Targeted modification of complex N-glycosylation results in a spontaneous CVID-like immunodeficiency with anti-lymphocyte autoimmunity (BA14P.204)

Abstract

Abstract Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency affecting humans. Although a clear disease etiology remains elusive, a common characteristic of CVID is deficient IgG antibody production to infection or vaccination. Many patients also exhibit symptoms of abnormal T cell function, including an apparent lack of naïve T cells which correlates with clinical severity. We describe here one of the first animal models of spontaneous CVID that incorporates aspects of both humoral and T cell dysfunction. The CVID mice exhibit characteristic deficiencies in IgG responses to both protein and polysaccharide vaccines. Interestingly, the immunodeficiency is associated with decreased T cell activity due to a persistent autoimmune response depleting naïve T cells, which appears to be mechanistically linked to changes in erythrocyte surface N-glycosylation. The N-glycosylation dependent auto-epitopes that emerge on erythrocytes were found to cross-react with naïve T cells independent of changes to the latter’s glycosylation profile. While the use of Ig replacement therapy and antibiotics has reduced the number of infections in CVID, the major inflammatory complications such as lung disease, cancer, and autoimmunity still develop; thus our findings provide potential insight into human CVID beyond hypogammaglobulinemia by addressing the mechanisms that may contribute to the more broad defects in adaptive immunity linked to clinical severity.