OBJECTIVE: Lupus-prone BXSB mice develop monocytosis characterized by selective accumulation of the Gr-1- monocyte subset. The aim of this study was to explore the possible role of activating IgG Fc receptors (FcgammaR) in the development of monocytosis and to characterize the functional phenotype of the Gr-1- subset that accumulates in lupus-prone mice bearing the NZB-type defective Fcgr2b allele for the inhibitory FcgammaRIIB. METHODS: The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factor-transgenic C57BL/6 mice deficient in activating FcgammaR. Moreover, we assessed the expression levels of activating FcgammaR and inhibitory FcgammaRIIB on Gr-1+ and Gr-1- monocyte subsets in C57BL/6 mice bearing the C57BL/6-type or the NZB-type Fcgr2b allele. RESULTS: We observed monocytosis with expansion of the Gr-1- subset in anti-IgG2a-transgenic C57BL/6 mice expressing IgG2a, but not in those lacking IgG2a. Moreover, monocytosis barely developed in BXSB and anti-IgG2a-transgenic C57BL/6 mice deficient in activating FcgammaR. The Gr-1- subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory FcgammaRIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating FcgammaRIV. This was in contrast to high levels of FcgammaRIIB expression and no FcgammaRIV expression on the Gr-1+ subset. CONCLUSION: Our results demonstrated a critical role of activating FcgammaR in the development of monocytosis and in the expansion of a Gr-1-FcgammaRIIB(low)FcgammaRIV+ hyperactive monocyte subset in lupus-prone mice. Our findings further highlight the importance of the NZB-type Fcgr2b susceptibility allele in murine lupus, the presence of which induces increased production of hyperactive monocytes as well as dysregulated activation of autoreactive B cells.