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 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-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-gamma and IFN-alphabeta 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-alphabeta. 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-alphabeta 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.
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.
Ariane
A
Chapgier
Robert F
RF
Wynn
Emmanuelle
E
Jouanguy
Orchidée
O
Filipe-Santos
Shenying
S
Zhang
Jacqueline
J
Feinberg
Kay
K
Hawkins
Jean-Laurent
JL
Casanova
Peter D
PD
Arkwright
D001500:BCG Vaccine / Q000009:adverse effects; D001483:Base Sequence; D003241:Consanguinity; D016207:Cytokines / Q000096:biosynthesis; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D066298:In Vitro Techniques; D007223:Infant; D007370:Interferon Type I / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000494:pharmacology; D008297:Male; D009154:Mutation; D010375:Pedigree; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000235:genetics*; D014780:Viruses / Q000276:immunology / Q000472:pathogenicity
D001500:BCG Vaccine; D016207:Cytokines; D018076:DNA, Complementary; D007370:Interferon Type I; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma