B lymphocytes producing demyelinating autoantibodies: development and function in gene-targeted transgenic mice.
We studied the cellular basis of self tolerance of B cells specific for brain autoantigens using transgenic mice engineered to produce high titers of autoantibodies against the myelin oligodendrocyte glycoprotein (MOG), a surface component of central nervous system myelin. We generated "knock-in" mice by replacing the germline JH locus with the rearranged immunoglobulin (Ig) H chain variable (V) gene of a pathogenic MOG-specific monoclonal antibody. In the transgenic mice, conventional B cells reach normal numbers in bone marrow and periphery and express exclusively transgenic H chains, resulting in high titers of MOG-specific serum Igs. Additionally, about one third of transgenic B cells bind MOG, thus demonstrating the absence of active tolerization. Furthermore, peritoneal B-1 lymphocytes are strongly depleted. Upon immunization with MOG, the mature transgenic B cell population undergoes normal differentiation to plasma cells secreting MOG-specific IgG antibodies, during which both Ig isotype switching and somatic mutation occur. In naive transgenic mice, the presence of this substantial autoreactive B cell population is benign, and the mice fail to develop either spontaneous neurological disease or pathological evidence of demyelination. However, the presence of the transgene both accelerates and exacerbates experimental autoimmune encephalitis, irrespective of the identity of the initial autoimmune insult.
Litzenburger
T
T
Max-Planck-Institut für Neurobiologie, D-82152 Martinsried, Germany.
Fässler
R
R
Bauer
J
J
Lassmann
H
H
Linington
C
C
Wekerle
H
H
Iglesias
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005434:Flow Cytometry; D018390:Gene Targeting; D007108:Immune Tolerance / Q000276:immunology*; D007114:Immunization; D007074:Immunoglobulin G / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D017421:Sequence Analysis; D013116:Spinal Cord / Q000166:cytology
D001323:Autoantibodies; D007074:Immunoglobulin G; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein