Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity.
In otherwise non-autoimmune-prone C57BL/6 (B6) mice rendered genetically deficient in CD152 (CTLA-4), polyclonal hypergammaglobulinemia with increased levels of systemic lupus erythematosus (SLE)-associated IgG autoantibodies, glomerular IgG and C3 deposition, and interstitial nephritis all developed by 3-5 wk of age. Remarkably, superimposing genetic deficiency of BAFF (B cell-activating factor belonging to the TNF family) onto CD152 deficiency did not substantially attenuate humoral autoimmunity and immunopathology in these mice, despite the resulting marked reduction in B-lineage cells. Although superimposing a BAFF transgene (resulting in constitutive BAFF overexpression) onto CD152-deficient mice did lead to increases in B-lineage cells and serum levels of certain SLE-associated IgG autoantibodies, renal immunopathology remained largely unaffected. Taken together, these results demonstrate that global T cell dysregulation, even in an otherwise non-autoimmune-prone host, can promote systemic humoral autoimmunity and immunopathology in a BAFF-independent manner. Moreover, supraphysiologic expression of BAFF in the setting of ongoing autoimmunity does not necessarily lead to greater immunopathology. These findings may help explain the limited clinical efficacy appreciated to date of BAFF antagonists in human SLE.
Stohl
William
W
Department of Medicine, Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. stohl@usc.edu
Jacob
Noam
N
Quinn
William J
WJ
Cancro
Michael P
MP
Gao
Huaxin
H
Putterman
Chaim
C
Gao
Xiaoni
X
Pricop
Luminita
L
Koss
Michael N
MN
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D053264:B-Cell Activating Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D003176:Complement C3 / Q000378:metabolism; D006942:Hypergammaglobulinemia / Q000276:immunology / Q000473:pathology; D007136:Immunoglobulins / Q000276:immunology; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
D015703:Antigens, CD; D001323:Autoantibodies; D053264:B-Cell Activating Factor; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D003176:Complement C3; C556707:Ctla4 protein, mouse; D007136:Immunoglobulins; C505720:Tnfsf13b protein, mouse