Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes

https://doi.org/10.1016/j.coi.2012.04.011Get rights and content

The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.

Highlights

▶ Autosomal recessive complete loss-of-function STAT1 deficiency predisposes to mycobacterial and viral diseases. ▶ Autosomal recessive partial loss-of-function STAT1 deficiency predisposes to mild mycobacterial and viral diseases. ▶ Autosomal dominant loss-of-function STAT1 deficiency predisposes to mycobacterial disease. ▶ Autosomal dominant gain-of-function STAT1 disorder predisposes to chronic mucocutaneous disease.

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