Transgenic expression of a human polyreactive Ig expressed in chronic lymphocytic leukemia generates memory-type B cells that respond to nonspecific immune activation.
We generated transgenic mice, designated SMI, expressing unmutated H and L chain Ig genes encoding a low-affinity, polyreactive human (h)IgM/kappa rheumatoid factor. These animals were compared with control AB29 transgenic mice expressing a hIgM/kappa rheumatoid factor specific for human IgG, with no detectable reactivity with mouse proteins. SMI B cells expressed significantly lower levels of surface hIgM/kappa than did the B cells of AB29 mice, but still could be induced to proliferate by surface Ig cross-linking in vitro and could be deleted with anti-Id mAb in vivo. Transgene-expressing B cells of AB29 mice had a B-2 phenotype and were located in the primary follicle. In contrast, a relatively high proportion of hIgM-expressing B cells of SMI mice had the phenotype of B-1 B cells in the peritoneum or marginal zone B cells in the spleen, where they were located in the periarteriolar sheath, marginal zone, and interfollicular areas that typically are populated by memory-type B cells. Although the relative proportions of transgene-expressing B cells in both types of transgenic mice declined with aging, SMI mice experienced progressive increases in the serum levels of IgM transgene protein over time. Finally, SMI transgene-expressing B cells, but not AB29 transgene-expressing B cells, were induced to secrete Ab when cultured with alloreactive T cells. These results indicate that expression of polyreactive autoantibodies can allow for development of B cells that are neither deleted nor rendered anergic, but instead have a phenotype of memory-type or Ag-experienced B cells that respond to nonspecific immune activation.
Widhopf
George F
GF
Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Brinson
Diana C
DC
Kipps
Thomas J
TJ
Tighe
Helen
H
D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001160:Arterioles / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000096:biosynthesis / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010537:Peritoneum / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012217:Rheumatoid Factor / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000098:blood supply / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D019076:Transgenes / Q000276:immunology*
D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D012217:Rheumatoid Factor