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.
Amino Acid Sequence ; Animals ; Cytokines/chemistry/*secretion ; Humans ; Interferon-gamma/secretion ; Metabolism, Inborn Errors/metabolism ; Models, Biological ; Molecular Sequence Data

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.
Granulomatous Disease