Genetic remodeling of protein glycosylation in vivo induces autoimmune disease

Abstract

Autoimmune diseases are among the most prevalent of afflictions, yet the genetic factors responsible are largely undefined. Protein glycosylation in the Golgi apparatus produces structural variation at the cell surface and contributes to immune self-recognition. Altered protein glycosylation and antibodies that recognize endogenous glycans have been associated with various autoimmune syndromes, with the possibility that such abnormalities may reflect genetic defects in glycan formation. We show that mutation of a single gene, encoding ␣-mannosidase II, which regulates the hybrid to complex branching pattern of extracellular asparagine (N)-linked oligosaccharide chains (N-glycans), results in a systemic autoimmune disease similar to human systemic lupus erythematosus. ␣-Mannosidase IIdeficient autoimmune disease is due to an incomplete overlap of two conjoined pathways in complex-type N-glycan production. Lymphocyte development, abundance, and activation parameters are normal; however, serum immunoglobulins are increased and kidney function progressively falters as a disorder consistent with lupus nephritis develops. Autoantibody reactivity and circulating immune complexes are induced, and anti-nuclear antibodies exhibit reactivity toward histone, Sm antigen, and DNA. These findings reveal a genetic cause of autoimmune disease provoked by a defect in the pathway of protein N-glycosylation.autoimmunity ͉ genetics ͉ lupus ͉ glomerulonephritis

Altered lipid raft–associated proximal signaling and translocation of CD45 tyrosine phosphatase in B lymphocytes from patients with systemic lupus erythematosus

“…In support of this proposition are findings of hyposialated CD45RA in B cell lymphomas and activated human cells (42). Interestingly, a recent study has shown that a mutation in the gene encoding ␣-mannosidase II, an enzyme involved in the branching of asparagine N-linked oligosaccharide chains (N-glycans), resulted in lupus-like disease in mice (43).…”

Respiratory Distress and Neonatal Lethality in Mice Lacking Golgi α1,2-Mannosidase IB Involved in N-Glycan Maturation

“…Inactivation of ␣-mannosidase II (22,23,25), and ␣-mannosidase IIx (24,25) individually reduces overall complex N-glycan synthesis significantly, but the mice are viable, albeit with different consequences, causing anemia or male infertility, respectively. However, ablation of both genes completely abrogates complex N-glycan formation with the accumulation of hybrid structures (25,38).…”

“…Furthermore, the unique cell-and tissuespecific roles of individual members of multigene enzyme families have also been revealed by these studies. For example, ␣-mannosidase II-deficient mice develop dyserythropoietic anemia and autoimmune disease (22,23), yet disruption of the mouse ␣-mannosidase IIx gene results in hypospermatogenesis and male infertility (24). However, ablation of both ␣-mannosidase II and IIx completely abrogates complex N-glycan biosynthesis with the accumulation of hybrid structures, and causes hepatic and pulmonary ultrastructural defects.…”

Conformation and Glycosylation of a Megalin Fragment Correlate with Nephritogenicity in Heymann Nephritis

“…Con A reactivity of nM60s, indicative of high mannose, reproduces a feature of the native glycoprotein (35) that has been exploited in affinity purification (5) and for characterization of megalin in rat kidney (30). Various post-translational modifications, and glycosylation in particular, can introduce or mask immunoreactive determinants that can be associated with pathogenic autoimmune responses (36,37). The specific attribution of such a determinant to this model of pathogenic autoimmunity could lead to additional insight into the mechanism of disease progression.…”