Anti-CD180 (RP105) Activates B Cells To Rapidly Produce Polyclonal Ig via a T Cell and MyD88-Independent Pathway

Abstract

CD180 is homologous to TLR4 and regulates TLR4 signaling, yet its function is unclear. We report that injection of anti-CD180 mAb into mice induced rapid Ig production of all classes and subclasses except IgA and IgG2b, with up to 50-fold increases of serum IgG1 and IgG3. IgG production after anti-CD180 injection was not due to reactivation of memory B cells and was retained in T cell-deficient (TCR KO), CD40 KO, IL-4 KO and MyD88 KO mice. Anti-CD180 rapidly increased both transitional and mature B cells, with especially robust increases in transitional B cell number, MZ B cell proliferation, and CD86 but not CD80 expression. In contrast, anti-CD40 induced primarily FO B cell and myeloid expansion with increases in expression of CD80 and CD95 but not CD86. The expansion of splenic B cells was due in part to proliferation and occurred in WT and TCR KO mice whereas T cell expansion occurred in WT but not in B cell-deficient (μMT) mice, indicating a direct role for B cells in CD180 stimulation in vivo. Combinations of anti-CD180 with various MyD88-dependent TLR ligands biased B cell fate as co-injection diminished Ig production but purified B cells exhibited synergistic proliferation. Anti-CD180 had no effect on cytokine production from B cells but increased IL-6, IL-10, and TNF-α production in combination with LPS or CpG. Thus CD180 stimulation induces intrinsic B cell proliferation and differentiation, causing rapid increases in IgG, and integrates MyD88-dependent TLR signals to regulate proliferation, cytokine production, and differentiation.

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

“…Anti-RP105 has not been tested in humans; however, it was recently shown in a mouse model that i.v. anti-RP105 Abs induced Ig production of several subclasses and was well tolerated by the mice (20). mAbs are now being used routinely in the treatment of diseases such as cancer and rheumatoid arthritis, and there is no obvious reason why humanized anti-RP105 Abs should not be tested for treatment of CVID.…”

“…Multiple studies reported defective TLR9 signaling in CVID-derived B cells (15)(16)(17); recently, defective signaling from TLR9 in combination with RP105 (CD180) was reported in three CVID patients (18). The natural ligand for RP105 has not been identified, but anti-RP105 Abs are potent activators of RP105 both in vitro (19) and in vivo (20).…”

A novel B cell population revealed by a CD38/CD24 gating strategy: CD38−CD24− B cells in centenarian offspring and elderly people

“…In a recent paper (Chaplin et al 2011), differentiation from transitional to mature B cells was induced by stimulation with CD180 (RP105), a toll-like receptor (TLR)-4 homologue expressed by monocytes, macrophages, dendritic cells, and B lymphocytes which regulates TLR-4 signaling and induces B cell proliferation.…”

Rewiring of sIgM-Mediated Intracellular Signaling through the CD180 Toll-like Receptor

“…CD180/RP105 is a membrane-associated orphan receptor that drives normal human and mouse B-cell activation and proliferation (11)(12)(13)(14). Anti-CD180 monoclonal antibody (mAb) induces upregulation of MHC class II, CD40 and CD80/CD86 on human and mouse B cells (4,11,15) and differentiation and rapid secretion of immunoglobulin G (IgG) in vivo (16). We have shown previously that approximately 60% of CLL samples express CD180.…”