Background/Purpose: Lupus nephritis (LN) is an autoimmune destruction of the kidney glomeruli and loss of kidney function affecting almost half of lupus patients. Although the disease is classified and treated based on accumulated glomerular damage and proliferative lesions, it has been shown that tubulointerstitial inflammation deeper in the organ is a better predictor of long-term renal viability. Autoimmune B cells have been identified as an important mediator of this inflammation, and recent work has identified interesting transcriptional maturation of these cells upon tissue engraftment. Here, we examine other critical properties of these cells that remain yet unexplored.

Methods: Kidney biopsies and matched blood from patients with Class II, III, or IV (+/- V) LN were obtained and processed for next-generation B cell receptor sequencing. The resulting B cell repertoire was analyzed to understand the properties of kidney B cells (KBCs), and their relationship to established compartments in the blood.

Results: Through repertoire sequencing and analysis, we report a highly dynamic B cell environment hallmarked by in situ development of kidney-derived B cell (KBC) lineages from naive-like precursors. These KBC lineages are capable of class switching, undergo extensive division, and display levels of somatic hypermutation not seen even in the memory autoimmune B cell compartment in the blood. Importantly, these highly selected B cell lineages are not restricted to the kidney following maturation, and can be identified in the blood of patients years after initial expansion in the kidney. Finally, biopsies of patients during acute onset of LN versus patients with a longer LN history reveal distinct phases of humoral development within the renal environment that is not captured by current disease classification systems, and may be relevant to disease treatment.

Conclusion: Through these data we draw the surprising conclusion that rather than serving as a target of autoimmune attack, the renal environment serves as a primary site of humoral autoimmune development. This development is progressive by nature, and the early phase of disease onset may represent a distinct therapeutic opportunity for aggressive B cell directed intervention. Additionally, these data may help explain mixed results when applying B cell directed therapies towards these patients. In all, this study reveals a dynamic, progressive, and pervasive humoral immune component in the renal environment in every LN patient assessed to-date, and highlights a surprising gap between traditional histological classification of the disease and the underlying immune status.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/diseased-lupus-nephritis-kidneys-serve-as-a-primary-site-of-systemic-autoimmune-development/