Genetic remodeling of protein glycosylation in vivo induces autoimmune disease

Autoimmune diseases are among the most prevalent of afflictions, yet the ge netic factors responsible are largely undefined. Protein glycosylation in t he Golgi apparatus produces structural variation at the cell surface and co ntributes to immune self-recognition. Altered protein glycosylation and ant ibodies that recognize endogenous glycans have been associated with various autoimmune syndromes, with the possibility that such abnormalities may ref lect genetic defects in glycan formation. We show that mutation of a single gene, encoding a-mannosidase II, which regulates the hybrid to complex bra nching pattern of extracellular asparagine (N)-linked oligosaccharide chain s (N-glycans), results in a systemic autoimmune disease similar to human sy stemic lupus erythematosus, cu-Mannosidase II-deficient autoimmune disease is due to an incomplete overlap of two conjoined pathways in complex-type N -glycan production. Lymphocyte development, abundance, and activation param eters are normal; however, serum immunoglobulins are increased and kidney f unction progressively falters as a disorder consistent with lupus nephritis develops. Autoantibody reactivity and circulating immune complexes are ind uced, and anti-nuclear antibodies exhibit reactivity toward histone, Sm ant igen, and DNA. These findings reveal a genetic cause of autoimmune disease provoked by a defect in the pathway of protein N-glycosylation.