An example of idiotypic mimicry.
We have evaluated the impact of transgenic immunoglobulin (TGIg) expression on endogenous antibody repertoires. The transgenic system was chosen as to allow for normal recombination of endogenous Ig genes, secretion of TGIg from early development on, and distinguishing the TGIg from endogenous Ig by several serological markers on the C and V regions of the molecules. The transgenic construct encodes a complete anti-(4-hydroxy-3-iodo-5-nitrophenyl)acetyl (NP) antibody molecule carrying a well-defined idiotype, bearing a lambda 1 light chain and a chimeric heavy chain encoded by a human alpha 2 C region devoid of its membrane exon, and the murine B1.8 VDJ-region. Endogenous antibody repertoires were analyzed in mitogen-driven limiting dilution cultures, in single-cell assays for naturally activated Ig-secreting cells, and in hybridomas derived by direct fusion of spleen cells from unmanipulated animals. The results show that a very high frequency of splenic resting B cells and plasma cells in transgenic animals produce IgM with B1.8-cross-reactive idiotypes. This was confirmed by hybridoma analysis which also established that the levels of transgene expression and of idiotype-positive IgM production by the same cell are not correlated. The affinities of idiotype-positive endogenous Ig varied, but were generally several orders of magnitude lower than the transgene-encoded idiotype. V regions from idiotype-cross-reactive IgM heavy chains showed marked diversity in sequences that were all different from the transgenic B1.8. These results are compatible with idiotypic mimicry resulting from intercellular selection based on degenerate, whole V region reactivities.
Grandien
A
A
Unite d'Immunobiologie, CNRS URA1961, Institut Pasteur, Paris, France.
Andersson
J
J
Portnoi
D
D
Coutinho
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D000915:Antibody Affinity / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006825:Hybridomas; D007130:Immunoglobulin Idiotypes / Q000096:biosynthesis / Q000235:genetics*; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology*; D008969:Molecular Sequence Data
D000911:Antibodies, Monoclonal; D007130:Immunoglobulin Idiotypes; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region