Structural Immunology

National Institute Of Environmental Health Sciences

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Abstract

Myositis Many autoimmune conditions are believed to result from chronic inflammation as a consequence of the interaction of genetic and environmental factors in susceptible individuals. One common feature in some autoimmune diseases is the decrease in terminal galactosylation of the constant region N-glycan of the total plasma immunoglobulin. To determine whether a similar pattern is characteristic for the autoimmune disorder myositis, we analyzed the antibody subclass specific glycosylation in patients with myositis, their asymptomatic siblings, and healthy unrelated age- and sex-matched controls. The antibody subclass specific glycosylation was determined from the LC-MS analyses of the IgG glycopeptides generated by trypsin digestion of the antibody heavy chain. The glycosylation profiles of the IgG subclasses were determined relative to the abundance of the monogalactosylated core-fucosylated glycoform, G1F. We found elevated amounts of glycoforms lacking terminal galactose in myositis patients. Pairwise statistical analyses reveals that galactosylation is statistically different between the myositis patients and control groups. Furthermore, the trend analysis for glycosylation indicates a pattern of decreasing galactosylation in the order: controls>siblings>myositis patients, suggesting the existence of a genetic, immune-related predisposition in the group of asymptomatic siblings that can be detected before the onset of clinical symptoms at the level of plasma proteins. The IgG glycosylation pattern of one set of monozygotic twins, where one twin was asymptomatic and one twin was symptomatic, was also studied. Our IgG glycosylation data may indicate that different serologic phenotypes may be associated with discordance of monozygotic twins and that there is an environmental factor in the progression of the disease as well as genetic factors. Sjogrens Syndrome. Structural and functional studies of the autoantigens are necessary to increase our understanding of the pathogenesis of Sjogrens syndrome. Structural studies involving chemical modification and oxidative footprinting in combination with mass spectrometric analyses have been used to gain information regarding the surface accessibility of amino acids in the LaSSB antigen. As an extension of this work, the interactions of LaSSB with RNA are currently under investigation. Collectively, these data provide useful information regarding the tertiary structures of LaSSB and has been used to help generate a structural model of the full-length LaSSB.