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Digestion of human IgG by a new lysine-specific protease, isolated from the basidiomycete Armillaria mellea, produced Fc and Fab fragments similar to those produced by papain digestion of the same molecule. Digestion appeared to be restricted to a single cleavage point within the hinge region of the IgG molecule. Myeloma proteins of IgG1, IgG3 and IgG4 subclasses were found to be digested at an extremely rapid rate whereas IgG2 myeloma proteins appeared to be resistant to digestion by this enzyme.

Rabbits neonatally tolerized with native monomeric human IgG and subsequently immunized with heat-aggregated human IgG emulsified in Freund's complete adjuvant, at a time when B cells but not T cells should have spontaneously recovered from tolerization, resulted in the production of an antibody resembling human rheumatoid factors directed against a single antigenic determinant in the Fc region of the IgG molecule. Rabbits immunized in an identical fashion after adult tolerization treatments failed to respond during the period corresponding to B-cell tolerance, but subsequently produced antibody or similar specificity to that produced by neonatally tolerized animals. These results indicate that no completely new antigenic determinants are created on heat aggregation of IgG, but there appears to be some potentiation of immunodominance of an already existing determinant. A possible mechanism for the production of rheumatoid factors in rheumatoid arthritis is suggested.

Joint lesions, closely resembling the main features of those seen in rheumatoid patients, were produced by intra-articular injections of asialylated homologous IgG into presensitized rabbits. The inflammatory changes were characterized by areas of extremely dense chronic inflammatory cell infiltration, where the lymphocytes were often aggregated into lymphoid follicles. There were also signs of involvement of the contralateral, saline-injected knee. Formation of an experimental rheumatoid factor-like antibody, detected by its ability to agglutinate sheep erythrocytes sensitized with baboon IgG, was also demonstrated. In addition, the rabbits developed other manifestations associated with rheumatoid arthritis, namely increases in erythrocyte sedimentation rate, serum haptoglobin concentration and joint size.

In order to characterize the precise structure within human and rabbit IgG molecules against which 'general' rheumatoid factors are directed, an immunochemical comparison has been made of the effects of the selective substitution of specific amino acid side-chains on various types of antigenicity exhibited by human and rabbit IgG. The epsilon-amino groups of lysine residues have been substituted by citraconylation and carbamylation; whilst tyrosine residues have been substituted by nitration with tetranitromethane. In this manner, evidence has been obtained which indicates that the autoantigenic determinants of human IgG are structurally distinct from species-specific ones and from certain Fc-located allotypic markers (Gm(a) and Gm(x)). It is also concluded that lysine residues are probably not involved in the site of IgG reactivity with 'general' rheumatoid factors, in contrast to tyrosine residues which appear to be implicated in the activity of human but not rabbit IgG.