Antigenic modulation of acetylcholine receptor (AChR), i.e., acceleration of its internalization and degradation rate by antibody-cross-linking, is considered to be one of the two main causes of AChR loss in myasthenia gravis (MG). The majority of the antibodies to AChR are directed to the main immunogenic region (MIR) on the alpha-subunit of the receptor. We here examine the relative contribution of the anti-MIR antibody fraction (as well as of another fraction) to the antigenic modulation caused by MG patients' sera. Fab fragments of an anti-MIR monoclonal antibody (mAb) or a mAb to the beta-subunit (neither of which causes antigenic modulation) were allowed to shield their corresponding regions on the AChR on the mouse muscle cell line BC3H1. The 27 MG sera subsequently added thus bound to all other regions except to the protected one, and the resulting antigenic modulation was measured. The anti-MIR mAb protected the AChR by 68 +/- 16%. This is interpreted as the contribution to antigenic modulation of the anti-MIR antibody fraction in the human sera. This percentage correlated very well with the occurrence of the anti-MIR antibodies in the same sera. The anti-beta mAb gave only small protection of the AChR. No significant pattern differences were observed between sexes, early and recent onset of the disease, or high and low antibody titers. It is concluded that as far as it concerns the one of the pathogenic mechanisms in MG, i.e., the antigenic modulation, the MIR seems to be the main pathogenic region. The observation that a single mAb can efficiently protect the AChR in this system may prove to be of therapeutic interest.