Thirty-six human monoclonal immunoglobulins with antibody activity against cytoskeleton proteins, thyroglobulin, and native DNA: immunologic studies and clinical correlations

Abstract

Six hundred and twelve monoclonal Ig (MIg) were studied for their antibody activity against the following autoantigens: actin, tubulin, thyroglobulin, myosin, myoglobin, fetuin, albumin, transferrin, and double-stranded DNA (dsDNA). Of these 612 MIg, 36 (i.e., 5.75%) were shown to possess antibody activity. Thirty-two of these 36 (5.22% of the total) were mainly directed against actin. The four others were directed, respectively, against tubulin, myosin, thyroglobulin, and dsDNA. The interaction of the MIg with the respective antigen was demonstrated by immunoenzymatic methods with monospecific antisera and by blotting experiments. Furthermore, this interaction in the 12 cases studied was mediated by the dimeric fragment F(ab')2 of the MIg. The MIg with antitubulin, antithyroglobulin, and anti-dsDNA activities were exclusively inhibited by their homologous antigens. Those with antiactin activity were predominantly inhibited by actin and also by tubulin and thyroglobulin. The one binding to myosin was, for the most part, inhibited by myosin and also significantly by actin and tubulin. Retrospective clinical analysis was possible for 31/36 patients. Twenty- six of 31 had malignant lymphoplasmocytic disorders. The five others were followed for miscellaneous disorders without overt signs of multiple myeloma (MM) or Waldenstrom's macroglobulinemia (WM). The correlation between the antibody activity of the MIg and the clinical features is discussed. These results indicate that a high proportion of MIg possess antibody activity against actin (5.22%). This incidence contrasts sharply with the positive reactions found toward all the other antigens tested: only one each for dsDNA, tubulin, thyroglobulin, and myosin, and none against myoglobin, fetuin, albumin, and transferrin. The significance of these results and the relationship between MIg and natural antibodies are discussed.

High prevalence of autoimmune phenomena in hepatitis C virus antibody positive patients with lymphoproliferative and connective tissue disorders

“…In B-chronic lymphocytic leukaemia, about 20-25% of the patients develop, over the course of the disease, either autoimmune haemolytic anaemia or autoimmune thrombocytopenia that, in the vast majority of cases, are due to polyclonal autoAbs (Kipps & Carson, 1993). In 10-15% of patients with monoclonal gammopathy, autoreactive Ab activity can be detected: RF, DNA-binding properties and a whole variety of autoAbs have been described in MM and WM (Dighiero et al, 1983). Interestingly, the vast majority of these autoAbs do not cause apparent autoimmune clinical manifestations and are frequently polyclonal (Dighiero et al, 1983).…”

“…In 10-15% of patients with monoclonal gammopathy, autoreactive Ab activity can be detected: RF, DNA-binding properties and a whole variety of autoAbs have been described in MM and WM (Dighiero et al, 1983). Interestingly, the vast majority of these autoAbs do not cause apparent autoimmune clinical manifestations and are frequently polyclonal (Dighiero et al, 1983). The relationships observed in the present study suggest a specific association between HCV and the development of anti-self abnormalities and indicate that HCV plays a more important role than HBV in perturbing the immune system towards autoreactivity.…”

Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system

“…Usually this occurs with different affinities, but can involve comparable binding affinities and competition for the same portions of the combining site (31,46). Second, the same epitope can be recognized by a variety of distinct antibodies or T cell receptors (22,28,29,43,44,47,48). This is illustrated by the high degree of variability especially in the third hypervariable region of the variable domains of heavy chains binding DNA (36,49,50) or T cell receptors (43,51).…”

“…Moreover, the human pool contains NABs to regulatory molecules including cytokines and their receptors (61), markers of cell differentiation such as CD4 and CD5 (59 -61), HLA class I molecule (62), FAS (63), and coreceptors involved in binding of HIV (64). Natural antibodies of many species react with internal cellular proteins, including actin and myosin (47). Figure 1 illustrates in a Venn diagram the universe of antigens recognized by the primordial combinatorial antibody repertoire as would be generated by the stochastic system in the absence of selection.…”

Limiting dilution cloning of B cells from patients with multiple myeloma: Emergence of non‐malignant B‐cell lines

“…Studies carried out using anti-idiotypic antisera must now be reconsidered in view of a recent report demonstrating that such anti-idiotypic antibodies, which are specific for a given myeloma protein and which do not recognize polyclonal serum Ig, can also recognize a small proportion of normal B cells activated by pokeweed mitogen (Kiyotaki et al, 1987). The majority of myeloma proteins are indeed germlineencoded auto-antibodies sharing cross-reactive idiotypes with polyclonal germline-encoded auto-antibodies (Dighiero et al, 1983;Zouali et al, 1984;Davidson et al, 1987). Thus, the Idf B cells found in the PB of patients with MM may in fact be polyclonal B cells sharing cross-reactive idiotypes with the tumor cells, resulting from disturbances in idiotypic regulation.…”