Treatment of autoimmune hyperthyroidism in a murine model of Graves' disease with tumor necrosis factor-family ligand inhibitors suggests a key role for B cell activating factor in disease pathology.
Hyperthyroid Graves' disease is a common autoimmune disorder mediated by agonistic antibodies to the TSH receptor, termed thyroid stimulating antibodies (TSAbs). Recently members of the TNF superfamily, B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), have been identified along with their receptors, B cell maturation antigen and transmembrane activator and calcium-modulator and cyclophilin ligand interactor, and the BAFF-specific receptor. BAFF is a fundamental B cell survival/maturation factor, and both BAFF and APRIL have been implicated in antibody production. We investigated the effect of interfering with BAFF- and APRIL-mediated signals in an induced model of Graves' disease by blockade of these factors using soluble decoy receptors. In a therapeutic setting in mice with established hyperthyroidism, we show that blockade of BAFF or BAFF+APRIL with BAFF-specific receptor-Fc and B cell maturation antigen-Fc, respectively, leads to significant reductions in the induced hyperthyroidism. This was supported by a parallel pattern of declining TSAbs in the responding animals. Histopathological analysis of splenic sections from treated animals revealed marked reductions in the B cell follicle regions, but staining with anti-CD138 revealed the persistence of plasma cells. Thus, the reductions in TSAbs in the treated animals were not related to overall plasma cell numbers in the secondary lymphoid organs. Our results are the first to demonstrate attenuation of established hyperthyroidism by therapeutic intervention aimed at autoreactive B cells and indicate that both BAFF and APRIL appear to play important roles in the development and survival of the autoantibody producing cells in this model.
Gilbert
Jacqueline A
JA
Division of Gene and Cell-Based Therapy, King's College London School of Medicine, Bessemer Road, London SE5 9PJ, United Kingdom.
Kalled
Susan L
SL
Moorhead
Jane
J
Hess
Donna M
DM
Rennert
Paul
P
Li
Zhifang
Z
Khan
M Zareen
MZ
Banga
J Paul
JP
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000502:physiology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005822:Genetic Vectors; D006111:Graves Disease / Q000188:drug therapy* / Q000473:pathology; D018828:Immunoglobulins, Thyroid-Stimulating / Q000378:metabolism; D007150:Immunohistochemistry; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011989:Receptors, Thyrotropin / Q000235:genetics; D013967:Thyroiditis, Autoimmune / Q000188:drug therapy* / Q000473:pathology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000502:physiology
D053264:B-Cell Activating Factor; D018828:Immunoglobulins, Thyroid-Stimulating; D008024:Ligands; D008565:Membrane Proteins; D011989:Receptors, Thyrotropin; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha; C048009:bis(3-bis(4-chlorophenyl)methyl-4-dimethylaminophenyl)amine; D004159:Diphenylamine