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Rheumatoid factor (RF) develop in response to ICs in many clinical and experimental settings. We investigated whether and how polyethylene glycol (PEG) precipitated ICs from rheumatoid arthritis (RA) sera and synovial fluid (SF) can influence cytokine production by peripheral blood mononuclear cells. We also examined the relationship between RF and IC induced cytokine production. Parallel sera and SF from 47 RA patients and sera from 15 healthy control individuals were PEG precipitated. The precipitates were added to serum-free peripheral blood mononuclear cell cultures and tumour necrosis factor (TNF)-\u03b1 levels were measured after 20 hours. In separate cell culture experiments Fc\u03b3RIIa and Fc\u03b3RIII were blocked and monocytes were depleted or enriched. RF in serum was determined by nephelometry, and IgG levels in precipitates and anti-cyclic citrullinated peptide antibodies in serum were measured using ELISA. Clinical data were collected from the patients' charts. In two separate investigations, we demonstrated a correlation between RF, PEG-precipitated IgG levels and induction of the proinflammatory cytokine TNF-\u03b1 by PEG-precipitated SF ICs. No such correlation was found for serum ICs. TNF-\u03b1 levels induced by SF precipitates, but not serum precipitates, correlated with the number of swollen and tender joints. Monocytes\/macrophages were shown to be the main responder cells, and blockade of Fc\u03b3RIIa, but not blockade of Fc\u03b3RIII, inhibited TNF-\u03b1 production in cultures stimulated with precipitated ICs. Anti-cyclic citrullinated peptide correlated with RF but exhibited no association with IgG content in PEG precipitates or with precipitate-induced TNF-\u03b1 levels. These findings support the hypothesis that SF ICs and correlated RF production are directly linked to cytokine-dependent inflammation in RA. Suppression of monocytes\/macrophages in RA joints or blockade of the primate-specific activating Fc\u03b3RIIa receptor might be ways to reduce IC-induced TNF-\u03b1 production in the joints of seropositive RA patients.<\/jats:p>","DOI":"10.1186\/ar1926","type":"journal-article","created":{"date-parts":[[2006,4,6]],"date-time":"2006-04-06T09:30:18Z","timestamp":1144315818000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":106,"title":["Immune complexes from rheumatoid arthritis synovial fluid induce Fc\u03b3RIIa dependent and rheumatoid factor correlated production of tumour necrosis factor-\u03b1 by peripheral blood mononuclear cells"],"prefix":"10.1186","volume":"8","author":[{"given":"Linda","family":"Mathsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Lampa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Mullazehi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"R\u00f6nnelid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2006,3,28]]},"reference":[{"key":"1804_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1006\/clim.2002.5210","volume":"104","author":"MM Newkirk","year":"2002","unstructured":"Newkirk MM: Rheumatoid factors: host resistance or autoimmunity?. 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