Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.

Increased blood levels of type I interferon (IFN-I) and expression of a broad signature of gene transcripts that reflect induction by IFN-I are observed in many patients with systemic autoimmune diseases, and that pattern is most striking in systemic lupus erythematosus (SLE). Persistent production of IFN-α, the most abundant subtype measured in these patients, is an important feature of the immunopathogenesis of lupus and has stimulated current efforts to develop and test therapeutics that either block IFNI or its receptor directly or target components of the IFN-I pathway involved in induction of or response to IFN-I. This review will describe data from animal models of chronic viral infection, examples of lupus-like syndromes associated with single-gene mutations that impact the IFN-I pathway, and longitudinal studies from lupus patients to support the rationale for therapeutic targeting of the IFN-I pathway in SLE. However, the complexity of IFN-I regulation and the diversity of its effects on immune system function suggest that the definitive demonstration of that pathway as a valid and productive therapeutic target will only come from clinical trials of agents tested in patients with systemic autoimmune disease, with lupus patients likely to be the most informative.

The inhibitory receptor Fc␥RIIb is a negative regulator of antibody production and inflammatory responses. The ؊343 G 3 C polymorphism in the human FCGR2B promoter is associated with systemic lupus erythematosus. The ؊343 C mutant promoter has decreased transcriptional activity. In the present study, we show that the transcriptional change correlates with quantitative differences in the interaction of the activating protein 1 complex with the mutant FCGR2B promoter. Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter. Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities. The ؊343 G 3 C substitution enabled the specific interaction of the transcription factor YinYang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with activating protein 1 for binding at the ؊343 site, and contributed to the repression of the mutant FCGR2B promoter activity. This mechanism could be responsible for the decreased expression of Fc␥RIIb associated with the ؊343 C/C homozygous FCGR2B genotype in lupus patients. These findings provide a rationale for the transcriptional defect mediated by the ؊343 C/C FCGR2B promoter polymorphism associated with systemic lupus erythematosus, and add to our understanding of the complex transcriptional regulation of the human FCGR2B promoter.Fc ␥-receptors (Fc␥R) 2 bind IgG-containing immune complexes and mediate important immune functions such as phagocytosis, degranulation, antibody-dependent cellular cytotoxicity, and production of inflammatory mediators. Human hematopoetic cells express several Fc␥R isoforms encoded by seven separate genes. Unlike activating Fc␥R, Fc␥RIIb is unique in that it contains an immunoreceptor tyrosine-based inhibitory motif in the intracellular domain. A specific amino acid sequence in the immunoreceptor tyrosine-based inhibitory motif domain of Fc␥RIIb allows the recruitment of phosphatases and the initiation of inhibitory signaling. Cross-linking of Fc␥RIIb with activating receptors on B cells and mononuclear phagocytes leads to down-regulation of antibody production, phagocytosis, and cytokine secretion. Several lines of evidence demonstrate that Fc␥RIIb is important in the maintenance of self-tolerance. Fc␥RIIb deficiency is associated with spontaneous development of autoimmune manifestations in several mouse genetic backgrounds (1). Autoimmune prone mouse strains share an Fcgr2 promoter haplotype containing deletions and polymorphisms associated with reduced expression of Fc␥RIIb on the surface of activated B cells and macrophages (2-4). Whereas the engineered deletion and the natural deficiency in Fc␥RIIb confer susceptibility to development of lupus-like disease, transplantation of bone marrow cells transduced with Fc␥RIIb-expressing retrovirus restored the healthy phenotype (5). This body of data created the impetus for the study of Fc␥RIIb...

Multiple lines of evidence have revealed a key role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) as negative modulators of innate and adaptive immune responses. Acquired and genetic factors regulate the expression of FcgammaRIIb receptors and modify their inhibitory potential. Recent advances have highlighted the importance of FcgammaRIIb receptors in influencing the development of cancer and autoimmunity. The association of increased FcgammaRIIb expression with tumor development is believed to operate at effector cell level resulting in inhibition of antitumor cytotoxicity. In autoimmune diseases, FcgammaRIIb receptors play a major role in controlling the amplitude of antibody- and immune complex-mediated reactions. Generally, FcgammaRIIb deficiency is associated with increased susceptibility and severity to organ-specific and systemic autoimmunity. This article discusses the proposed mechanisms for FcgammaRIIb deregulation associated with malignant and autoimmune pathology in animal models and human diseases.