Alternatively, high levels of CXCL13 production may reflect a pathologic process in which synovial plasma cell production of RF is selectively enhanced relative to ACPA or other IgGs. Indeed, a strong CXCL13 RF relationship does not establish causality. therefore, another possibility is that elevated RF levels somehow drive increased pro duction of CXCL13. Conclusion In our present report, we demonstrate that serum levels of the B cell chemokine CXCL13 exhibit a strong relation ship with seropositive RA. The nature of this correlation appears to be particularly strong for both IgM and IgA RF, whereas there is a weaker relationship with IgG ACPA. A particular strength of this finding is its presence to nearly identical degrees in both an early RA cohort and an estab lished RA cohort.

Elevations of serum CXCL13 did not consistently associate with disease duration, sex or mea sures of disease activity in seropositive RA patients. More over, CXCL13 levels did not appear to associate with other features of seropositivity, such as the shared epitope. These results suggest that elevated CXCL13 levels may possibly be used to identify a distinct subset of seroposi tive RA patients that may either promote or result from the expansion of RF producing B cells. Introduction Rheumatoid arthritis is characterized by inflamed synovial tissue containing a massive infiltration of lym phocytes and macrophages with synovial fibroblast prolif eration. IL 18, an IL 1 family member, is involved in RA pathogenesis. We and others have shown that IL 18 plays an important role in the immune response, in local or systemic angiogenesis, and in monocyte recruit ment.

Various sources of IL 18 have been identified in cluding antigen presenting cells, as well as keratinocytes, articular chondrocytes, osteoblasts, and synovial fibro blasts. IL 18, is produced as a biologically inactive precursor protein containing a propeptide domain localized Drug_discovery to the cytoplasm. To be activated, pro IL 18 requires cleavage by the IL 1B converting enzyme, which is a member of the aspartate specific cysteine protease family. Caspase 1 is pro duced as an inactive form. To be activated, its needs to be cleaved into 20 kDa and 10 kDa subunits. Both sub units form heterodimers with interactions with other proteins and are involved in inflammasome formation and activation of inflammatory processes.

Active caspase 1 is located in the plasma membrane, where it cleaves pro IL 18 to IL 18. Caspase 1 and pro IL 18/IL 18 are complexed to other proteins that are involved in the secretion of IL 18. Caspase 1 is also a critical putative target in patients with cryopyrin associated periodic syndromes. When IL 18 is secreted, it becomes active. IL 18 bioactivity is dependent on both IL 18 and IL 18 binding protein levels.