Antigen presentation to T-helper (Th) cells by MHC class II proteins is an important event in the initiation and/or maintenance of autoimmune disease. The class II proteins have a wide, degenerate specificity and are capable of binding several different peptides, including self-peptides. However, recent data suggest that a protein called invariant chain, Ii, binds to the class II molecule in the endoplasmic reticulum in such a way that precludes the binding of peptides derived from intracellular self- or non-self-proteins. The class II-Ii complex is transported through the endoplasmic reticulum to the endosomes, which contain peptides derived from extracellular proteins. The acidic pH and proteolysis in the endosomes cause dissociation of the class II-Ii complex, making the class II protein available for binding to the peptides. Thus, the Ii chain appears to play an important role in suppressing autoimmune responses. A hypothesis that a defect in the Ii chain could lead to autoimmune disorders is proposed. These defects would include alterations in the Ii chain such that it is no longer able to compete with the self-peptides for binding to the class II protein.