HLA class II genes are strongly associated with the risk of autoimmunity, but the mechanisms that link these genes to the pathogenesis of autoimmune diseases remain unclear. Invariant chain (Ii) is essential for peptide presentation by major histocompatibility complex class II (MHC-II) molecules and protects newly synthesized MHC-II molecules from aberrant protein interactions at the endoplasmic reticulum. Loss of Ii expression results in MHC-II loading with unfolded proteins in the ER. In a study in Cell, Hisashi Arase and colleagues propose that self-antigens presented in the absence of Ii drive autoreactivity in systemic lupus erythematosus (SLE).

Adult mice with induced, but not constitutive, knockout of the Ii (also known as Cd74) gene developed signs of SLE, including expansion of T follicular helper (TFH) cells, germinal centre B cells, memory B cells and plasma cells, as well as high levels of autoantibodies and a lupus nephritis-like pathology. Even a moderate decrease in Ii led to the association of MHC-II molecules with diverse types of protein, which were termed ‘neoself-antigens’, and disrupted the presentation of classical self-peptides.