Anti-CD180 monoclonal antibody, clone FQS25831

RP105 is a B-cell surface molecule that has been recently assigned as CD180. RP105 ligation with an antibody Induces B-cell activation In humans and mice, leading to proliferation and up-regulation of a costimulatory molecule, B7.2/CD86. RP105 Is associated with an extracellular molecule, MD-1. RP105/MD-1 has structural similarity to Toll-like receptor 4 (TLR4)/MD-2. TLR4 signals a membrane constituent of Gram-negative bacteria, lipopolysaccharlde (LPS). MD-2 Is indispensable for TLR4-dependent Lips responses because cells expressing TLR4/ MD-2, but not TLR4 alone, respond to LPS. RP105 also has a role in LPS responses because B cells lacking RP105 show hyporesponsiveness to LPS. Little is known, however, regarding whether MD-1 is important for RP105-dependent LPS responses, as MD-2 is for TLR4. To address the issue, we developed mice lacking MD-1 and generated monoclonal antibodies (mAbs) to the protein. MD-1-null mice showed impairment in LPS-induced B-cell proliferation, antibody production, and B7.2/CD86 up-regulation. These phenotypes are similar to those of RP105-null mice. The similarity was attributed to the absence of cell surface RP105 on MD-1-null B cells. MD-1 is indispensable for cell surface expression of RP105. A role for MD-1 in LIPS responses was further studied with anti-mouse MD-1 mAbs. In contrast to highly mitogenic anti-RP105 mAbs, the mAbs to MD-1 were not mitogenic but antagonistic on LPS-induced B-cell proliferation and on 57.2 up-regulation. Collectively, MD-1 is important for RP105 with respect to B-cell surface expression and LPS recognition and signaling.

Activation of TLR7 and TLR9 by endogenous RNA- or DNA-containing ligands, respectively, can lead to hyper-activation of immune cells, including macrophages and DCs, subsequently contributes to the pathogenesis of SLE. CD180, a TLR-like protein, is specifically involved in the development and activation of immune cells. Our previous study and others have reported that CD180-negative B cells are dramatically increased in SLE patients and responsible for the production of auto-antibodies. However, the mode of CD180 expression on macrophages and DCs in SLE remains unclear and the role of CD180 on regulating TLR7- and TLR9-mediated activation of macrophages and DCs are largely unknown. In the present study, we found that the percentages of CD180-negative macrophages and DCs were both increased in SLE patients and lupus-prone MRL/lpr mice compared with healthy donors and wild-type mice, respectively. Notably, ligation of CD180 significantly inhibited the activation of TLR7 and TLR9 signaling pathways in macrophages and DCs through the Lyn-SHP-1/2 axis. What's more, injection of anti-CD180 Ab could markedly ameliorate the lupus-symptoms of imiquimod-treated mice and lupus-prone MRL/lpr mice through inhibiting the activation of macrophages and DCs. Collectively, our results highlight a critical role of CD180 in regulating TLR7- and TLR9-mediated activation ofmacrophages and DCs, hinting that CD180 can be regarded as a potential therapeutic target for SLE treatment.