Lymphocytes from autoimmune MRL lpr/lpr mice are hyperresponsive to IL-18 and overexpress the IL-18 receptor accessory chain

MRL lpr/lpr mice spontaneously develop a severe autoimmune lupus syndrome c haracterized by strong autoantibody production and massive lymphoproliferat ion, in which IFN-gamma plays a major pathogenic effect. The role of the IF N-gamma -inducing cytokine IL-18 in the autoimmune syndrome of lpr/lpr mice has been investigated. In response to IL-18, lymph node cells of lpr/lpr m ice produce significant amounts of IFN-gamma and proliferate more potently as compared with cells from +/+ mice. Cells likely responsible for such hyp erresponsiveness to IL-18 include NK cells and the CD4(+)/CD8(+) self-react ive T lymphocytes characteristically present in lymph nodes of lpr/lpr mice . Analysis of the expression of IL-18R complex revealed that mRNA for the I L-18R alpha -chain is constitutively expressed at similar level both in +/ and lpr/lpr lymphocytes, In contrast, the expression of the accessory rece ptor chain IL-18R beta is low in unstimulated +/+ cells but significantly h igh in lpr/lpr cells. Thus, the abnormally high expression of the IL-18R ch ain IL-18R beta could be one of the causes of the hyperresponsiveness of lp r/lpr cells to IL-18 at the basis of consequent enhancement of IFN-gamma pr oduction and development of IFN-gamma -dependent autoimmune pathology.