Systemic lupus erythematosus (SLE) is a complex, systemic autoimmune disease in which the traditional, compartmentalised approach of studying either adult or paediatric lupus patients in isolation is ineffective to unravel the underlying disease mechanisms.

We used an immunomics platform for high-dimensional, unbiased interrogation of SLE with mass cytometry to capture its inherent heterogeneity and provide a holistic depiction of the immunome to identify age-related differences. Two key similarities were identified in both adult and paediatric lupus patients. First, a novel CD8⁺CD45RA⁺BAFF⁺ subset was significantly increased in SLE. Validation using fluorescence-based flow cytometry showed that this population is unique and distinct from the cytotoxic (granzyme B positive) and interferon-γ positive CD8⁺ T cells. Notably, the B cell activating factor (BAFF) can be targeted by an anti-BAFF monoclonal antibody (belimumab). Second, a novel regulatory T cell-like population (CD4⁺FoxP3⁺CTLA4⁺TIGIT⁺PD1^+/-CLA^+/-) was significantly enriched in disease.

Next, we used network analysis to analyse immune cell interactions at the systems level which showed that the adult-onset SLE immune architecture was more modular than in children, suggesting a more cohesive and organised immune response in adults. These findings indicate that although similarities exist between the adult- and childhood-onset SLE immunomes that are amenable to similar therapies, there are dissimilarities that warrant different treatment approaches.