Targeted Modulation of Immune Signaling Pathways in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by hyperactive B cell activity leading to production of autoantibodies and aberrant cytokine signaling. In this dissertation, we focused on improving our understanding of the role of protein signaling pathways in SLE. We modified disease by targeting the adenosine receptor and through germline deletion of targeting the NIK protein. For our adenosine receptor studies, we utilized NZB/W F1 female lupus mice. As these mice develop clinical manifestations of lupus at about 23 weeks-of-age, we injected the mice with an Adenosine 2A Receptor (A2AR) agonist and an Adenosine 2B Receptor (A2BR) antagonist from 21-weeks-of-age to 34-weeks-of-age to determine if modification of the adenosine receptor subtypes would decrease disease severity. Overall, we found that the A2BR antagonist (ADO-5024) was able to improve various disease-associated parameters in these mice, including prolonging survival, while decreasing proteinuria, C3 renal deposition, autoantibody production, and inflammatory cytokine secretion, to be comparable to the standard treatment, dexamethasone. On the other hand, the A2AR agonist, ADO-6001, failed to reduce lupus disease. Treatment with the A2AR agonist, ADO-6001 resulted in disease parameters that were not significantly different from our negative controls. Significantly, ADO-5024 resulted in reduced plasma cell abundance and autoantibody production, demonstrating an important autoimmune role for this signaling pathway. Using MRL/lpr lupus mice, we targeted the map3k14 gene. We found that Map3k14 deletion on the MRL/lpr background identified contrasting roles for the gene encoding for NIK in systemic immunity vs tissue inflammation. NIK is the master regulator for the non-canonical NF-B pathway which is responsible for many immunoregulatory roles. Although map3k14 KO mice rapidly deteriorated compared to their wild type and heterozygous counterparts, autoantibodies were reduced along with type 2 conventional dendritic cells (cDC2), T helper cells and their subsets, and cytokines like CCL2 and IL-5. However, there was a significant increase of C3, IgG, and SiglecF deposition into the renal tissue leading to elevated proteinuria and reduced renal function. The findings presented in this dissertation will provide a foundation to further examine the role of NIK in immune specific cell populations as NIK may have differential roles on immune cell function. Understanding cell specific pathways regarding NIK function may lead to development of more selective therapeutics for the treatment of SLE.