We describe, in rheumatoid arthritis (RA), abnormalities in the expression and distribution of heat shock protein (hsp) and dendritic cells (DCs) that are conducive to cross-priming and DC cross-talk. As detected by ELISA, inducible (i)hsp70 was dramatically increased in RA synovial fluid (RASF) vs normal human and RA sera and osteoarthritis and gout synovial fluid. Immunoblot analysis of fresh RASF cells revealed marked increases in ihsp70 and activation of its transcription factor heat shock factor-1, compared with fresh normal peripheral blood cells. Flow cytometry and microscopy demonstrated high levels of ihsp70 on the surface of RASF myeloid DCs (but not normal myeloid DCs) that occurred concurrently with hspRs (CD91/CD14). ihsp70 present in RASF exhibited chaperoning potential, as indicated by the capture of ihsp70 present in RASF on the surface of normal DCs. Binding was partially competitively inhibited by excess alpha(2)-macroglobulin, indicating that hspRs in addition to CD91 participate in the capture process. These data indicate that ihsp70 may chaperone autologous Ags into immature RASF DCs via hspRs, and that cross-talk between DCs coexpressing hsp/hspRs reflects a disease process in RA. The induction of surface ihsp70 on normal cells after sublethal heat stress and the release of ihsp70 from normal DCs after inflammatory stress also suggest that the pattern of ihsp70 expression in RASF occurs in response to sustained stress.