Genética/métodos , Hepatócitos/citologia , Hiperlipoproteinemia Tipo II/imunologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Lipoproteínas LDL/metabolismo , Diferenciação Celular , Linhagem Celular , Células Cultivadas , LDL-Colesterol/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Citotoxicidade Imunológica , Hepatócitos/metabolismo , Homozigoto , Humanos , Hiperlipoproteinemia Tipo II/genética , Células-Tronco Pluripotentes Induzidas/transplante , Lipoproteínas LDL/genética , Mutação/genéticaRESUMO
Rheumatologic manifestations of hyperlipidemia and lipid-associated arthritis are rarely seen in the rheumatologist's office. On the other hand, a rheumatologist may be the clinician who identifies and initiates proper therapy for disorders related to hyperlipidemia when the musculoskeletal manifestations of these syndromes are recognized. In this article both the joint and tendon manifestations are reviewed, including the lesser known lipid liquid crystal form of arthritis. The relationship between gout and hyperuricemia is briefly discussed, as are the autoimmune manifestations of lipid-lowering therapy.
Assuntos
Artrite/complicações , Hiperlipoproteinemia Tipo III/complicações , Hiperlipoproteinemia Tipo II/complicações , Xantomatose/complicações , Artrite/imunologia , Artrite/metabolismo , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Gota/complicações , Gota/imunologia , Gota/metabolismo , Humanos , Hiperlipoproteinemia Tipo II/imunologia , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo III/imunologia , Hiperlipoproteinemia Tipo III/metabolismo , Hiperuricemia/complicações , Hiperuricemia/imunologia , Hiperuricemia/metabolismo , Metabolismo dos Lipídeos , Tendões , Xantomatose/imunologia , Xantomatose/metabolismoRESUMO
The levels of natural antibodies against catecholamines in 138 patients with cardiovascular diseases was studied and the comparative analysis of influence of antiatherosclerotic diets with different origin of PUFA omega-3 on dynamic of these parameters was made. For the first time discovered universal action of diets with PUFA omega-3 vegetable and animal origin on parameters of humoral immunity: in case of primary excess of norm of the contents of natural antibodies to adrenaline, noradrenaline and dopamine as a result of treatment these parameters were reduced or did not change; and at is primary a low their level--parameters increased in most cases. The greatest immunocorrection effect was rendered by diet, enriched PUFA omega-3 of freshwater fishes fat.
Assuntos
Autoanticorpos/sangue , Catecolaminas/imunologia , Ácidos Graxos Ômega-3/uso terapêutico , Hiperlipoproteinemia Tipo II/dietoterapia , Hipertensão/dietoterapia , Isquemia Miocárdica/dietoterapia , Arteriosclerose/prevenção & controle , Pressão Sanguínea/efeitos dos fármacos , Catecolaminas/sangue , Colesterol/sangue , Dopamina/sangue , Dopamina/imunologia , Epinefrina/sangue , Epinefrina/imunologia , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/imunologia , Hipertensão/sangue , Hipertensão/imunologia , Técnicas Imunoenzimáticas , Masculino , Isquemia Miocárdica/sangue , Isquemia Miocárdica/imunologia , Norepinefrina/sangue , Norepinefrina/imunologia , Triglicerídeos/sangueRESUMO
Effect of antiatherosclerotic diet of 112 patients with cardioishemic disease IIa, IIb, and IV types was observed. Positive dynamics of clinical picture of disease, values of lipid metabolism and T-cell cents immunity were shown, particularly for patients with hyperlipidemy, which developed as result of effect of medium cents and genetic cents factors. Including to antiatherosclerosis diet polyunsaturated fatty acids of family (w-3) intensified hypolipidemic effect.
Assuntos
Dieta Aterogênica , Ácidos Graxos Ômega-3/administração & dosagem , Hiperlipoproteinemia Tipo II/dietoterapia , Hipertensão/dietoterapia , Isquemia Miocárdica/dietoterapia , Adulto , Idoso , Feminino , Humanos , Hiperlipoproteinemia Tipo II/imunologia , Hiperlipoproteinemia Tipo II/metabolismo , Hipertensão/imunologia , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/metabolismo , Linfócitos T/imunologiaRESUMO
Human lymphocytes respond optimally to mitogenic stimulation when cultured in serum-free medium supplemented with transferrin if fatty acids necessary for maximal proliferation are provided. Either lipoproteins or exogenous fatty acids support optimal lymphocyte responses. The current studies examined the role of cell surface receptors for low density lipoprotein (LDL) in the enhancement of lymphocyte proliferation. Support of lymphocyte growth by limiting concentrations of LDL was found to involve interaction of the lipoprotein with LDL receptors. Thus, modification of LDL by reductive methylation so as to inhibit receptor-mediated interactions markedly decreased the capacity of LDL to enhance lymphocyte proliferation. Moreover, growth of lymphocytes obtained from patients with LDL receptor-negative homozygous familial hypercholesterolemia was minimal when cultures were supplemented with low concentrations of LDL (less than 10 micrograms cholesterol/ml). LDL also enhanced lymphocyte proliferation by a receptor-independent mechanism since high concentrations (greater than or equal to 50 micrograms cholesterol/ml) supported growth of both normal and familial hypercholesterolemia lymphocytes. In contrast, support of lymphocyte proliferation by high density lipoprotein (HDL) subclass 3 was completely independent of LDL receptors. Thus, HDL3 enhanced responses of both normal and familial hypercholesterolemia lymphocytes in an equivalent concentration-dependent manner; this effect was not altered by reductive methylation of HDL3. One function of lipoproteins in this system may be the provision of fatty acids since oleic and linoleic acids enhanced DNA synthesis by both normal and familial hypercholesterolemia lymphocytes in the absence of lipoproteins. These results indicate that lipoproteins may provide fatty acids necessary for optimal proliferation of human lymphocytes by both LDL receptor-mediated and LDL receptor-independent interactions.