Antibodies binding 3H-reovirus RNA in systemic lupus erythematosus.
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Biomedical subjects
Publications and source records attributed to N Talal.
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Thymocytes from NZB and DBA/2 mice were injected into lethally irradiated C57 B1/6 recipients. DNA synthesis in spleen and lymph node was measured as the incorporation of radioactive 5-iodo-2-deoxyuridine. The generation of cytotoxic effector cells was also studied in an in vitro cytotoxicity assay, with EL-4 lymphoma target cells. The kinetics of DNA synthesis were similar for 2- and 8-week-old DBA/2 donors and for 2-week-old NZB donors with a peak on day 4. Thymocytes from 8-week-old and 9-month-old NZB donors showed a delayed onset of DNA synthesis which was still increasing on day 6. When NZB donor thymocytes from 2- and 8-week-old mice were mixed together before injections, as few as 25% of 8-week-old cells gave a DNA synthetic response characteristic of this aged population. These results suggest an abnormal thymocyte development in NZB mice which may relate to the subsequent emergence of autoimmune disease.
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Hypogammaglobulinemia due to a new pathophysiological mechanism was studied in a patient with Sjögren's syndrome, a monoclonal IgM and a mixed (IgM-IgG) cryoglobulinemia. The IgM (IgMdk) component of the cryogel possessed light chains of lambda-type with highly restricted electrophoretic mobility analagous to those of a Waldenström's macroglobulin. IgMdk reacted specifically with native IgG, with IgG subclasses 1, 2, and 4, and with the Fc piece of IgG to form a cryogel. Serum concentrations of IgG 1, 2, and 4 were 10% of normal, whereas the IgG3 level was slightly increased and the IgM level was markedly increased. Viscosity and analytical ultracentrifugation studies with the purified mixed cryogel (IgM-LgG) indicated soluble complex formation over a temperature range (36-38 degrees C) attainable in vivo. Immunoglobulin turnover studies revealed a markedly elevated rate of IgM synthesis with a normal survival of IgM, IgA, and IgE. IgG3, which failed to form complexes with IgMdk at body temperature, had a normal synthetic rate and survival. In contrast, the other IgG subclasses showed reduced synthesis and shortened survival. These studies are the first indicating a short survival of some IgG subclasses with a normal survival of another. The hypogammaglobulinemia appears to be due in part to a new mechanism of accelerated protein catabolism: The rapid elimination of IgG due to its interaction with an IgG-reactive monoclonal IgM.
The specificities of anti-RNA antibodies of diverse origin were studied by inhibition of the binding of radioative polyinosinic polycytidylic acid. The antibodies were from human patients with systemic lupus erythematosus (SLE), older NZB/NZW F(1) mice who have SLE, and young NZB/NZW F(1) mice immunized with either synthetic or viral double-stranded (ds) RNA. The inhibitors were two viral ds and two synthetic ds RNAs, ribosomal RNA and transfer RNA. The human sera were more heterogeneous than the mouse lupus sera, and had greatest specificity for reovirus RNA. The mouse lupus sera were more homogeneous and, in general, were inhibited efficiently by all four ds RNAs. Sera from mice immunized with synthetic RNA reacted poorly with viral RNA, whereas sera from mice immunized with viral RNA reacted with all four ds RNAs and resembled the lupus sera. These results suggest a role for viruses in the induction of anti-RNA antibodies, and are compatible with the concept that virus infection as well as excessive antibody responses are involved in the pathogenesis of SLE.
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