Roberts, Andrew James; (1990) Idiotypic antibodies in myasthenia gravis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Myasthenia gravis is an autoimmune disease characterised by autoantibodies against acetylcholine receptor (AChR). The idiotypic properties of ten monoclonal anti-human AChR antibodies (mabs) have been investigated using anti-idiotypic antibodies. Using F(ab')2 fragents of each mab to inhibit the binding of intact mab to AChR, five partially overlapping binding regions of human AChR were defined. Polyclonal anti-idiotypic sera were raised in syngeneic mice against the anti-human AChR mabs. A total of 47 mice were immunised, of which 27 had anti-idiotypic antibodies against antigen binding site idiotopes, and four against non-antigen binding site idiotopes. Using the anti-idiotypic sera to inhibit the binding of heterologous mab to AChR, both private and cross-reactive idiotypes were detected within the antigen binding site. Three sets of anti-idiotypic sera inhibited the binding to AChR of just the immunising mab. Cross-reactive idiotypes were found in three pairs of mabs, but were always restricted to mabs that bound to the same region of AChR. A cross-reactive idiotype was found outside the antigen binding site, but again this was only shared by two mabs having the same specificity for AChR. No inhibition by the polyclonal anti-idiotypic sera of the binding of myasthenic antibodies to AChR was found. Seven IgM monoclonal anti-idiotypes against three different anti-human AChR mabs were produced by fusing the splenocytes of mice immunised with mab by direct intrasplenic injection. Anti-idiotypic activity was measured by direct binding to anti-human AChR mabs in an ELISA. The cross-reactive idiotypes detected by five of the seven monoclonal anti-idiotypes were less restricted than those found with the polyclonal anti-idiotypic sera. The specificity of the anti-idiotypes was confirmed by inhibition of binding by soluble idiotype. None of the seven monoclonal anti-idiotypes inhibited the binding of mab to AChR, but the small amount of binding to mab-AChR complexes sugggested that they were directed against idiotopes outside the antigen binding site of the anti-human AChR mabs.

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