Mammalian N-Glycan Branching Protects against Innate Immune Self-Recognition and Inflammation in Autoimmune Disease Pathogenesis

• Published in: Immunity (Cambridge, Mass.) Vol. 27; no. 2; pp. 308 - 320
• Main Authors: Green, Ryan S., Stone, Erica L., Tenno, Mari, Lehtonen, Eero, Farquhar, Marilyn G., Marth, Jamey D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-08-2007; Elsevier Limited
• Subjects: alpha-Mannosidase - deficiency; alpha-Mannosidase - genetics; Animals; Autoimmune diseases; Autoimmunity - immunology; Bone marrow; CELLIMMUNO; Complement C3 - genetics; Complement C3 - metabolism; Glomerular Mesangium - cytology; Glomerular Mesangium - enzymology; Glomerular Mesangium - immunology; Immune system; Immunity, Innate; Inflammation - immunology; Kidney - growth & development; Kidney diseases; Ligands; Lupus; Lupus Erythematosus, Systemic - enzymology; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Nephritis - immunology; Mammals; Mice; Mice, Mutant Strains; MOLIMMUNO; Morphogenesis; Pathogenesis; Polysaccharides - metabolism; Receptors, Mitogen - metabolism; Rodents; Self Tolerance - genetics; Statistical methods; MOLIMMUNO; CELLIMMUNO
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2007.06.008

Autoimmune diseases are prevalent and often life-threatening syndromes, yet the pathogenic triggers and mechanisms involved remain mostly unresolved. Protein asparagine linked- (N-) glycosylation produces glycan structures that substantially differ among the extracellular compartments of evolutionarily divergent organisms. Alpha-mannosidase-II (αM-II) deficiency diminishes complex-type N-glycan branching in vertebrates and induces an autoimmune disease in mice similar to human systemic lupus erythematosus. We found that disease pathogenesis provoking glomerulonephritis and kidney failure was nonhematopoietic in origin, independent of complement C3 and the adaptive immune system, mitigated by intravenous administration of immunoglobulin-G, and linked to chronic activation of the innate immune system. N-glycans produced in αM-II deficiency bear immune-stimulatory mannose-dependent ligands for innate immune lectin receptors, disrupting the phylogenic basis of this glycomic recognition mechanism. Thus, mammalian N-glycan branching safeguards against the formation of an endogenous immunologic signal of nonself that can provoke a sterile inflammatory response in the pathogenesis of autoimmune disease.