title: Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupus-prone New Zealand mixed 2328 mice deficient in BAFF.
abstract: Constitutive overexpression of B cell-activating factor belonging to the TNF family (BAFF) promotes development of systemic lupus erythematosus (SLE), and treatment of SLE mice with BAFF antagonists ameliorates disease. To determine whether SLE can develop de novo in BAFF-deficient hosts, BAFF-deficient New Zealand Mixed (NZM) 2328 (NZM.Baff(-/-)) mice were generated. In NZM.Baff(-/-) mice, spleen B cells (including CD5(+) B1a and CD5(-) B1b B cells), germinal centers, Ig-secreting cells, and T cells were reduced in comparison to NZM.Baff(+/+) mice. Serum total Ig and autoantibody levels were reduced at 4-6 mo but approached wild-type levels with increasing age, indicating that autoreactive B cells can survive and secrete autoantibodies despite the complete absence of BAFF. At least some of these autoantibodies are nephrophilic in that glomerular deposition of total IgG and IgG1 (but not of IgG2a, IgG2b, or C3) was substantial in NZM.Baff(-/-) mice by 12-13 mo of age. Despite proliferative glomerulonephritis, highlighted by widespread glomerular hyaline thrombi, being common among NZM.Baff(-/-) mice by 6-7 mo of age, severe proteinuria and mortality were greatly attenuated. These results demonstrate that the lifelong absence of BAFF does not protect NZM 2328 mice from serological autoimmunity and renal pathology. Nevertheless, the character of the renal pathology is altered, and the mice are largely spared from clinically overt disease (severe proteinuria and premature death). These observations may have profound ramifications for the use of BAFF antagonists in human SLE and related diseases.
authors.affiliation: Department of Medicine, Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
authors.forename: Chaim O
authors.initials: CO
authors.lastname: Jacob
authors.forename: Luminita
authors.initials: L
authors.lastname: Pricop
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
authors.forename: Michael N
authors.initials: MN
authors.lastname: Koss
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Maria
authors.initials: M
authors.lastname: Kollaros
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Bixler
authors.forename: Christine M
authors.initials: CM
authors.lastname: Ambrose
authors.forename: Martin L
authors.initials: ML
authors.lastname: Scott
authors.forename: William
authors.initials: W
authors.lastname: Stohl
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood*; D053264:B-Cell Activating Factor; D005260:Female; D020022:Genetic Predisposition to Disease; D007668:Kidney / Q000276:immunology* / Q000473:pathology*; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D053264:B-Cell Activating Factor; D008565:Membrane Proteins; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha