Dossier: Autoimmunity and BiotherapyMultidrug resistance-1 (MDR-1) in autoimmune disorders IV. P-glycoprotein overfunction in lymphocytes from myasthenia gravis patients
Introduction
Myasthenia gravis (MG) is an acquired, neuromuscular autoimmune disorder characterized by skeletal muscle weakness and fatigue. It is generally caused by antibodies against nicotinic acetylcholine receptor (AChR) [1]. The disease is heterogeneous with respect to age at onset, thymic pathology and distribution of muscle weakness, all of which, together with its genetics, need to be kept in mind when considering treatment [2]. Most patients benefit from pyridostigmine. In nonthymomatous ocular MG, prednisone (PDN) is often effective. Thymectomy is indicated for thymoma and is an option for AChR antibody-positive patients with generalized weakness developing under the age of 45 years. Therapeutic failures are often seen among MG patients and plasma exchange, the use of cyclosporine A, metothrexate, cyclophosphamide, or intravenous immunoglobulin G administration may provide improvement of symptoms. Notwithstanding, all of these therapeutic schemes have a high risk of side effects and their cost is often considerable. In older patients or in those failing to respond to thymectomy, PDN alone or combined with azathioprine (AZA) remains the mainstay therapy [2].
Acquired unresponsiveness to corticosteroids in MG may be related to drug resistance mechanisms. Among these, one of the most extensively studied, mainly in cancer, is the so-called multidrug resistance-1 (MDR-1) which is characterized by the overfunction of a 170 kDa P-glycoprotein (P-gp) [3]. This molecule belongs to a superfamily of the ATP-binding cassette (ABC) transporters [4]. The MDR-1 phenotype involves a decreased sensitivity to several agents including vinca alkaloids, anthracyclines and glucocorticoids among others [5]. This phenomenon is the consequence of the drug extrusion by P-gp, which diminishes the intracellular drug concentration, thus reducing its therapeutic action [6]. Although the physiological role of P-gp is not yet completely understood, it has been implicated in bacterial product detoxification, and in hormone as well as metabolite secretion [4].
Little is known about the possible role of P-gp in autoimmune diseases that require therapy with drugs actively effluxed by this energy-dependent pump, e.g. PDN. The aim of this study was to explore whether P-gp function could be related to the clinical response to treatment in MG patients.
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Patients
The study included 30 MG patients, 20 women and 10 men (age range from 20 to 62 years, mean 36 years). The diagnostic was made on clinical grounds and confirmed by positive edrophonium chloride test and by a diminished electrophysiologic muscule response to repetitive supramaximal stimulation [7]. Individual features at the time of the study are shown in Table 1. Patients were classified into two groups according to their response to treatment as follows: (i) responders (those patients with no
Results
The whole group of MG patients showed higher percentages ( = 4.92 ± 5.26%, range 0.33–18.6%) of lymphocytes able to extrude DNR when compared with healthy subjects ( = 0.7 ± 0.48%, range 0.05–1.98%) (P < 0.0001). When patients were compared according to their clinical response to treatment a clear-cut difference was observed. Thus, the refractory patients exhibited increased P-gp values than the responder MG group ( = 10.18 ± 6.39% vs. = 2.66 ± 2.45%, respectively; P = 0.0076) (Fig. 1A).
Discussion
The study of drug resistance mechanisms, particularly MDR-1, is no longer circumscribed exclusively to neoplastic diseases. Recent information concerning the possible role of P-gp function in other disorders like HIV infection, epilepsy, and inflammatory bowel disease as well as in autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus and immune thrombocytopenic purpura, has opened an exciting area of research, for therapeutic failures are often seen among these
Acknowledgements
We thank Dr. Juanita Romero for her collaboration with statistical analysis. Dr. Antonio Vidaller was visiting professor. This work was supported in part by a research grant from the Fundación Miguel Alemán, A.C., Mexico City, Mexico.
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