AGALACTOSYL lgG IN AGGREGATES FROM THE RHEUMATOID JOINT

Abstract

It has been postulated that agalactosyl immunoglobulin G (IgG) self-associates to form pathological aggregates in the rheumatoid joint. To examine this hypothesis, IgG aggregates from synovial fluid (SF) of 22 patients with RA were prepared by precipitation with polyethylene glycol (PEG) 6000. The PEG precipitates and SFs were reduced with 2-mercaptoethanol (2ME) and bound to protein G. This procedure isolated the IgG in the PEG precipitates from other contaminating glycosylated proteins. The levels of galactose and N-acetylglucosamine (GlcNAc) residues present on the reduced IgG were quantified by their ability to bind the lectins Ricinus communis (RCA)120 and Bandeiraea simplicifolia (BS) II. Proportionally less galactose (expressed as a ratio of bound RCA120 to BS II) was present on the IgG from the PEG precipitates than on the IgG in the paired SF (P = 0.001). However, in many cases more RCA120 as well as BS II bound to IgG from PEG precipitates than from the corresponding SF. It is considered that agalactosyl IgG occurs preferentially in RA SF PEG precipitates and that this IgG may also exhibit increased Fab glycosylation.

Lectin-reactive Anti-α-Gal in Patients with Crohnʼs Disease

“…A number of studies have described elevated levels of agalactosyl IgGs in the synovium or joints of patients with RA when compared with osteoarthritis. 24,25 Although none of our patients had a diagnosis of RA, it seems plausible that patients with CD who have extensive tissue involvement, including joints, would be more likely to secrete IgGs with aberrant glycosylation based on the triggers noted above. Alternatively, this subgroup of patients may feature differences in the pathogenesis of their condition, reflected in different disease phenotype and agalactosyl anti-α-Gal antibody levels.…”

Glycosylation as a marker for inflammatory arthritis

“…Truncated IgG glycans result in antigenicity and cause an altered immune response of these antibodies, as has extensively been reviewed by Alavi et al and Gornik et al [53][54][55]. These IgGs can bind to and trigger the production of autoantibodies [56], bind to pathogenic rheumatoid factor (Rf) [57,58] and are prone to form immune complexes [59,60]. Hypogalactosylated IgG interacts with lectin-like molecules, such as mannosebinding protein, which activates a complement pathway leading to inflammatory response [61,62].…”

The pivotal nature of sugars in normal physiology and disease

“…This is an important paradigm, which may explain the increased levels of ICs and their atypical glycosylation status in RA [138,149]. It may also shed more light on how these ICs may induce/perpetuate the pathological processes in RA [40,86,130,143,152,153]; in particular in the synovial joint, which is the site for both increased production of hypogalactosylated IgG and RFs [141,154].…”

“…The formation of these ICs, in particular the multimeric IgG-IgG aggregates [134,138,154] can lead to the inappropriate trigger and activation of various arms of the immune response [86,92], leading to the production of inflammatory cytokines, which together with other factors, such as C` can cause damage to the joint. The damage, in turn, can itself act as a trigger and reactivate this whole cascade of self-perpetuating inflammatory reactions that are a characteristic feature of the pathology associated with a RA joint (Fig.…”