Primary Sjögrenʹs syndrome and deficiency of ICA69

Background Sjögrenʹs syndrome is a common (about 1% of the population) autoimmune disease of salivary and lacrimal glands. Its cause and pathogenesis are poorly understood, and treatments are mostly for symptoms of the disease. ICA69 is a self-antigen expressed in brain, pancreas, salivary, and lacrimal glands. NOD-strain mice are an animal model of spontaneous Sjögrenʹs syndrome. We aimed to assess the role of ICA69 in autoimmunity against Sjögrenʹs syndrome. Methods We inactivated the genomic ICA69 locus, generated NOD congenic mice that were deficient in ICA69, and assessed development of Sjögrenʹs syndrome. ICA69 autoimmunity was investigated in controls and in patients with primary Sjögrenʹs syndrome or systemic lupus erythematosus, and in various NOD mice, some of which were given an ICA69-directed prototype peptide vaccine. Findings Disruption of the ICA69 locus prevented lacrimal gland disease and greatly reduced salivary gland disease in NOD mice. In healthy NOD mice, ICA69-specific T cells accumulated in lymph nodes that drain salivary tissue. T-cell and B-cell autoreactivity against ICA69 was much the same in patients with primary Sjögrenʹs syndrome, but not in those with systemic lupus erythematosus or in healthy controls. Immunotherapy with a high-affinity mimicry peptide targeting ICA69-specific T-cells reduced established Sjögrenʹs syndrome in wild-type NOD mice in the long term. Interpretation ICA69 is a new autoantigen in primary Sjögrenʹs syndrome that has an important role in progression of disease and could be of diagnostic value. Immunotherapy of primary Sjögrenʹs syndrome is promising, since autoimmunity in NOD mice with Sjögrenʹs syndrome seems to be uniquely susceptible to such treatment even late in disease.