Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia

Abstract

Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell–intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma–derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus–like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL–RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell–intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment.

RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes

“…Another possibility is that OPG treatment could likely affect the function and phenotype rather than the composition of immune cells, directing them toward a less inflammatory phenotype, as suggested by our in vitro human immune cell studies. There is increasing evidence in other autoimmune diseases (multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease) that the RANKL/RANK pathway is involved in the induction of a proinflammatory phenotype of immune cells and exacerbation of the disease (73)(74)(75)(76)(77)(78). Inhibition of the RANKL/RANK pathway ameliorates inflammation through multiple mechanisms, including affecting innate immune cells, natural killer cells, B cells, and T cells.…”

Antibodies Produced by CLL Phenotype B Cells in Patients With Myasthenia Gravis Are Not Directed Against Neuromuscular Endplates

“… 35 , 36 It may also be that certain genetic and environmental risk factors, for example, genetic risk variants in the PTPN22 and TNFRSF11A loci, predispose these patients to both diseases, (late-onset) AChR + MG and CLL. 36 - 38 In addition, the patient with MG-CLL had antibodies against thyroid peroxidase and a history of vitiligo, but no other autoimmune phenomena were noted, in particular, no anemia or thrombocytopenia ( Table 1 and eTable 2, links.lww.com/NXI/A800 ). Although clonal CLL B cells often produce autoantibodies, the immunoglobulins, that they express, generally do not contribute directly to autoimmune disorders such as autoimmune hemolytic anemia or immune thrombocytopenia.…”

CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness

“…To investigate if CXCR4 hyperactivation alone creates a predisposition favoring TCL1-driven B-cell proliferation and CLL development, we performed B-cell immunophenotyping of CXCR4 C1013G mice, focusing on transitional B cells and the population of CD19+/ B220dim/CD5+ B1 B cells. A potential mechanism of CLL development in the Eµ-TCL1 mouse involves accumulation of autoreactive B cells in the transitional T1 population, giving rise to CD19+/B220dim and, to limit autoreactivity, CD5+ B cells, which eventually progress to lethal B-cell leukemia [33][34][35]. Indeed, in spleens of CXCR4 C1013G mice, T1 B cells were increased, and T2 B cells were decreased (Fig.…”