Somatic Hypermutation and Selection of B Cells in Thymic Germinal Centers Responding to Acetylcholine Receptor in Myasthenia Gravis

• Published in: The Journal of immunology (1950) 2001-08, Vol.167 (4), p.1935-1944
• Main Authors: Sims, Gary P, Shiono, Hiroyuki, Willcox, Nick, Stott, David I
• Format: Article
• Language: English
• Subjects: Adult; Amino Acid Sequence; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; B-Lymphocyte Subsets - pathology; Bungarotoxins - metabolism; Clone Cells; Complementarity Determining Regions - biosynthesis; Complementarity Determining Regions - genetics; Female; Gene Amplification; Gene Rearrangement, B-Lymphocyte, Heavy Chain - genetics; Germinal Center - cytology; Germinal Center - immunology; Germinal Center - metabolism; Germinal Center - pathology; Humans; Immunoglobulin Heavy Chains - biosynthesis; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - biosynthesis; Immunoglobulin Variable Region - genetics; Immunologic Memory - genetics; Interphase - genetics; Interphase - immunology; Iodine Radioisotopes - metabolism; Lymphocyte Activation - genetics; Lymphoid Tissue - cytology; Molecular Sequence Data; Multigene Family - immunology; Mutation; Myasthenia Gravis - genetics; Myasthenia Gravis - immunology; Receptors, Cholinergic - immunology; Receptors, Cholinergic - metabolism; somatic hypermutation; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism; Thymus Gland - pathology; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.4.1935

The muscle weakness in myasthenia gravis (MG) is mediated by autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. Production of these pathogenic autoantibodies is believed to be associated with germinal centers (GC) and anti-AChR-secreting plasma cells in the hyperplastic thymus of patients with early onset MG (EOMG). Here, we describe the repertoire of rearranged heavy chain V genes and their clonal origins in GC from a typical EOMG patient. Three hundred fifteen rearranged Ig V(H) genes were amplified, cloned, and sequenced from sections of four thymic GC containing AChR-specific B cells. We found that thymic GC contain a remarkably heterogeneous population of B cells. Both naive and circulating memory B cells undergo Ag-driven clonal proliferation, somatic hypermutation, and selection. Numerous B cell clones were present, with no individual clone dominating the response. Comparisons of B cell clonal sequences from different GC and known anti-AChR Abs from other patients showed convergent mutations in the complementarity determining regions. These results are consistent with AChR driving an ongoing GC response in the thymus of EOMG patients. This is the first detailed analysis of B cell clones in human GC responding to a defined protein Ag, and the response we observed may reflect the effects of chronic stimulation by autoantigen.