ABSTRACT
The postsynaptic muscle-specific kinase (MuSK) coordinates formation of the neuromuscular junction (NMJ) during embryonic development. Here we have studied the effects of MuSK autoantibodies upon the NMJ in adult mice. Daily injections of IgG from four MuSK autoantibody-positive myasthenia gravis patients (MuSK IgG; 45 mg day(1)i.p. for 14 days) caused reductions in postsynaptic ACh receptor (AChR) packing as assessed by fluorescence resonance energy transfer (FRET). IgG from the patients with the highest titres of MuSK autoantibodies caused large (51-73%) reductions in postsynaptic MuSK staining (cf. control mice; P < 0.01) and muscle weakness. Among mice injected for 14 days with control and MuSK patient IgGs, the residual level of MuSK correlated with the degree of impairment of postsynaptic AChR packing. However, the loss of postsynaptic MuSK preceded this impairment of postsynaptic AChR. When added to cultured C2 muscle cells the MuSK autoantibodies caused tyrosine phosphorylation of MuSK and the AChR beta-subunit, and internalization of MuSK from the plasma membrane. The results suggest a pathogenic mechanism in which MuSK autoantibodies rapidly deplete MuSK from the postsynaptic membrane leading to progressive dispersal of postsynaptic AChRs. Moreover, maintenance of postsynaptic AChR packing at the adult NMJ would appear to depend upon physical engagement of MuSK with the AChR scaffold, notwithstanding activation of the MuSK-rapsyn system of AChR clustering.
Subject(s)
Autoantibodies/physiology , Matrix Attachment Regions/physiology , Myasthenia Gravis/metabolism , Neuromuscular Junction/metabolism , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Receptor Protein-Tyrosine Kinases/deficiency , Receptors, Cholinergic/metabolism , Synapses/enzymology , Animals , Autoantibodies/toxicity , Cells, Cultured , Disease Models, Animal , Female , Humans , Immunoglobulin G/physiology , Immunoglobulin G/toxicity , Mice , Mice, Inbred C57BL , Myasthenia Gravis/enzymology , Myasthenia Gravis/etiology , Neuromuscular Junction/enzymology , Neuromuscular Junction/genetics , Receptor Protein-Tyrosine Kinases/immunology , Receptor Protein-Tyrosine Kinases/metabolism , Receptors, Cholinergic/chemistry , Receptors, Cholinergic/deficiency , Receptors, Cholinergic/immunology , Synapses/genetics , Synapses/metabolismABSTRACT
The purpose of this study was to evaluate, retrospectively, the profile of patients with oral squamous cell carcinoma. They were referred to two hospitals of Belo Horizonte (MG, Brazil) between 1986 and 1996. The medical records of 740 patients presenting oral squamous cell carcinoma were reviewed in detail. The TNM classification and staging, age, gender, race, occupation, and site of the primary tumor were recorded. The male-to-female ratio was 4.8:1. The mean age was 58.6 years. Most of the patients were in their sixties and were farm workers. The tumors were found principally on the tongue. There was a close relationship between some habits (tobacco and alcohol consumption) and the development of oral squamous cell carcinoma. Most of the patients sought medical care in the first year, even though almost half of them had lesions in stage T4. The identification of the characteristics of this specific population might reflect either accomplishments or problems in oral cancer control and can enable the development of a primary prevention program for oral squamous cell carcinoma.
