The C1s and C1r combine with C4b to form C14b

The C1s and C1r combine with C4b to form C14b. use in acetylcholine receptor antibody-positive MG. Second- and third-generation complement inhibitors are in development and approaching pivotal efficacy evaluations. This review will summarize the history and present the state of knowledge of this new therapeutic modality. Keywords: complement, C5, myasthenia (myasthenia gravisMG), eculizumab, zilucoplan Introduction Myasthenia gravis (MG) is an autoimmune disease in which the postsynaptic membrane is usually depleted of acetylcholine receptor (AChR) causing a compromise of neuromuscular transmission (1). Antibodies directed against the AChR are the primary driver of pathology in most patients. In those patients without detectable circulating AChR antibodies, the muscle-specific kinase (MuSK) and low-density lipoprotein receptor-related protein 4 (LRP4) have been identified as pathological targets, and other neuromuscular junction proteins are under investigation (2, 3). Myasthenic autoantibodies are polyclonal with variations in subclasses, epitope targets, binding avidity, and pathogenic mechanisms (4). The characteristics of the population of autoantibodies among SERPINA3 individual patients vary and change over the course of the disease. The mechanisms of pathology are best comprehended for MuSK and AChR antibodies. The predominant subclass of MuSK autoantibodies is usually immunoglobulin G (IgG)4, which lacks the ability to activate the complement cascade and is considered to be functionally monovalent. MuSK is usually a receptor tyrosine kinase crucial for formation and maintenance of neuromuscular junction, and MuSK autoantibodies interfere with clustering of the AChR. Studies starting in the 1970s exhibited the three pathogenic mechanisms for AChR antibodies: blockade of AChR channel function, cross-linking of AChR by the divalent AChR antibody (antigenic modulation), and complement activation (5C8). Antibody binding to a variety of determinants of the multimeric AChR may result in a functional block of AChR channel function or prevent acetylcholine binding. Interestingly, most of the antibodies do not directly block the transmitter binding site on AChR. In antigenic modulation of AChR, binding of antibody and subsequent cross-linking lead to an increase in the natural degradation cycle of the receptors. The third, and likely most critical mechanism, is for AChR antibodies to activate complement with ultimate formation of GSK2801 the terminal complement component (TCC) causing damage to the muscle membrane (Physique 1) (3, 9). The role of complement activation in patients without AChR antibodies is usually poorly defined (10). Open in a separate window Physique 1 Schematic of complement cascade (see text for details). This review will provide a broad overview of the complement system, the preclinical data that support the role of complement in driving MG pathology, and application of complement inhibitors GSK2801 in the treatment GSK2801 of MG. The Complement Cascade Complement is usually part of the innate immune system and a key mediator of antibody function through the ultimate formation of the TCC, which serves to rupture bacterial and cellular membranes as well as signaling phagocytic cells to remove pathogens (11, 12). Over 30 proteins compose the complement cascade (Physique 1), which is usually activated by either antibody (classical pathway), spontaneously formed C3b (option), and binding of lectins found on bacterial cell surfaces (option). In human AChR Ab-positive MG, the classical pathway is initiated (activation step) when GSK2801 IgG1 or IgG3 (less so IgG2) autoantibodies attached to the AChR bind C1q. C1q binds the Fc domain name of the antibody, leading to the autoactivation of C1r and the subsequent activation of C1s. C1s then cleaves C4 to C4a and the larger C4b. The C1s and C1r combine with C4b to form C14b. The amplification phase occurs when C14B enzymatically converts C2 to C2a and C2b. The C14B combines C2a to form C14b2a, which is also known as C3 convertase. Spontaneous hydrolysis of C3 may also occur, and the formation C3b combining with Factor B produces C3 convertase of the alternative pathway (Physique 1). C3 convertase enzymatically cleaves C3 into C3a and C3b. C3b with the C3 convertase forms C14b2a3b, which is the C5 convertase. The C5 convertase then cleaves C5.