Gp49B is a pathogenic marker for auto-antibody-producing plasma cells in lupus-prone BXSB/Yaamice

Abstract

Immune homeostasis is critically regulated by the balance between activating and inhibitory receptors expressed on various immune cells such as T and B lymphocytes, and myeloid cells. The inhibitory receptors play a fundamental role in the immune checkpoint pathway, thus maintaining peripheral tolerance. We recently found that expression of leukocyte immunoglobulin-like receptor (LILR)B4, an inhibitory member of the human LILR family, is augmented in auto-antibody-producing plasmablasts/plasma cells of systemic lupus erythematosus (SLE) patients. However, the mechanism behind the ‘paradoxical’ up-regulation of this inhibitory receptor upon pathogenic antibody-secreting cells is yet to be known. To this end, in this study, we examined if glycoprotein 49B (gp49B), the murine counterpart of human LILRB4, is also elevated in auto-antibody-producing cells in several SLE mouse models, and tried to clarify the underlying mechanism. We found that gp49B is expressed on plasma cells of lupus-prone models but not of healthy C57BL/6 mice, and the level was positively correlated to the anti-double-stranded DNA IgG titer in serum. Gp49B genetic deletion, however, did not abolish the serum auto-antibodies or fully ameliorate the lethal glomerulonephritis, indicating that gp49B is not the sole regulator of lupus but a pathogenic element in the disease. We conclude that the elevated expression of this inhibitory receptor on pathogenic plasma cells was also relevant upon the murine SLE model. The mechanism of gp49B underlying the disease progression in lupus-prone mice has been discussed.

LILRB4 promotes tumor metastasis by regulating MDSCs and inhibiting miR-1 family miRNAs

“…For antibody treatment, the B6 mice were inoculated intravenously at a low dose of 5 × 10 5 LLC-Luc2 cells or 5 × 10 4 B16F10 cells. At 3 days post-tumor inoculation, mice were treated with anti-PD-1 (RPM1-14, Bio X Cell; 200 μg/mouse), anti-gp49 (H1.1-Amenian hamster IgG from hybridoma cells 26 or H1.1-mIgG1, 200 μg/mouse), or isotype matched control antibody (2A3 (Bio X cell), HTK888 (Biolegend) or MOPC-21 (Bio X Cell); 200 μg/mouse) by intraperitoneal injection six times at 3-day intervals. LLC-Luc2 tumor-bearing mice with antibody treatment were imaged using the IVIS Spectrum In Vivo Imaging System (Perkin Elmer) at three weeks after tumor inoculation, and sacrificed at five weeks after tumor injection for detection of tumor metastases in lung and liver by H&E staining.…”

Disruption of Circadian Clock Induces Abnormal Mammary Morphology and Aggressive Basal Tumorigenesis by Enhancing LILRB4 Signaling

“…In this study, we further demonstrated that CRD enhanced the expression of LILRB4 in vivo in healthy mammary glands and mammary tumors. LILRB4 is an inhibitory receptor that plays a key role in immune checkpoint pathways ( 63 ). Regarding signals transmitted by LILRs, the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activating motifs (ITAMs) are of great significance ( 64 ).…”

LILRB4 Checkpoint for Immunotherapy: Structure, Mechanism and Disease Targets

“…Therefore, pinpointing autoantibody-producing plasmablasts (PBs) and plasma cells (PCs) by finding effective target molecules is essential for downregulating pathogenic plasma cell activity. It was found that PBs and PCs from untreated SLE patients would have high LILRB4 expression, and that the level of LILRB4 expression was positively correlated with the production of anti-double-stranded DNA IgG in serum [19,79]. Therefore, utilizing the highly expressed LILRB4 molecule to recognize pathogenic PBs/PCs and target pathogenic PBs/PCs could provide a new avenue for effective treatment of SLE.…”