Human complete Stat-1 deficiency is associated with defective type I and IIIFN responses in vitro but immunity to some low virulence viruses in vivo

The autosomal recessive form of human complete Stat-1 deficiency is a rare disorder, thus far reported in two unrelated patients, both of whom developed disseminated bacillus Calmette-Guerin (BCG) and subsequently died of viral illnesses before detailed studies of the condition could be performed. It is associated with impaired cellular responses to both IFN-gamma and IFN-alpha beta via Stat-1-containing complexes. We describe a third patient with complete Stat-1 deficiency and disseminated BCG infection, who died 3 mo after bone marrow transplantation. The patient's EBV-transformed B cells did not express Stat-1 protein and did not activate Stat-1-containing transcription factors. We also report the ex vivo responses of a Stat-1-deficient patient's fresh blood cells to IFN-gamma and the in vitro responses of a SV40-transformed fibroblastic cell line to IFN-gamma and IFN-alpha beta. There was no response to IFN-gamma in terms of IL-12 production and HLA class II induction, accounting for vulnerability to BCG. Moreover, IFN-alpha beta did not suppress HSV and vesicular stomatitis virus replication in fibroblasts, although in vivo the patient was able to successfully clear at least some viruses. This study broadens our understanding of complete Stat-1 deficiency, a severe form of innate immunodeficiency. Stat-1 deficiency should be suspected in children with severe infections, notably but not exclusively patients with mycobacterial or viral diseases.