title: Interferon alpha as a primary pathogenic factor in human lupus.
abstract: Interferon alpha (IFN-α) is a critical mediator of human systemic lupus erythematosus (SLE). This review will summarize evidence supporting the role for IFN-α in the initiation of human SLE. IFN-α functions in viral immunity at the interface of innate and adaptive immunity, a position well suited to setting thresholds for autoimmunity. Some individuals treated with IFN-α for chronic viral infections develop de novo SLE, which frequently resolves when IFN-α is withdrawn, supporting the idea that IFN-α was causal. Abnormally high IFN-α levels are clustered within SLE families, suggesting that high serum IFN-α is a heritable risk factor for SLE. Additionally, SLE-risk genetic variants in the IFN-α pathway are gain of function in nature, resulting in either higher circulating IFN-α levels or greater sensitivity to IFN-α signaling in SLE patients. A recent genome-wide association study has identified additional novel genetic loci associated with high serum IFN-α in SLE patients. These data support the idea that genetically determined endogenous elevations in IFN-α predispose to human SLE. It is possible that some of these gain-of-function polymorphisms in the IFN-α pathway are useful in viral defense, and that risk of SLE is a burden we have taken on in the fight to defend ourselves against viral infection.
authors.affiliation: Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois 60637, USA. tniewold@medicine.bsd.uchicago.edu
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Niewold
mesh_terms: D020022:Genetic Predisposition to Disease; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000097:blood / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000276:immunology*; D018448:Models, Immunological; D011110:Polymorphism, Genetic; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology
chemical_list: D050835:Interferon Regulatory Factors; D016898:Interferon-alpha; D011971:Receptors, Immunologic