Role of activatory Fc gamma RI and Fc gamma RIII and inhibitory Fc gamma RII in inflammation and cartilage destruction during experimental antigen-induced arthritis

IgG-containing immune complexes, which are found in most RA joints, communi cate with hematopoietic cells using three classes of Fc receptors(Fc gamma RI, -II, -III). In a previous study we found that if a chronic T-cell-media ted antigen-induced arthritis (AIA) was elicited in knee joints of Fell gam ma -chain-deficient mice that lack functional Fc gamma RI and Fc gamma RIII , joint inflammation was comparable but severe cartilage destruction was ab sent. We now examined the individual role of the stimulatory Fc gamma RI an d Fc gamma RIII and inhibitory Fc gamma RII in inflammation and functional cartilage damage in knee joints with AIA using Fc gamma RI-, Fc gamma RII-, and Fc gamma RIII-deficient mice. Three weeks after immunization with the antigen-methylated bovine serum albumin (BSA), cellular (T-cell responses a s measured by lymphocyte proliferation) immunity raised against mBSA was co mparable in all groups examined. Humoral (total IgG, IgG1, IgG2a, and IgG2b levels) immunity against mBSA was comparable in Fc gamma RI-/- and Fc gamm a RIII-/- but higher in Fc gamma RII-/- if compared to controls. joint swel ling as measured by Tc-99m uptake at days 1, 3, and 7 was similar in Fc gam ma RI-/- and Fc gamma RIII-/- mice and significantly higher in Fc-/Rll-/-. Chronic inflammation and cartilage damage (depletion of proteoglycans, meta lloproteinase (MMP)-induced neoepitopes, and matrix erosion) was studied hi stologically in total knee joint sections stained with hematoxylin or safra nin-O. Histologically, at day 7 after AIA induction, exudate and infiltrate in the knee joint was similar in Fc gamma RI-/- and Fc gamma RIII-/- and s ignificantly higher (230% and 340%) in Fc gamma RII-/- mice if compared to controls. Aggrecan breakdown in cartilage caused by MMPs and, which is rela ted to severe irreversible cartilage erosion, was further studied by immuno localization of MMP-mediated neoepitopes (VDIPEN) and image analysis. MMP-i nduced neoepitopes determined in various cartilage layers (tibia and femur) were primarily inhibited in Fc gamma RI-/- (79 to 87% and 87 to 88%, respe ctively) and comparable in Fe gamma RIII-/-. VDIPEN neoepitopes were much h igher (82 to 122% and 200 to 250%, respectively) in Fc gamma RII-/- mice. I nitial depletion of proteoglycans was similar (60 to 100%) in all groups. I n the chronic phase, cartilage matrix erosion in the lateral and medial tib ia was significantly elevated in Fc gamma RII-/- (222% and 186%, respective ly) but not in Fc gamma RI-/- or Fc gamma RIII-/- mice. These results sugge st that during T-cell-mediated AIA, Fc gamma RI and Fc gamma RIII act in co ncert in acute and chronic inflammation whereas FcyRI is the dominant Fell involved in severe cartilage destruction. Fc gamma RII is a crucial inhibit ing factor in acute and chronic inflammation and cartilage erosion.