Patients with heterozygous STAT1 gain-of-function (GOF) mutations develop a complex syndrome of immune dysregulation. Although STAT1 GOF mutations were originally identified in patients with chronic mucocutaneous candidiasis, recent studies have documented a markedly increased risk of humoral (antibody- mediated) autoimmunity in this disease. Importantly, whereas defects in T helper 17 (Th17) cell differentiation likely account for recurrent fungal infections in these patients, the immune events promoting systemic autoimmunity remain poorly understood. Given links between increased type 1 interferon (IFN) activity and the pathogenesis of systemic lupus erythematosus (SLE), the leading hypothesis is that enhanced STAT1 signals downstream of the type 1 IFN receptor directly promote class-switched autoantibody production in STAT1 GOF syndrome. In contrast to this idea, our group recently reported that B cell-intrinsic type 1 IFN signals are redundant for murine SLE. Rather, we demonstrated that B cell type II IFN (interferon gamma; IFN-?) signals and B cell-derived IL-6 orchestrate the formation of spontaneous autoimmune germinal centers (GCs) in a STAT1-dependent manner. Based on this new model of autoimmune pathogenesis, we hypothesize that B cell-intrinsic expression of STAT1 GOF mutations will be sufficient to drive autoantibody production, by lowering the threshold of cytokine signals necessary for spontaneous GC formation. To test this idea, we have generated a novel murine knock-in model allowing conditional expression of a pathogenic STAT1 mutation originally reported in human patients. Using this novel animal model, we will first test whether enhanced IFN-?- driven STAT1 signals promotes B cell activation and B cell cytokine production in vitro. In parallel, we will determine whether B cell-specific expression of mutant STAT1 results in the generation of spontaneous, autoimmune GCs and the development of systemic autoimmunity. These studies are significant since an improved understanding of disease mechanisms in subjects with rare genetic syndromes of immune dysregulation may improve the treatment of patients with more common autoimmune diseases, like SLE, rheumatoid arthritis and type 1 diabetes.
Patients with gain-of-function (GOF) mutations in the transcription factor STAT1 exhibit immune dysregulation characterized by both recurrent infections and a markedly increased risk of antibody-mediated autoimmunity. Our group recently described a new model of autoimmune pathogenesis in which B cell-intrinsic, STAT1- dependent cytokine signals orchestrate the formation of spontaneous germinal centers resulting in B cell tolerance breaks. Based on these data, we hypothesize that expression of pathogenic STAT1 GOF mutations in B cells will be sufficient to drive the development of humoral autoimmunity, and will test this hypothesis using a novel mouse model allowing conditional (cell-specific) expression of a well-characterized, pathogenic human mutation in STAT1.
| Hale, Malika; Rawlings, David J; Jackson, Shaun W (2018) The long and the short of it: insights into the cellular source of autoantibodies as revealed by B cell depletion therapy. Curr Opin Immunol 55:81-88 |
