title: Chronic graft-versus-host in Ig knockin transgenic mice abrogates B cell tolerance in anti-double-stranded DNA B cells.
abstract: Anti-dsDNA Abs are specific diagnostic markers of systemic lupus erythematosus, and are also implicated in kidney pathology. Anti-dsDNA B cells have been shown to be tolerized in nonautoimmune mice. The immunodysregulation that causes these cells to break tolerance is presumably part of the fundamental defects in systemic lupus erythematosus. To explore these mechanisms, we used the chronic graft-versus-host model mediated by MHC class II differences. Induction of chronic graft-vs-host in anti-DNA H chain knockin (3H9.KI) transgenic mice on a nonautoimmune background resulted in specific activation of anti-dsDNA B cells, as evidenced by high titers of soluble Ab in sera and a high frequency (70%) of anti-dsDNA B cell clones recovered as hybridomas. In addition, the lambda(+)-anti-dsDNA B cells developed increased expression of cell surface activation markers, and concentrated in the T cell area of the follicle with an Ab-forming cell-compatible phenotype. Genetic analysis of the hybridoma clones showed strong evidence of secondary rearrangements of the L chain associated with anti-dsDNA reactivity. Thus, our study indicates that alloreactive T cell help can break tolerance in a complex manner, involving several events.
authors.affiliation: Department of Medicine, Division of Rheumatology, Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Debora R
authors.initials: DR
authors.lastname: Sekiguchi
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Jainandunsing
authors.forename: Michele L
authors.initials: ML
authors.lastname: Fields
authors.forename: Michael A
authors.initials: MA
authors.lastname: Maldonado
authors.forename: Michael P
authors.initials: MP
authors.lastname: Madaio
authors.forename: Jan
authors.initials: J
authors.lastname: Erikson
authors.forename: Martin
authors.initials: M
authors.lastname: Weigert
authors.forename: Robert A
authors.initials: RA
authors.lastname: Eisenberg
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D004247:DNA / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000096:biosynthesis; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic / Q000235:genetics / Q000276:immunology*; D016297:Mutagenesis, Site-Directed; D013154:Spleen / Q000473:pathology / Q000637:transplantation; D019076:Transgenes / Q000276:immunology
chemical_list: D000974:Antibodies, Antinuclear; D007143:Immunoglobulin Heavy Chains; D007146:Immunoglobulin lambda-Chains; D004247:DNA