Drs. Santiago-Raber and Amano contributed equally to this work.
Systemic Lupus Erythematosus Basic Science Studies
Fcγ receptor–dependent expansion of a hyperactive monocyte subset in lupus-prone mice
Version of Record online: 30 JUL 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 8, pages 2408–2417, August 2009
How to Cite
Santiago-Raber, M.-L., Amano, H., Amano, E., Baudino, L., Otani, M., Lin, Q., Nimmerjahn, F., Verbeek, J. S., Ravetch, J. V., Takasaki, Y., Hirose, S. and Izui, S. (2009), Fcγ receptor–dependent expansion of a hyperactive monocyte subset in lupus-prone mice. Arthritis & Rheumatism, 60: 2408–2417. doi: 10.1002/art.24787
- Issue online: 30 JUL 2009
- Version of Record online: 30 JUL 2009
- Manuscript Accepted: 1 MAY 2009
- Manuscript Received: 6 JAN 2009
- Swiss National Foundation for Scientific Research
- Alliance for Lupus Research
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 (FcγR) 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 FcγRIIB.
The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factor–transgenic C57BL/6 mice deficient in activating FcγR. Moreover, we assessed the expression levels of activating FcγR and inhibitory FcγRIIB on Gr-1+ and Gr-1– monocyte subsets in C57BL/6 mice bearing the C57BL/6-type or the NZB-type Fcgr2b allele.
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 FcγR. The Gr-1– subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory FcγRIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating FcγRIV. This was in contrast to high levels of FcγRIIB expression and no FcγRIV expression on the Gr-1+ subset.
Our results demonstrated a critical role of activating FcγR in the development of monocytosis and in the expansion of a Gr-1–FcγRIIBlowFcγRIV+ 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.