The Binding of Synovial Tissue‐Derived Human Monoclonal Immunoglobulin M Rheumatoid Factor to Immunoglobulin G Preparations of Differing Galactose Content

Abstract

There are several sites on IgG Fc that have been reported to be the epitopes for binding rheumatoid factors (RF). It is now established that there are alterations in the oligosaccharides on IgG from patients with rheumatoid arthritis and it has been suggested that these changes may enhance immune complex and cryoglobulin formation. We have used a series of IgG preparations differing in their content of oligosaccharide chains lacking galactose from 18 to 86% to determine whether changes in sugar content affect the binding of rheumatoid factor. Five of 16 monoclonal rheumatoid factors prepared from synovial tissue, from patients with juvenile or adult rheumatoid arthritis, bound better to IgG which was deficient in galactose. Six of the 16 rheumatoid factors from the same patients bound independently of the galactose content. Four of the 16 rheumatoid factors could not be absolutely grouped in this manner but seemed to demonstrate a preference for agalactosyl IgG. One rheumatoid factor bound better to fully galactosylated IgG. There was an association between enhanced binding to galactose-deficient IgG and monoreactivity and a very strong association between the functional affinity of the rheumatoid factors and the dependent binding.

Comparison of Antigenic Regions Identified on IgG1Fc Using Bioinformatics vs Pepscan Analysis

“…Three antibodies exhibited specifi city to a single domain: both RFAbs TS2 and TS1 to a region in the CH3 domain, epitope (iii) 360-KNQVSLTCLVKGFYP-374 and RFAb SJ1 to a region in the CH2 domain, epitope (ii) 294-EQYNSTYRVVSVLTV-308. Overall, this data was consistent with the monospecifi city of the rheumatoid factors [12]. Interestingly epitope (iii) was adjacent to amino acids previously cited RF antigenic sites but novel in terms of its position (Fig.…”

“…Details of the characterisation and purifi cation of these antibodies TS2, TS1, SJ1, PRSJ2 and PRTS1 has previously been reported [12]. In particular RFAbs TS2, TS1 and SJ1 were monospecifi c with regard to their reactivity against native IgG, whilst RFAbs PRSJ2 and PRTS1 were polyspecifi c.…”

Sugar printing rheumatic diseases: A potential method for disease differentiation using immunoglobulin G oligosaccharides

“…It has also been shown that, in vitro, terminal GlcNAc on IgG is accessible for binding with mannosebinding protein and this, in turn, results in activation of complement (17). In addition, rheumatoid factors may selectively bind IgG that is hypogalactosylated (18), which may explain why immune complexes are abundant in RA. There may be factors other than disease that influence the oligosaccharide composition of IgG, since a greater degree of hypogalactosylation occurs at the extremes of life in healthy individuals (19).…”

IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

“…IgG1, the dominant ACPA isotype, is recognized by all of the so far described RA-derived RF (29). Moreover, RF seem to exhibit enhanced avidity toward agalactosylated forms of IgG (30), which are elevated in RA patients with high disease activity (31). In RA patients, it was reported that ACPA IgG1 tended to be more agalactosylated compared with total serum IgG1, and that, in the joints, ACPA IgG1 was more heavily agalactosylated than in the general circulation (32).…”