Dissecting signalling pathways associated with intrarenal synthesis of complement components in lupus nephritis

Abstract

Lupus nephritis is one of the most common and serious complications of systemic lupus erythematosus, attributed to increased morbidity and mortality. The in situ deposition of intrarenal immune complexes promote the accumulation of inflammatory cells and cause kidney injury in lupus nephritis. Among potential sources of intrarenal complement deposits, the concept of intrarenal complement synthesis has been described more than three decades ago in experimental lupus nephritis. By using transcriptome datasets, we here identified accelerated intrarenal synthesis of distinct classical and alternative complement pathway components, most associated with impaired kidney function. Contrasting to this, no such induction of intrarenal complement synthesis was observed in disease controls, further supporting relevance of intrarenal complement synthesis especially in human lupus nephritis. Gene set enrichment identified that glomerular complement synthesis predominantly associated with interferon signalling and signalling by interleukins in human lupus nephritis, whereas tubulointerstitial complement synthesis with aberrant T-cell receptor signalling. Because the pathomechanistic involvement of complement system activation contributed to recent advances in targeted therapy in lupus nephritis, this study provides additional insights into signalling pathways associated with intrarenal synthesis of complement components in lupus nephritis that might be also affected by targeted therapy of the complement system.