Dysregulation of cytokine and monocyte function in systemic lupus erythematosus
A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2015.
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterised by the presence of antibodies that recognise and target both protein and nucleic acid autoantigens. Elevated levels of a number of cytokines are a hallmark feature of disease, with B Lymphocyte Stimulator (BLyS) in particular showing an association with disease activity in prospective studies. Indeed an anti-BLyS targeted therapy, belimumab, has been successfully introduced for the treatment of SLE. In addition to cytokines the role that the innate immune system plays in disease pathogenesis is increasingly recognised with aberrant monocyte/macrophage function having been identified in SLE patients. Given the pivotal role that both monocytes and cytokines play in SLE we sought to investigate the role these may play in an Irish SLE cohort.
We identified BLyS as the pro-inflammatory cytokine that appears to have the strongest association with both disease activity, damage accrual as well as clinical phenotypes in SLE in Irish patients. In addition we investigated the effect of BLyS on monocyte function in SLE. Results demonstrated that BLyS promotes aberrant activation of multiple signalling pathways in healthy and SLE patient monocytes resulting in increased expression of a number of genes such a IL-6, IFN-a and BLyS itself, all of which play significant roles in SLE. We have also shown that BLyS stimulation results in enhanced activation and antigen presenting capacity of SLE patient monocytes with a consequential enhancement of T cell activation also observed on co-culture experiments. Finally we investigated the effect of BLyS on monocyte subset differentiation and microRNA expression. These investigations highlighted a role for BLyS in inducing a mixed monocyte population in SLE whilst at the same time identifying a number of microRNAs such mir-155-5p, mir-1246, mir- 132-3p and mir-125a-5p that a differentially expressed in SLE patients when compared to controls. Overall these preliminary findings highlight potential novel mechanisms that may be used to regulate BLyS production. Thus our findings have not only contributed to the understanding behind the molecular pathogenesis of SLE but also underlined the therapeutic potential in manipulating BLyS levels fo r the tre a tm e n t o f SLE.