A rheumatoid factor transgenic mouse model of autoantibody regulation.
To address whether B cells expressing a disease-associated autospecificity are regulated in normal mice, we have established a rheumatoid factor (RF) transgenic model of autoimmunity, using V genes derived from an IgA anti-IgG2a RF isolated from an autoimmune MRL/lpr mouse. As we wished to study induction of tolerance during B cell development, we cloned the VH gene into an IgM expression vector. The RF we chose binds only IgG2a of the 'a' allotype (IgG2a) but not IgG2ab allowing us to produce transgenic animals on IgHa and IgHb backgrounds, which either express or lack the self-antigen. Two transgenic lines were studied. Using mice which lack the self-antigen, we show by fluorescence activated cell sorting and hybridoma analysis that the H and L transgenes are expressed to the exclusion of endogenous genes in most splenic B cells. In spite of good allelic exclusion, transgenic mice which are genetically capable of expressing IgG2aa have reduced but significant (approximately 50 micrograms/ml) serum levels. Nonetheless, the frequency and numbers of transgene-expressing B cells in peripheral lymphoid organs of such mice which have the self-antigen are similar to those which lack it (IgHb mice). Thus, B cells expressing an anti-self IgG2a surface receptor can develop in this system. Whether such B cells are anergic or otherwise regulated in autoantigen-expressing mice is discussed.
Shlomchik
M J
MJ
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111.
Zharhary
D
D
Saunders
T
T
Camper
S A
SA
Weigert
M G
MG
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D005786:Gene Expression Regulation; D005803:Genes, Immunoglobulin; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012217:Rheumatoid Factor / Q000096:biosynthesis* / Q000235:genetics
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D012217:Rheumatoid Factor