Myeloid glycosylation defects lead to a spontaneous common variable immunodeficiency-like condition with associated hemolytic anemia and antilymphocyte autoimmunity.

Abstract

Common variable immunodeficiency (CVID), the most frequent symptomatic primary immune deficiency in humans, is a heterogeneous group of immunologic disorders estimated to affect 1:10,000-1:50,000. Although a clear disease etiology remains elusive, a common characteristic of CVID is deficient IgG Ab production in response to infection or vaccination. Patients often also exhibit autoimmune cytopenias with symptoms of abnormal T cell function, including reductions in naive T cells, which correlate with clinical severity. In this study, we discovered that targeted alterations in the glycome of the myeloid lineage lead to spontaneous immunodeficiency characteristic of both humoral and T cell dysfunction regularly found in human CVID. Mice carrying a myeloid-specific knockout of the Mgat2 gene encoding UDP-GlcNAc:α-6-d-mannoside β-1,2-N-acetylglucosaminyltransferase II enzyme exhibit deficiencies in IgG responses to both protein and polysaccharide conjugate vaccines. Interestingly, the immunodeficiency is associated with decreased T cell activity because of a persistent autoimmune-mediated depletion of naive T cells, which is induced by changes in erythrocyte surface glycosylation. The N-glycosylation dependent autoepitopes that emerge on erythrocytes lead to autoimmune hemolytic anemia, and the causative auto-IgM cross-reacts with naive T cells despite the lack of glycan change on T cells. These findings demonstrate that alterations in erythrocyte glycosylation trigger the development of autoantibodies directed at both erythrocytes and naive T cells, revealing a possible mechanistic link between the induction of autoimmune hemolytic anemia, the reduction in naive T cells, and poor Ab responses to vaccine in severe CVID patients.

• Authors: Sean O Ryan, Derek W Abbott, Brian A Cobb
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 12 Pg. 5561-70 (Jun 15 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24795453 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Autoantibodies
• Immunoglobulin G
• Immunoglobulin M
• N-Acetylglucosaminyltransferases
• alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase

Topics

• Anemia, Hemolytic, Autoimmune (enzymology, genetics, immunology, pathology)
• Animals
• Autoantibodies (blood, genetics, immunology)
• Common Variable Immunodeficiency (enzymology, genetics, immunology, pathology)
• Cross Reactions
• Erythrocytes (enzymology, immunology, pathology)
• Glycosylation
• Humans
• Immunity, Humoral
• Immunoglobulin G (genetics, immunology)
• Immunoglobulin M (genetics, immunology)
• Mice
• Mice, Knockout
• Myeloid Cells (enzymology, immunology, pathology)
• N-Acetylglucosaminyltransferases (genetics, immunology)
• Organ Specificity (genetics, immunology)
• T-Lymphocytes (immunology, metabolism, pathology)