Synovial Fluid from Rheumatoid Arthritis Patients Induces Polyclonal Antibody Formation in Vivo

Abstract

Our previous studies demonstrated the presence of a T-cell replacing factor in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) and that RA-SF can activate, selectively, the induction of IgG2b antibody secreting cells in lipopolysaccharide (LPS)-pretreated mouse spleen cell cultures. In the present study the effect of RA-SF was tested in vivo in mice. Injection of the polyclonal activator LPS induced the production of IgM and IgG3 secreting cells in normal mice. However, the addition of RA-SF led to a selective increase in the production of IgG2b with a peak response on day 5 and IgG1 plaque-forming cells (PFC) with a peak on day 7. Neither the IgG2b nor IgG1 responses were caused by specific immunity against heterologous proteins present in RA-SF, as injection of in vitro inactive RA-SF samples did not induce PFC. The effect on B cells of RA-SF was further evaluated by injection of RA-SF in combination with LPS to the Xid B-cell deficient CBA/N mice. RA-SF had identical effects in CBA/N as in normal mice. The biological implication of these findings is discussed. Our earlier results support the idea that B cells are endogenously activated in RA patients. We have speculated that this activation is caused by the B-cell differentiation factor which is present in SF. Therefore, we also tested whether RA-SF could influence antibody-forming cells in mice that spontaneously develop autoimmunity. We found that injection of RA-SF alone, in the absence of any other activating substance, induced a very marked increase of IgG producing cells in (NZW x NZB) F1 hybrid mice. From a relatively high background level the RA-SF could still induce an up to 100-fold increase in the numbers of PFC in spleens of such mice.

Human IgG Rheumatoid Factors and RF‐Like Immune Complexes Induce IgGl Rheumatoid Factor Production in Mice

“…In our earlier studies [7,8], we have shown that injection of whole synovial fluid from patients with seropositive RA induces IgGl antibody formation with RF activity in NZ mouse strains (NZB, NZW and (NZB x NZW)F1). but not in mice of MRL/lpr/lpr strain or in normal healthy CBA mice.…”

Synovial Fluid Cytokines in Patients with Rheumatoid Arthritus or Other Arthritic Lesions

“…Several cytokines, such as interleukin (IL)-1, IL-6, IL-8, IL-10, IL-15, transforming growth factor-b (TGF)-b, tumour necrosis factor-a (TNF)-a, granulocyte-macrophage-colony stimulating factor (GM-CSF) and IgG2b-inducing factor (IgG2bIF) have been found in RA-SF [5][6][7][8][9][10][11][12][13]. IgG2bIF has been shown to selectively induce antibody production of the IgG2b subclass in lipopolysaccharide (LPS)-activated mouse B cells in vitro [13] and in vivo [14]. It is a heparin-binding protein, sensitive to heat and extreme pH values.…”

Relationship between IgG2b‐inducing activity in rheumatoid arthritis synovial fluid and other well‐known cytokines and inflammatory mediators

“…The patients were being treated with nonsteroidal antiinflammatory drugs; one also took chloroquine, and another also took sulfasalazine. Samples were handled as previously described (2). Samples of SF were pooled (3-5 per pool) to a volume of 3bSO ml.…”

“…This RA SF activity is also a B cell-differentiation factor, which selectively induces IgG2b antibody production by mouse spleen cells in the presence of lipopolysaccharide (LPS) in vitro and in vivo (1,2). Our recent studies have shown that RA SF can also partly reconstitute the B cell defect in inflammation and cartilage destruction, are present in RA SF (7,8).…”

“…The synovial fluid (SF) of patients with rheumatoid arthritis (RA) contains a T cell-replacing helper factor (1). This RA SF activity is also a B cell-differentiation factor, which selectively induces IgG2b antibody production by mouse spleen cells in the presence of lipopolysaccharide (LPS) in vitro and in vivo (1,2). Our recent studies have shown that RA SF can also partly reconstitute the B cell defect in CBA/N mice that have X-linked B cell immunodeficiency in vitro and in vivo (2.3).…”