Defective B cell clonal regulation and autoantibody production in New Zealand black mice.
By using the splenic fragment assay in a KLH-primed host, we have evaluated the clonal anergy model of tolerance in DBA/2 and spontaneously autoimmune NZB mice. Unlike immature B cells from DBA/2 mice (which are tolerized by encounter with TNP-OVA), SIg- B cells from NZB mice respond to TNP-KLH with equal precursor frequency in TNP-OVA-tolerized or control fragments. In additional experiments, SIg- bone marrow or mature spleen cells of DBA/2 or NZB origin were adoptively transferred into irradiated (DBA/2 X NZB) F1 X xid hosts, and host-derived splenic fragments were stimulated in vitro with LPS and growth factors. These experiments revealed a substantial anti-ssDNA precursor frequency in NZB marrow and spleen (2.5 and 5.1, respectively, per 10(7) transferred cells). In DBA/2 SIg- marrow cells, there was an anti-ssDNA precursor frequency of 1.3 to 3.5/10(7) transferred cells; however, anti-ssDNA-producing clones were reduced in fragments derived from recipients of DBA/2 as compared with NZB spleen cells (0.2 to 1.9/10(7) transferred cells). By using a replica plate technique, we evaluated fragments from recipients of DBA/2 SIg- marrow cells or mature spleen cells for anti-TNP reactivity. In fragments derived from recipients of DBA/2 SIg- marrow cells, 92% of anti-TNP-producing fragments also bound ssDNA. In fragments derived from recipients of DBA/2 spleen cells, only 43% of anti-TNP-producing fragments also bound ssDNA. Our findings document that NZB marrow-derived immature B cells abnormally resist tolerance induction, and that clonal anergy/selection operates in directing the B cell repertoire away from autoantibody formation.
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D004277:DNA, Single-Stranded / Q000276:immunology; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008811:Mice, Inbred DBA / Q000276:immunology; D008814:Mice, Inbred NZB / Q000276:immunology; D013154:Spleen / Q000276:immunology; D014301:Trinitrobenzenes / Q000276:immunology
D001323:Autoantibodies; D004277:DNA, Single-Stranded; D014301:Trinitrobenzenes