Identifying B-Cell Targets for Lupus
Using novel mouse models to study the signals and pathways of systemic autoimmune diseases
The long-term effects of systemic lupus erythematosus (SLE) include kidney damage and accelerated atherosclerosis leading to cardiovascular disease. Although autoantibody-producing B cells are critical for lupus pathogenesis, the immune mechanisms whereby B cells are activated in autoimmunity are poorly understood, and exhibit significant heterogeneity between patients. Dr. Shaun Jackson’s research aims to uncover B cell activation pathways contributing to lupus pathogenesis using two novel murine lupus models.
First, Dr. Jackson uses a lupus model developed at SCRI, termed the WAS chimera model, to uncover the B cell specific signals underlying the formation of spontaneous, autoimmune germinal centers (GCs) in SLE. Notably, spontaneous germinal centers are known to be an important site for autoreactive B cell activation in SLE, implying that these studies may identify potential therapeutic targets in SLE.
In the WAS model, B cells, but not other hematopoietic lineages, lack expression of Wiskott Aldrich syndrome (WAS) protein, resulting in spontaneous humoral autoimmunity recapitulating several cardinal features of human SLE. Dr. Jackson’s research using this model has identified several novel B cell activation mechanisms in SLE (see Becker-Herman, et al. J Exp Med, 2011; Jackson, et al. J Immunol, 2014; Jackson, et al. J Exp Med, 2016). Importantly, critical roles for these activation pathways have subsequently been independently confirmed using other murine lupus models and by human clinical studies. For example, Dr. Jackson recently uncovered an unexpected role for B cell IFN-γ signals in promoting spontaneous GC formation in SLE (Jackson, et al. J Exp Med, 2016); findings that were corroborated by subsequent human lupus study showing elevated serum IFN-γ at the time of first autoantibody development (Munroe, et al. Ann Rheum Dis, 2016). Therefore, these human data suggest that disease mechanisms uncovered using the WAS chimera model may accurately inform the pathogenesis of human SLE.
Second, Dr. Jackson studies the mechanisms whereby the B cell survival cytokine BAFF/BLyS (the target of the lupus therapy Belimumab) promotes autoimmunity. Of the known BAFF family receptors, Dr. Jackson’s research has identified Transmembrane activator and CAML interactor (TACI) as the B cell surface receptor required for BAFF-driven autoimmunity. Mechanistically, his research identified a novel population of immature, transitional B cells expressing increased surface TACI, which directly contributes the pool of autoantibody-producing cells in SLE. In addition to informing lupus pathogenesis, Dr. Jackson’s work is also relevant to understanding autoimmunity in other high BAFF settings, including after stem cell transplantation.
In summary, Dr. Jackson’s research aims to characterize the immune pathways underlying the pathogenesis of autoimmunity, in the hope of identifying markers of early diagnosis and predictors of disease prognosis and response to treatment. Components of these pathways also offer new drug targets for preventing systemic autoimmune diseases or delaying their effects. Dr. Jackson has worked with industrial partners in the past on pre-clinical studies of potential therapeutic agents, including kinase inhibitors and candidate monoclonal antibodies.
Stage of Development
- Preclinical in vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Collaborative animal model development
- Rawlings DJ, Metzler G, Wray-Dutra M, Jackson SW. Altered B cell signalling in autoimmunity.Nat Rev Immunol. 2017 Jul;17(7):421-436. doi: 10.1038/nri.2017.24. Epub 2017 Apr 10. Review.
- Jacobs HM, Thouvenel CD, Leach S, Arkatkar T, Metzler G, Scharping NE, Kolhatkar NS, Rawlings DJ, Jackson SW. Cutting Edge: BAFF Promotes Autoantibody Production via TACI-Dependent Activation of Transitional B Cells. 2016. J Immunology 96(9):3525-31.
- Jackson SW, Jacobs HM, Arkatkar T, Dam EM, Scharping NE, Kolhatkar NS, Hou B, Buckner JH, Rawlings, DJ. B cell IFN-gamma receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. 2016. Journal of Experimental Medicine 213:733-750.
- Jackson SW, Scharping NE, Kolhatkar NS, Khim S, Schwartz MA, Li QZ, Hudkins KL, Alpers CE, Liggitt D, Rawlings DJ. Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. 2014. Journal of Immunology 192:4525-4532.
- Becker-Herman S, Meyer-Bahlburg A, Schwartz MA, Jackson SW, Hudkins KL, Liu C, Sather BD, Khim S, Liggitt D, Song W, Silverman GJ, Alpers CE, Rawlings DJ. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. Journal of Experimental Medicine 2011. 208:2033-2042.