Restricted heterogeneity of polyclonal rheumatoid factors

Abstract

The electrophoretic pattern of rheumatoid factor (RF) was investigated in 40 polyclonal sera, by using radiolabeled IgG. Thirty sera specifically bound IgG aggregates, correlating with their RF titer. The binding pattern was monoclonal or oligoclonal. The molecules responsible were classic RF antibodies, as shown by using purified IgM, inhibition experiments, and by the optimal size of aggregates (2,0004,000 kd). These data show that RF heterogeneity is restricted in polyclonal sera, and this can have a bearing on several mechanisms,, Since Waaler described the rheumatoid factor (RF) in sera of patients with rheumatoid arthritis (RA) (l), 2 types of RF have been delineated according to their molecular heterogeneity. Monoclonal RF, observed in lymphoproliferative disorders (2), are very abundant in serum and often provoke the cryoglobulin phenomenon by spontaneous combination with autologous IgG (mixed cryoglobulins) (3). Polyclonal RF, observed in patients with RA and in some inflammatory diseases, are usually less abundant in the serum and sometimes provoke the cryoglobulin phenomenon (polyclonal cryoglobulins) (3). Most of our knowledge of RF emerged from the findings of studies on the first type and was confirmed in studies of the second. Hence, specific idiotypes, shared by RF from different patients, were first evidenced on monoclonal molecules (4) and, thereafter, were observed in polyclonal sera (5). Further studies of the major cross-idiotypes showed that the majority of monoclonal RF L-chains shared closely related hypervariable regions and framework structures (6,7). This limited RF L-chain repertoire suggests a restricted heterogeneity for polyclonal RF, similar to that of experimental homogeneous antibodies (8). An isoelectric focusing analysis of purified inflammatory RF seemed to confirm this hypothesis because it showed that IgG-binding molecules were less heterogeneous than normal human immunoglobulins (9), but that study did not investigate the specificity of the binding.We recently described a method for native blot transfer after electrophoresis on cellulose acetate, which visualizes antibodies as they specifically bind radiolabeled antigens (10). This method easily delineates monoclonal from polyclonal antibodies, and discriminates high-affinity from low-affinity molecules.We present here the results obtained with the application of this method using RF-positive sera of patients with inflammatory diseases. We analyzed the electrophoretic pattern of IgG binding proteins and

TLR9 Promotes Tolerance by Restricting Survival of Anergic Anti-DNA B Cells, Yet Is Also Required for Their Activation

“…Alternatively or in addition, further extrinsic signals could alter the outcome of TLR9 signaling in anti-DNA B cells, including T cell-derived signals (41). In any case, the idea of rare activation of otherwise tolerized or clonally ignorant cells is consistent with the oligoclonal nature of the autoantibody response in lupus-prone mice (42) or in people (43). …”

A somatically mutated VκIV gene encoding a human rheumatoid factor light chain

“…In a mouse model of RA, the MRL/lpr mouse, oligoclonal expansion of somatically mutated RFs analogous to a secondary antigen-driven response was demonstrated [1]. Biochemical studies on immunoglobulins in synovial fluid and serum already indicate a quantitative predominance of certain clones [33,34].…”

Nachweis von systemischem und lokal synthetisiertem oligoklonalem IgM mittels isoelektrischer Fokussierung

“…bei Zustand nach Knochenmarktransplantation [9]). Interessanterweise wurde eine oligoklonale Restriktion auch bei IgM-Molekülen mit Rheumafaktor-Aktivität gefunden [10].…”