The roles of the individual elements of the BAFF axis in murine SLE
A characteristic feature of SLE is B cell hyperactivity, and central to normal B cell survival and differentiation is the BAFF axis, comprised of two ligands (BAFF, APRIL) and three receptors (BCMA, TACI, BR3). BAFF, the ligand, has been the focus of considerable investigation in both murine and human SLE, and the BAFF antagonist, belimumab, has been approved by the FDA for the treatment of adult seropositive SLE patients. Remarkably, > 40% of belimumab-treated patients in the phase-III trials failed to respond. To explain this incomplete responsiveness, we posit that not all BAFF/BAFF receptor interactions promote SLE. Whereas interactions with BCMA and BR3 promote disease, interactions with TACI are protective. Thus, selective blockade of specific interactions within the BAFF axis should lead to a more auspicious outcome.
To address this issue, the SLE-prone NZM 2328 (NZM) mouse model will be employed. We will characterize NZM mice singly-deficient in the individual BAFF receptors for features of SLE, focusing on serological autoimmunity; B cell, T cell, and plasma cell phenotype; spleen microarchitecture; renal immunopathology; and clinical disease. We will concentrate on cellular mechanisms by evaluating B10, Treg, Th1, and Th17 cells. We will evaluate BAFF/BCMA and BAFF/TACI interactions in the absence of APRIL, and we will test interactions between BAFF and each individual receptor by studying NZM mice deficient in the other two BAFF receptors.
To our knowledge, our mouse colony of SLE mice individually deficient in every ligand and receptor of the BAFF axis is unique in the world. With these mice, we will be able to dissect the importance of the individual interactions to development of bona fide SLE disease in vivo. We anticipate that our studies will lay the foundation for development of receptor-selective antagonists that specifically block the critical pathogenic interactions within the BAFF axis.