title: 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.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Sean O
authors.initials: SO
authors.lastname: Ryan
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Abbott
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106 brian.cobb@case.edu.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Cobb
mesh_terms: D000744:Anemia, Hemolytic, Autoimmune / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000235:genetics / Q000276:immunology*; D017074:Common Variable Immunodeficiency / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003429:Cross Reactions; D004912:Erythrocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D056724:Immunity, Humoral; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000276:immunology*; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D017351:N-Acetylglucosaminyltransferases; C063313:alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase