Enrichment of anti-glomerular antigen antibody-producing cells in the kidneys of MRL/MpJ-Fas(lpr) mice.
Lupus nephritis is characterized by immune complex deposition and infiltration of inflammatory cells into the kidney including Ab-producing cells (AbPCs). Although AbPCs play a central role in the pathogenesis of immune complex glomerulonephritis in lupus, the specificity and pathogenic role of AbPCs infiltrating into the kidneys in lupus are poorly understood. To characterize AbPCs present in lupus kidneys, we isolated AbPCs from diseased MRL/MpJ-Faslpr (MRL/lpr) mouse kidneys. ELISPOT assays, using glomerular Ag (GA) extracts as Ag, demonstrated significant enhancement of anti-GA AbPCs in the kidneys as compared in peripheral blood or spleen of the same mouse. We isolated hybridomas with anti-GA specificity from MRL/lpr mouse kidneys. All the anti-GA mAbs had polyreactive binding to ssDNA, dsDNA, and IgG (i.e., rheumatoid factor), but not to histones or Sm. Sequence analysis of anti-GA Abs suggested the occurrence of somatic mutations and amino acid replacement in complementarity-determining regions with a high replacement to silent ratio resulting in charged amino acids. Intravenous administration of the monoclonal anti-GA Abs into BALB/c mice resulted in graded deposition in glomeruli paralleling their ELISA anti-GA reactivity. These results suggest that AbPCs infiltrating the kidneys in MRL/lpr mice accumulate as a result of Ag selection and likely play a pathologic role in lupus nephritis.
Sekine
Hideharu
H
Medical Research Service, Ralph H Johnson Veterans Affairs Medical Center and Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Watanabe
Hiroshi
H
Gilkeson
Gary S
GS
D000595:Amino Acid Sequence; D000818:Animals; D000921:Antibody-Producing Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001323:Autoantibodies / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D001666:Binding Sites, Antibody / Q000235:genetics; D002455:Cell Division / Q000276:immunology; D022801:Complementarity Determining Regions / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000378:metabolism; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology* / Q000378:metabolism; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D027041:Somatic Hypermutation, Immunoglobulin
D001323:Autoantibodies; D001324:Autoantigens; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D007147:Immunoglobulin Light Chains