Annexins and autoantibodies in autoimmune diseases – Insights into SLE, APS and RA: A review

Autoimmune diseases are becoming increasingly prevalent and can cause multi-organ damage through dysregulated immune responses to self-antigens. This review aims to summarize the roles of annexin family proteins and annexin autoantibodies in the mechanisms of autoimmune diseases, as well as their potential diagnostic and therapeutic applications. A targeted PubMed search conducted on August 31, 2025, utilized annexin- and disease-related terms without year restrictions, focusing on English-language, peer-reviewed studies involving humans or recognized animal models. Evidence suggests that Annexin A1 (ANXA1) and formyl peptide receptor 2 (FPR2) signaling can influence inflammatory and T-cell responses. Additionally, Annexin A2 (ANXA2) is associated with organ-targeted injury, such as lupus nephritis (LN) in systemic lupus erythematosus (SLE), through its interactions with anti-double-stranded DNA antibodies (anti-dsDNA). Annexin A5 (ANXA5) serves as an anticoagulant phospholipid "shield," which can be compromised by antiphospholipid antibodies (aPLs), contributing to thrombosis and obstetric complications in antiphospholipid syndrome (APS) and increasing vascular risk in SLE. In rheumatoid arthritis (RA), ANXA1 exhibits context-dependent effects, while ANXA2 promotes synovial proliferation, invasion, and angiogenesis. Dysregulation of annexins has also been observed in primary Sjögren's syndrome (pSS), multiple sclerosis (MS), and systemic sclerosis (SSc). Additionally, the emerging utility of anti-ANXA1, anti-ANXA2, and anti-ANXA5 autoantibodies for phenotyping and risk stratification, including in seronegative antiphospholipid syndrome (SNAPS), highlights their clinical relevance. Overall, annexins and their autoantibodies represent promising biomarkers and therapeutic targets; however, the heterogeneity of assays and the limited availability of prospective multicenter data currently hinder clinical translation.