Relation between the heavy chain complementarity region 3 characteristics and rheumatoid factor binding properties.
Among the rheumatoid factors (RFs), monospecific and polyspecific types can be distinguished. However the molecular basis responsible for their different specificity is not well understood. In a previous report, we have shown that the binding of the majority of the polyspecific antibodies is salt-sensitive. No binding to IgG was observed under high ionic strength (0.3-0.5 M NaCl). This salt-sensitivity was only observed for 18% of the monospecific RFs. Here, we have analyzed 14 RFs representing the 3 different groups (6 salt-insensitive monospecific, 4 salt-sensitive monospecific and 4 salt-sensitive polyspecific RFs). By analysis of the amino acid composition and the distribution of polar and non-polar residues of their heavy chain complementarity-determining region 3 (H-CDR3) in relation to mono/polyspecificity, salt-sensitivity and reactivity against human IgG subclasses, we have identified common structural features responsible for their different binding properties. Salt-sensitive RFs (mono as well as polyspecific antibodies) were characterized by long H-CDR3's (15.3+/-2.7) that contained large numbers of hydrophilic residues such as arginine and serine, while salt-insensitive RFs had more hydrophobic H-CDR3's of smaller length (11.3+/-2.4). In addition, for the monospecific RFs, remarkably similar hydrophilicity H-CDR3 profiles were found that were correlated with their specificity for IgG subclasses. These observations confirm the importance of the H-CDR3 for the binding of RFs to IgG. Furthermore, on the basis of their shorter H-CDR3's and their rather unique H-CDR3 hydrophilicity profiles, it is likely that the majority of the monospecific RFs should be considered as a group of RFs that is independent of the polyspecific RF repertoire.
Bas
S
S
Department of Medicine, University Hospital, Geneva, Switzerland. bas-sylvette@diogenes.hcuge.ch
Djavad
N
N
Schwager
J
J
Vischer
T
T
Roosnek
E
E
D000595:Amino Acid Sequence; D000918:Antibody Specificity; D001667:Binding, Competitive; D022801:Complementarity Determining Regions; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry* / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000276:immunology; D007137:Immunoglobulin alpha-Chains / Q000737:chemistry* / Q000276:immunology; D012217:Rheumatoid Factor / Q000737:chemistry* / Q000276:immunology*; D012965:Sodium Chloride / Q000494:pharmacology; D013329:Structure-Activity Relationship
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007137:Immunoglobulin alpha-Chains; D012965:Sodium Chloride; D012217:Rheumatoid Factor