Hormonal control of IgG galactosylation in murine arthritis

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DESCRIPTION (provided by applicant): The effector functions of human immunoglobulin G (IgG) depend on two glycans internal to the Fc portion of the antibody. Adults with rheumatoid arthritis (RA) exhibit a characteristic abnormality in these glycans: a higher proportion of antibodies employ glycoforms lacking terminal galactose. Such antibodies fix complement more efficiently and may therefore be more likely to incite tissue inflammation. However, the factors governing antibody glycosylation are not understood. In the course of studies into IgG glycans in RA patients, we have uncovered compelling evidence that hormonal milieu is a key in vivo determinant of IgG glycan structure. Here, we show that we can model key aspects of this human physiology in the murine K/BxN model of inflammatory arthritis, enabling detailed mechanistic exploration. We therefore propose two Aims. First, we will investigate the endocrine factors that induce changes in IgG glycosylation by subjecting cultured B cells and pre-arthritic K/BxN mice to hormonal manipulation and studying the resulting IgG glycoforms. Second, we will investigate the in vivo importance of hormone-driven IgG glycosylation changes to arthritis through a series of experiments in which IgG from hormonally-manipulated K/BxN mice is transferred to normal recipient animals. The role of glycans in the differences we expect to observe will be evaluated by ex vivo enzymatic manipulation of the IgG, experiments which we further anticipate to answer definitively the importance of specific glycan changes in the arthritogenicity of pathogenic antibodies. These studies will therefore contribute to the understanding of the basic biology of antibody glycosylation, shed fresh light on gender discrepancies in inflammatory arthritis, and determine whether and how IgG glycans might be manipulated for the treatment of RA and related diseases. PUBLIC HEALTH RELEVANCE: Much evidence now points to a key role for antibodies in the chain of events that leads to joint inflammation and destruction in rheumatoid arthritis (RA). We have found that changes in the structure of sugars attached to antibodies - changes observed in RA, and that tend to make antibodies more pro-inflammatory - are under hormonal control in humans. This proposal requests support to develop tools to explore this observation experimentally in a mouse model of arthritis. Our long-term goals are to understand the cause and importance of antibody sugars in RA, to learn whether sugar changes contribute to gender differences in disease incidence, and to explore the possibility that manipulation of sugars could be a new therapeutic approach to RA and related diseases.