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Human Complete Stat-1 Deficiency Is Associated with Defective Type I and II IFN Responses In Vitro but Immunity to Some Low Virulence Viruses In Vivo¹

Ariane Chapgier^*, Robert F. Wynn, Emmanuelle Jouanguy^*, Orchidée Filipe-Santos^*, Shenying Zhang^*, Jacqueline Feinberg^*, Kay Hawkins, Jean-Laurent Casanova^* and Peter D. Arkwright^2,

^* Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche R550, Faculté de Médecine Necker-Enfants Malades, Paris, France; Royal Manchester Children’s Hospital, Manchester, United Kingdom; and University of Manchester, Booth Hall Children’s Hospital, Manchester, United Kingdom

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-Guérin (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- and IFN- 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- and the in vitro responses of a SV40-transformed fibroblastic cell line to IFN- and IFN-. There was no response to IFN- in terms of IL-12 production and HLA class II induction, accounting for vulnerability to BCG. Moreover, IFN- 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.

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The JI 2006 176: 4507-4508. [Full Text]  

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