Saturday September 22, 2012 16:00 - 16:30 @ Rhodes 6

Glycosylation Changes in Autoimmune Diseases

Abstract:

In many autoimmune diseases, including rheumatoid arthritis (RA), antibodies against self-antigens are believed to be the causative agent that drives disease pathogenesis. Antibodies are glycoproteins, with glycans attached to both constant and variable regions of the molecule. These glycans strongly influence the in-vitro and in-vivo biological characteristics of an antibody, such as serum half-life, binding to Fc-receptors and complement components, to lectins and to the specific antigen.

In RA, early work has demonstrated aberrant glycosylation of the Fc-tail of serum IgG, which mainly lacks galactose and sialic acid residues as compared to IgG in healthy individuals. This hypogalactosylation associates with disease activity. Work by us and others has demonstrated that not only the pool of serum IgG, but especially the pathogenetically relevant subset of autoantibodies against citrullinated protein antigens (ACPA) exhibits a specific, pro-inflammatory glycan profile. This feature is most prominent in synovial fluid, i.e. the site of inflammation and joint destruction, and was not found on non-specific IgG isolated from the same compartment. This finding is of particular interest as ACPA are highly specific for RA and associate with severe and active disease. Moreover, ACPA are also detectable in individuals prior to disease onset and predict disease development. In this context, it is intriguing that preliminary data indicate an increase in Fc hypogalactosylation several months before the onset of arthritis.

Our observations suggest that autoreactive B cells in RA produce antibodies with distinct glycan profiles, which modulates their pathogenicity. This specific glycan profile could develop under the influence of inflammatory mediators, as specific molecules such as IL-21 and CpG were found to increase IgG Fc-galactosylation in-vitro, while others, such as all-trans retinoic acid, decreased Fc-sialylation and galactosylation. In addition, more upstream defects in the B-cell glycosylation machinery of autoreactive B cells could also be involved.

Elucidating factors that determine antibody glycosylation and, thus, the biological properties of (auto-) antibodies is of crucial importance for understanding antibody-mediated disease processes and for the development of novel therapeutic interventions.