Impaired phagocytosis in macrophages from patients affected by lysinuric protein intolerance

Barilli, Amelia; Rotoli, Bianca Maria; Visigalli, Rossana; Bussolati, Ovidio; Gazzola, Gian C.; Gatti, Rita; Dionisi‐Vici, Carlo; Martinelli, Diego; Goffredo, Bianca Maria; Font-Llitjós, Mariona; Mariani, Francesca; Luisetti, Maurizio; DallˈAsta, Valeria

doi:10.1016/j.ymgme.2012.01.008

Cited by 37 publications

(38 citation statements)

References 25 publications

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“…In the first group, which includes OTC and ASS deficiency and HHH syndrome, the significant reduction of plasma Cr concentration appears to be the consequence of low cellular arginine availability (Brusilow and Horwich 2001). On the other hand, high plasma Cr levels in ASL deficiency and LPI parallels the increased intracellular arginine concentrations (Smith et al 1987;Mannucci et al 2005;Gladwin and Tejero 2011;Barilli et al 2012). In subjects with OTC deficiency and HHH syndrome, the significant correlations between GAA and arginine are consistent with this hypothesis, since it is well known that renal GAA synthesis is highly dependent on arginine levels (Brosnan and Brosnan 2010).…”

Section: Discussionmentioning

confidence: 55%

Creatine metabolism in urea cycle defects

Boenzi

Pastore

Martinelli

et al. 2012

J of Inher Metab Disea

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Creatine (Cr) and phosphocreatine play an essential role in energy storage and transmission. Maintenance of creatine pool is provided by the diet and by de novo synthesis, which utilizes arginine, glycine and s-adenosylmethionine as substrates. Three primary Cr deficiencies exists: arginine:glycine amidinotransferase deficiency, guanidinoacetate methyltransferase deficiency and the defect of Cr transporter SLC6A8. Secondary Cr deficiency is characteristic of ornithine-aminotransferase deficiency, whereas non-uniform Cr abnormalities have anecdotally been reported in patients with urea cycle defects (UCDs), a disease category related to arginine metabolism in which Cr must be acquired by de novo synthesis because of low dietary intake. To evaluate the relationships between ureagenesis and Cr synthesis, we systematically measured plasma Cr in a large series of UCD patients (i.e., OTC, ASS, ASL deficiencies, HHH syndrome and lysinuric protein intolerance). Plasma Cr concentrations in UCDs followed two different trends: patients with OTC and ASS deficiencies and HHH syndrome presented a significant Cr decrease, whereas in ASL deficiency and lysinuric protein intolerance Cr levels were significantly increased (23.5 vs. 82.6 μmol/L; p < 0.0001). This trend distribution appears to be regulated upon cellular arginine availability, highlighting its crucial role for both ureagenesis and Cr synthesis. Although decreased Cr contributes to the neurological symptoms in primary Cr deficiencies, still remains to be explored if an altered Cr metabolism may participate to CNS dysfunction also in patients with UCDs. Since arginine in most UCDs becomes a semi-essential aminoacid, measuring plasma Cr concentrations might be of help to optimize the dose of arginine substitution.

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Section: Discussionmentioning

confidence: 55%

Creatine metabolism in urea cycle defects

Boenzi

Pastore

Martinelli

et al. 2012

J of Inher Metab Disea

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“…We hypothesized that, in contrast to the earlier suggestions by other groups (Sebastio et al 2011;Ogier de Baulny et al 2012), arginine reservoirs and the subsequent NO levels may actually be diminished in LPI macrophages as a result of reduced arginine influx by the defective y + LAT1 transporter, known to be the most important transporter of arginine in macrophages, including those of alveolar origin (Barilli et al 2011;Rotoli et al 2007). In addition, the defective CAA transport also results in impaired phagocytic activity of LPI macrophages (Barilli et al 2012). This may, in turn, lead to an impaired clearance of phospholipoproteinaceous material from the alveoli.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact pathogenesis of PAP in LPI has been unclear, disturbances in the function and phagocytic activity of monocyte-derived macrophages have been demonstrated (Barilli et al 2010(Barilli et al , 2012Kurko et al 2015). Thus, accumulation of proteinous material into the lungs may be caused by insufficient clearance of proteins by poorly functioning alveolar macrophages.…”

Section: Introductionmentioning

confidence: 99%

Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance

et al. 2016

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Pulmonary alveolar proteinosis (PAP) is a potentially fatal complication of lysinuric protein intolerance (LPI), an inherited disorder of cationic amino acid transport. The patients often present with mild respiratory symptoms, which may rapidly progress to acute respiratory failure responding poorly to conventional treatment with steroids and bronchoalveolar lavations (BALs). The pathogenesis of PAP in LPI is still largely unclear. In previous studies, we have shown disturbances in the function and activity of alveolar macrophages of these patients, suggesting that increasing the activity and the number of macrophages by recombinant human GM-CSF (rhuGM-CSF) might be beneficial in this patient group.Two LPI patients with complicated PAP were treated with experimental inhaled rhuGM-CSF (sargramostim) after poor response to maximal conventional therapy.

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“…It has been suggested that this may have a role in the crosstalk between T lymphocytes and macrophage leading to a defect in lymphocyte cytotoxic activity that prevents the efficient removal of antigens and results in abnormal immune activation of CTLs and macrophages explaining HLH in LPI. 18,19 There have been rare case reports of HLH secondary to other inborn errors of metabolism. HLH was described in Wolman disease, a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia.…”

Section: Differential Diagnosis and Further Investigationsmentioning

confidence: 99%

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Ouederni

KHALED

Rekaya

et al. 2017

Mediterr J Hematol Infect Dis

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Abstract. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammationcaused by uncontrolled proliferation of activated lymphocytes and histiocytes. Often, HLH is an acquired syndrome. We report a case of a nine month-old-boy presented with hepatosplenomegaly, severe anemia, thrombocytopenia, hypertriglyceridemia and high hyperferritinemia. These clinical features of HLH prompted a wide range of infectious and autoimmune tests to be performed. After an extensive diagnostic workup, he was referred to the immune-hematologic unit for HLH suspicion with an unknown cause. Primary HLH due to familial lymphohistiocytosis (FLH) was first evoked in front of consanguinity, probable HLH in the family, early onset, and in the absence of a causative pathology like infection or cancer. However, functional tests were normal. Atypical features like the: absence of fever, hypotonia, recurrent diarrhea since diversification, hematuria, and proteinuria suggested an inborn metabolism error with gastrointestinal involvement. Specific tests were performed to reach a final diagnosis.

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Impaired phagocytosis in macrophages from patients affected by lysinuric protein intolerance

Cited by 37 publications

References 25 publications

Creatine metabolism in urea cycle defects

Creatine metabolism in urea cycle defects

Inhaled Sargramostim Induces Resolution of Pulmonary Alveolar Proteinosis in Lysinuric Protein Intolerance

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