Chronic Granulomatous Disease: An unreported mutation

@#Chronic Granulomatous Disease (CGD) is caused by defects in the phagocyte NADPH oxidase and occurs in approximately 1:200,000 births worldwide. It presents with early onset of severe recurrent bacterial and fungal infections. This is a case of a 9-year old male with severe, recurrent bacterial infections since 3 weeks of age. Initial Nitroblue tetrazolium (NBT) reduction tests were normal but a DNA analysis revealed a previously unreported homozygous mutation in CYBB, p.S418Y. Dihydrorhodamine (DHR) test showed poor neutrophil oxidation consistent with X-linked CGD. Definitive microbiologic diagnosis is essential for directing therapy for recurrent bacterial and fungal infections. Treatment of infections should be aggressive. Lifelong bacterial and fungal prophylaxis is necessary for prolonged survival. We report a case of confirmed CGD with the previously unreported mutation.

ISG15: leading a double life as a secreted molecule

ISG15 is a well-known intracellular ubiquitin-like molecule involved in ISGylation. However, a recent study has revived the notion first put forward two decades ago that ISG15 is also a secreted molecule. Human neutrophils, monocytes and lymphocytes can release ISG15, even though this protein has no detectable signal peptide sequence. ISG15 has also been found in the secretory granules of granulocytes. The mechanism underlying ISG15 secretion is unknown. Secreted ISG15 acts on at least T and natural killer (NK) lymphocytes, in which it induces interferon (IFN)-gamma production. However, the mechanism by which ISG15 stimulates these cells also remains unclear. ISG15 and IFN-gamma seem to define an innate circuit that operates preferentially, but not exclusively, between granulocytes and NK cells. Inherited ISG15 deficiency is associated with severe mycobacterial disease in both mice and humans. This infectious phenotype probably results from the lack of secreted ISG15, because patients and mice with other inborn errors of IFN-gamma immunity also display mycobacterial diseases. In addition to raising mechanistic issues, the studies described here pave the way for clinical studies of various aspects, ranging from the use of recombinant ISG15 in patients with infectious diseases to the use of ISG15-blocking agents in patients with inflammatory diseases.

Recurrent non-typhoidal salmonella bacteremia in a patient with interleukin -12p40 deficiency

The South eastern region of Iran is an endemic area for salmonellosis. Sometimes bacteremia due to nontyphoidal salmonella occurs but certain patients are at increased risk for recurrent bacteremia. The risk of invasive salmonellosis and recurrent bacteremia is increased in the patients with immunosuppression, especially impaired cell-mediated immunity, lymphoproliferative diseases and in patients with IL-12 deficiency. In recent years, a series of inherited disorders of IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by environmental mycobacteria and non-typhoidal salmonella. We report here the first such patient originating from and living in Iran. The patient was a 26-year-old man, suffering from IL-12p40 deficiency and presented with recurrent episodes of systemic salmonellosis. This report indicates that there are patients with inherited defects of the IL-12-IFN-gamma circuit in Iran. We recommended to consider this group of disorders in all patients with recurrent non-typhoidal salmonella bacteremia, wherever they are found