Bodman, Katherine Birgitta; (1995) IgG glycoforms in arthritis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Serum IgG Fc has been shown to contain two conserved N-glycosylation sites, on which mannose rich, bi-antennary oligosaccharide chains are found. These oligosaccharide chains are postulated to conserve the three-dimensional structure of the IgG molecule and usually terminate in galactose. A decrease in terminal galactose (resulting in exposure of N-acetylglucoseamine (GlcNAc)) was described in rheumatoid arthritis (RA) patients and as a function of age m the healthy control population. This thesis develops two rapid methodologies for the determination of the amount of terminal galactose in serum, synovial fluid and supernatant IgG molecules. These methodologies were then used to examine this glycoform in RA patients and murine models of arthritis. The age-related decrease of IgG galactose in human control populations was reestablished and age-related changes in a variety of autoimmune prone and non-prone strains of mice were revealed. Agalactosyl IgG was shown to have a predictive value in RA patients presenting with early synovitis and as a longitudinal marker of the disease where it could be used to predict disease outcome. The involvement of this glycoform in complex formation was analysed along with its relationship between the serum, synovial fluid and levels of interleukin 6. Spontaneous (MRL lpr/lpr mice) and collagen induced (DBA/1 mice) models of arthritis were shown to have decreased levels of terminal galactose on their serum IgG molecules. The defect was shown to occur as a pre-secretory event in human peripheral blood and synovial fluid mononuclear cells and increased spontaneous production was seen in MRL lpr/lpr spleen and peripheral blood cell suspensions when compared to the same compartments in the control strain of mice (CBA/Ca). Using human T- and B-cell enriched populations and IgG secreting cell lines, T-cells and the cytokine interleukin 6 were shown to affect the regulation of IgG glycosylation. Sera from mice treated with a non-depleting anti-CD4 antibody were also investigated in order to provide further clues relating to T-cell regulation of this phenomenon. Finally a putative link between mycobacterial infection and decreased serum galactose was observed using Freund's complete adjuvant in arthritis prone and non-prone strains of mice and by looking at healthy spouses and relatives of RA patients in humans.

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