Human IgG rheumatoid factors and RF-like immune complexes induce IgG1 rheumatoid factor production in mice

The synovial fluid of patients with rheumatoid arthritis (RA) was found to contain IgG and/or IgG-containing immune complexes (ICs) that stimulated an intense antibody formation when injected into mice of certain strains, notably of NZ background. The response was characterized by high and sustained levels of IgG1 antibodies with rheumatoid factor (RF) activity. In the study described, we investigated whether it is the antibodies with RF activity in the synovial fluid, that are responsible for stimulation of mouse RF in vivo. Different mouse strains were injected with synovial fluid from a seropositive RA patient (RA-SF), with human monoclonal antibodies with RF activity, with a human non-RF monoclonal antibody or with different preformed RF-like antibody-antibody (Ab-Ab) ICs. The experimental mice were monitored subsequently for IgG1 RF production. IgG1 RF antibodies were found in all strains (NZB, BALB/c and CBA) injected with Ab-Ab ICs formed at equivalence, but only in NZB using RA-SF or human monoclonal antibodies with RF activity. Optimal production of IgG1 RF by Ab-Ab ICs required the integrity of Fc and F(ab)'2 portions respectively of the antibodies; soluble and truncated ICs were less effective. Further studies demonstrated that the IgG1 RF response was not simply the result of a specific immune response against human IgG, since humoral immunity against human IgG was induced only when combined with an efficient adjuvant. During a typical adjuvant-associated primary response specific antibodies of IgM, IgG1 and IgG2a isotypes were found, i.e. quite different from the selective IgG1 response induced by RF-like containing immune complexes. This conclusion is substantiated further by the clear differences in responses to IgG containing fraction obtained from RA-SF in NZ mice compared to other strains. Our findings argue for a different type of reaction leading to the selective IgG1 response and might aid in elucidating the mechanisms for chronic production of antibodies with RF activity in patients with RA.