Recent studies have identified a promoter polymorphism in C-reactive protein (CRP) as a susceptibility locus for systemic lupus erythematosus (SLE). Protective haplotypes associated with higher CRP levels confer a 2- 3-fold reduced risk of SLE. This proposal will test the novel hypothesis that higher baseline CRP levels increase the activation threshold of monocytes and dendritic cells (DC) by increasing expression Fc gamma RIIb, an inhibitory receptor. This then limits innate responses that promote autoimmunity. In support of this hypothesis, we found that CRP inhibits the differentiation of monocytes into DC, and increases expression of FcRIIb. In addition, a study in normal volunteers found that genetically higher baseline CRP levels were associated with dramatically lower in vivo cytokine responses to lipopolysaccharide. FcRIIb is a key regulator of B cell, monocyte and DC responses with important roles in preventing autoimmunity and inflammation. However, the physiological regulation of FcRIIb expression is incompletely understood. This proposal will investigate the role of CRP in this key regulatory pathway. Aim 1 will examine the mechanism by which CRP increases FcRIIb expression on DC. Aim 2 will determine whether CRP limits responses of DC to immune complexes and toll like receptor (TLR) agonists. Aim 3 will determine the effect of CRP genotypes and baseline serum levels of CRP on FcRIIb expression and responses of monocytes and DC. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE) is a disease of improper regulation of the immune system. Large population studies are identifying genes that are important in preventing SLE. One gene that has been found by this approach is the C-reactive protein (CRP) gene. Individuals with genetically higher levels of CRP have a decreased risk of developing SLE. CRP is a blood protein that helps shut down the body's response after injury or infection. Injection of CRP is an effective treatment for SLE in mice. This project will investigate how CRP dampens the immune responses that lead to SLE.