The erosion of seronegative autoimmune diseases through the lens of autoantibodies.

Abstract

Autoantibodies are central to the diagnosis, classification, and stratification of many autoimmune diseases, particularly those characterised by B-cell activation and MHC class II associations. However, a substantial proportion of patients have historically been labelled as seronegative, creating diagnostic uncertainty and suggesting either technical limitations in autoantibody detection or genuinely distinct pathogenic mechanisms. Advances in laboratory assays, encompassing the adoption of recombinant antigens, high-throughput autoantibody profiling, and autoantigen discovery, have progressively reduced the boundaries of seronegativity across several autoimmune diseases. In this Personal View, we discuss how improved autoantibody detection and the identification of novel specificities have reshaped concepts of seronegative disease across different clinically relevant examples of autoimmune diseases. We further examine how autoantibodies inform patient stratification, influence cancer-associated autoimmunity, and even reverse translational immunology implications and pathogenic hints, while highlighting contexts in which genuinely seronegative autoimmunity might still exist.