RESUMEN
BACKGROUND: Propionate inborn errors of metabolism (PIEM), including propionic (PA) and methylmalonic (MMA) acidemias, are inherited metabolic diseases characterized by toxic accumulation of propionic, 3-hydroxypropionic, methylcitric, and methylmalonic organic acids in biological fluids, causing recurrent acute metabolic acidosis events and encephalopathy, which can lead to fatal outcomes if managed inadequately. PIEM patients can develop hematological abnormalities and immunodeficiency, either as part of the initial clinical presentation or as chronic complications. The origin and characteristics of these abnormalities have been studied poorly. Thus, the aim of the present work was to evaluate and describe lymphoid, myeloid, and erythroid cell population profiles in a group of clinically stable PIEM patients. METHODS: This was a retrospective study of 11 nonrelated Mexican PIEM patients. Clinical, biochemical, nutritional, hematological, and lymphocyte subsets were analyzed. RESULTS: Despite being considered clinically stable, 91% of patients had hematological or immunological abnormalities. The absolute lymphocyte subset counts were low in all patients but one, with CD4+ T-cell lymphopenia, being the most common one. Furthermore, of the 11 studied subjects, nine presented with a low CD4/CD8 ratio. Among the observed hematological alterations, bicytopenia was the most common (82%) one, followed by anemia (27%). CONCLUSION: Our results contribute to the landscape of immunological abnormalities observed previously in PIEM patients; these abnormalities can become a life-threatening chronic complications because of the increased risk of opportunistic diseases. These findings allow us to propose the inclusion of monitoring immune biomarkers, such as subsets of lymphocytes in the follow up of PIEM patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/sangre , Linfocitos B/patología , Subgrupos Linfocitarios/patología , Linfocitos T/patología , Errores Innatos del Metabolismo de los Aminoácidos/inmunología , Antígenos de Diferenciación/metabolismo , Linfocitos B/metabolismo , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Lactante , Subgrupos Linfocitarios/metabolismo , Masculino , Acidemia Propiónica/sangre , Acidemia Propiónica/inmunología , Estudios Retrospectivos , Linfocitos T/metabolismoRESUMEN
Hypermethioninemia is a disorder characterized by high plasma levels of methionine (Met) and its metabolites such as methionine sulfoxide (MetO). Studies have reported associated inflammatory complications, but the mechanisms involved in the pathophysiology of hypermethioninemia are still uncertain. The present study aims to evaluate the effect of chronic administration of Met and/or MetO on phenotypic characteristics of macrophages, in addition to oxidative stress, purinergic system, and inflammatory mediators in macrophages. In this study, Swiss male mice were subcutaneously injected with Met and MetO at concentrations of 0.35-1.2 g/kg body weight and 0.09-0.3 g/kg body weight, respectively, from the 10th-38th day post-birth, while the control group was treated with saline solution. The results revealed that Met and/or MetO induce an M1/classical activation phenotype associated with increased levels of tumor necrosis factor alpha and nitrite, and reduced arginase activity. It was also found that Met and/or MetO alter the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, as well as the levels of thiol and reactive oxygen species in macrophages. The chronic administration of Met and/or MetO also promotes alteration in the hydrolysis of ATP and ADP, as indicated by the increased activity of ectonucleotidases. These results demonstrate that chronic administration of Met and/or MetO promotes activated pro-inflammatory profile by inducing M1/classical macrophage polarization. Thus, the changes in redox status and purinergic system upon chronic Met and/or MetO exposure may contribute towards better understanding of the alterations consistent with hypermethioninemic patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/inmunología , Glicina N-Metiltransferasa/deficiencia , Macrófagos/inmunología , Metionina/análogos & derivados , Animales , Catalasa/metabolismo , Polaridad Celular , Glutatión Peroxidasa/metabolismo , Glicina N-Metiltransferasa/inmunología , Macrófagos/efectos de los fármacos , Masculino , Metionina/administración & dosificación , Metionina/metabolismo , Metionina/farmacología , Ratones , Oxidación-Reducción , Estrés Oxidativo , Fenotipo , Superóxido Dismutasa/metabolismoRESUMEN
The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 µmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) levels in the blood, as well as levels of IL-1ß, TNF-α, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1ß and TNF-α levels. Concomitantly, MMA increased levels of IL-1ß, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/inmunología , Errores Innatos del Metabolismo de los Aminoácidos/psicología , Corteza Cerebral/metabolismo , Mediadores de Inflamación/metabolismo , Trastornos de la Memoria/inducido químicamente , Ácido Metilmalónico/toxicidad , Conducta Espacial/efectos de los fármacos , Errores Innatos del Metabolismo de los Aminoácidos/inducido químicamente , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Corteza Cerebral/inmunología , Regulación de la Expresión Génica , Humanos , Interleucina-1beta/metabolismo , Ácido Metilmalónico/administración & dosificación , Neuroinmunomodulación , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
We describe 4 cases of lysinuric protein intolerance, which all fulfilled the diagnostic criteria for hemophagocytic lymphohistiocytosis. Mature histiocytes and neutrophil precursors participated in hemophagocytosis in the bone marrow. Moreover, serum levels of ferritin and lactate dehydrogenase were elevated, hypercytokinemia was present, and soluble interleukin-2 receptor levels were increased up to 18.6-fold. The diagnosis of lysinuric protein intolerance should therefore be considered in any patient presenting with hemophagocytic lymphohistiocytosis.