Deletion of C-reactive protein exacerbates collagen-induced arthritis: A role for CRP in immune tolerance? (96.23)

Abstract

Abstract Heightened C-reactive protein (CRP) blood level associates with inflammation and tissue damage in rheumatoid arthritis (RA), and so CRP is assumed to have a detrimental effect. However, the exact role of CRP in RA remains unknown. To ascertain the contribution of CRP in RA we subjected wild type mice (WT) and CRP deficient mice (moCRP-/-) to collagen-induced arthritis (CIA). To our surprise, disease developed 14 days earlier in moCRP-/- than WT, achieving a threefold higher clinical score. The beneficial effect of CRP in CIA appears to be linked to the protein’s ability to dampen the activation state of dendritic cells (DCs). For example, incubation of bone marrow-derived CD11c+ DCs (BMDCs) with 10 μg/ml purified human CRP reduced display of MHC class II and CD80/86 compared to BMDCs exposed to media alone (8 ± 4% lower and 5 ± 5.5% lower, respectively). This effect was observed whether BMDCs were derived from WT or moCRP-/- but was lost if cells were from mice lacking expression of FcγRIIB, the latter showing increased activation in response to CRP. Based on these observations we suggest that CRP binding to the inhibitory FcγRIIB conveys a signal leading to reduced display of DC activation markers. Accordingly, in the absence of CRP or FcγRIIB this pathway is disrupted, thereby de-inhibiting DCs and rendering moCRP-/- more prone to CIA. Experiments now underway are investigating whether a CRP→FcγRIIB pathway on DCs contributes to maintenance of immune tolerance.