Tu149 - Multiparametric Comparison of the Adult-onset and Childhood-onset Systemic Lupus Erythematosus (SLE) Immunomes Reveals Multiple Derangements

Joo Guan Yeo – Translational Immunology Institute, Rheumatology and Immunology Service – SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Medical School, KK Women's and Children's Hospital; Annie Hui Nee Law – Department of Rheumatology & Immunology – Singapore General Hospital, Duke-NUS Medical School; Martin Wasser – Translational Immunology Institute – SingHealth Duke-NUS Academic Medical Centre; Thaschawee Arkachaisri – Rheumatology and Immunology Service – KK Women's and Children's Hospital, Duke-NUS Medical School; Kai Liang Teh – Rheumatology and Immunology Service – KK Women's and Children's Hospital; Yun Xin Book – KK Women's and Children's Hospital; Julian Thumboo – Department of Rheumatology & Immunology – Singapore General Hospital, Duke-NUS Medical School; Andrea Hsiu Ling Low – Department of Rheumatology & Immunology – Singapore General Hospital, Duke-NUS Medical School; Su Li Poh – Translational Immunology Institute – SingHealth Duke-NUS Academic Medical Centre; Salvatore Albani – Translational Immunology Institute, Rheumatology and Immunology Service – SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Medical School, KK Women's and Children's Hospital

Abstract Text: SLE is a complex autoimmune disease. Therapy is mainly immunosuppression, which has many side-effects. Using a holistic, multiparametric approach to understand disease mechanisms can improve theragnostics. Peripheral blood mononuclear cells(PBMCs) from 26 adult-onset SLE (timepoints:40, median age:40 years)/23 age-matched healthy subjects and 30 childhood-onset SLE (53,14 years)/17 age-matched healthy subjects underwent mass cytometry. Data was analysed using the Extended Polydimensional Immunome Characterisation(EPIC) machine learning platform. Normalization and FlowSOM clustering were performed with 43 immune markers.

Unsupervised analysis revealed significant differences (p < 0.05,Mann Whitney U) between adult-onset and childhood-onset SLE immunomes. A CD11c+Tbet+CD21- B cell subset was significantly enriched in childhood-onset SLE (median:0.42%, interquartile range 0.16-0.72% of CD45+ PBMCs) versus adult-onset SLE (0.15%;0.09-0.31%;p < 0.001). These age-associated B cells(ABCs) increase with age and autoimmune disease. This may offer insights into differences between adult-onset and childhood-onset SLE; the latter tends to have more active disease. Transitional B cells (CD24+CD38+) were also significantly increased in childhood-onset SLE (0.91%;0.41-1.84%) compared to adults (0.3%;0.043-0.65%;p < 0.001). In T cells, an activated CD4+IL21+ subset was expanded in childhood-onset SLE (0.41%;0.23-0.68%) compared to adult-onset SLE (0.19%;0.1-0.38%;p < 0.001). IL21 is key to B cell activation and therefore of mechanistic interest. Another CD8+CD45RA+BAFF+ T cell subset was enriched in adult-onset (1.95%;1.24-2.86%) versus childhood-onset SLE (0.88%;0.45-1.37%;p < 0.001). B-cell activating factor(BAFF) supports autoreactive B cell survival in autoimmune disease and an anti-BAFF drug (belimumab) is FDA-approved for SLE. However, patient response varies, so BAFF inhibition alone may not adequately alter disease activity.

Studying these mechanistically important cell subsets further may identify pathological networks to facilitate SLE theragnostic improvements.