Schematic representation of a local autoantibody-induced inflammatory network in an arthritic joint. Autoantibodies and autoantigen form immune complexes (ICs) in the vascular system and are captured on cartilage surfaces. The intracellular Fc receptor (FcRn) may sustain certain arthritogenic autoantibody levels and enhance IC formation by antibody recycling. The increased IC levels on the cartilage can then activate the complement cascade to produce C5a and also directly activate macrophage (present locally) through the FcγRIII receptor to trigger initial gradient waves of inflammatory cytokines around the affected joint. The C5a resulting from complement activation diffuses out into local tissues, increasing vascular permeability and cellular chemotaxis, thereby effecting the downregulation of inhibitory FcγRIIb receptors and reducing the activation threshold of inflammatory cells. This results in a rapid influx of neutrophils around affected joint tissues and in the activation of mast cells by C5a to release histamine, which again may diffuse out further to activate more mast cells. The rapid activation cascade of neutrophils and mast cells can result in the production of vast amounts of local inflammatory cytokines such as IL-1 and tumor necrosis factor-α (TNF-α) potent enough to attract large waves of influx of activated macrophages to the site of inflammation. At the joints, macrophages can further be activated through FcγRIII by the ICs deposited on cartilage supplemented by the inflammatory cytokine milieu. This large number of activated macrophages then can sustain the constant production of inflammatory mediators and cartilage-degrading enzymes that ultimately can result in joint destruction. MMPs, matrix metalloproteinases.