Abstract Background/Aims Elucidating underlying immunological and transcriptomic signatures in first-degree relatives (FDR) of SLE patients is crucial for understanding pathogenesis of disease before clinical onset. Our objectives were to characterise serological autoantibody profile, cytokine and chemokine levels, and evaluate differential gene expression in FDRs of SLE patients, focussing on identifying key genes and pathways distinguishing autoantibody-positive (ABP) from autoantibody-negative (ABN) subgroups. Methods One FDR from each SLE patient (n = 197) was analysed. Demographic and complete blood counts, ANA by IIF, serum autoantibodies to cardiolipin, B2GP1, TPO, citrullinated peptide, phosphatidylserine/prothrombin (PS/PT), glutamic acid decarboxylase (GAD), islet antigen 2 (IA2), and heat shock protein (HSP) were tested by ELISA (commercial kits). High-sensitivity C-reactive protein (hsCRP), rheumatoid factor (RF) by nephelometer, serum cytokine and chemokines were analysed using Luminex. Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and transcriptomics gene expression comparing ABP and ABN subgroups was performed. Results Mean age was 39.5 years (SD 13.1), with a predominance of females (64%). ANA was positive in 19%, and 31% were positive for at least one autoantibody (Table 1). The prevalence of other autoantibodies was generally low: anti-cardiolipin IgG (2%), anti-cardiolipin IgM (6%), anti-B2GP1 IgG (3%), anti-B2GP1 IgM (1%), anti-TPO (6%), ACPA (4%), anti-PT/SP (3%), anti-GAD (2%), anti-IA2 (2%), and anti-HSP antibodies (23% of 80 tested). RF positivity was noted in 4% (of 80 tested). Anaemia was significantly prevalent in autoantibody positive FDR, when compared to ABN groups. Cytokines and chemokines such as IL-1b, TNF-a, IL-17, MIP-1, IL-2, IL-7 and IL-5 were significantly lower in ABP group when compared to ABN group. Differential gene expression analysis between ABP and ABN groups revealed several significantly dysregulated genes. NEBL, carbonic anhydrase IV (CA4), ENTPD2, KCNV2, DIPK2B, and SMIM22 were among the upregulated genes in the ABP group, while OR7D2, SNX7, NT5DC4, CFAP97D2, SLC6A8, SLC2A14, and OTOF were downregulated. GO enrichment analysis showed that differentially expressed genes were significantly involved in G protein-coupled receptor (GPCR) signaling pathways, cAMP-mediated signaling, and cyclic-nucleotide-mediated signal transduction. Network visualization highlighted genes such as GPR78, CXCL10, and CHRM5 as central nodes within these pathways. Conclusion This study demonstrates a moderate prevalence of various autoantibody positivity in FDRs of SLE patients, with significant differences in gene expression profiles between autoantibody positive and negative individuals. Enrichment of GPCR and cAMP-related signaling pathways suggests a possible mechanistic role in autoantibody production and immune dysregulation. These findings support the integration of transcriptomic data with serological profiling for improved disease stratification and personalized therapeutic strategies in autoimmune diseases. Disclosure P. Narasimhan: None. G. Mohan: None. A. Narayanan: None. K. Ezhumalai: None. C. Kavadichanda: None. M. Thabah: None. V. Negi: None.
Narasimhan et al. (Wed,) studied this question.