Heavy chain revision in MRL mice: a potential mechanism for the development of autoreactive B cell precursors.
Abs reactive to DNA and DNA/histone complexes are distinguished by the presence of positively charged amino acids, such as arginine, in the heavy chain complementarity-determining region 3. The presence of these amino acids partly results from atypical V(H)-D-J(H) rearrangements such as D-D fusions and D inversions. Previous results in our laboratory demonstrated that newborn autoimmune MRL/MpJ-+/+ mice undergo these unusual recombinations more frequently when compared with normal C3H/HeJ controls. In addition, the heavy chain junctions in newborn MRL mice demonstrated a preferred usage of V(H)-proximal D genes and distal J(H) genes suggestive of secondary gene rearrangements. In this study we explore the possibility that adult MRL B220(+)IgM(-) pre B cells, which have not yet undergone Ag selection, exhibit similar rearrangement patterns. Indeed, MRL pre-B cells possessed more atypical rearrangements (D-D fusions) than those of C3H/HeJ mice. However, the biased use of upstream D genes and downstream J(H) genes observed in the newborn MRL mice was not present in the pre-B cell library. These results suggest that the heavy chain rearrangement process persists later during B cell life in lupus-prone mice and lead us to propose a model of heavy chain receptor revision in the periphery of autoimmune mice.
Klonowski
K D
KD
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Monestier
M
M
D000375:Aging / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D022801:Complementarity Determining Regions / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015723:Gene Library; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics*; D007144:Immunoglobulin J-Chains / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000276:immunology
D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007144:Immunoglobulin J-Chains; D007135:Immunoglobulin Variable Region