Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes.
Eliminating autoantigen-specific B cells is an attractive alternative to global B-cell depletion for autoimmune disease treatment. To identify the potential for targeting a key autoimmune B-cell specificity in type 1 diabetes, insulin-binding B cells were tracked within a polyclonal repertoire using heavy chain B-cell receptor (BCR) transgenic (VH125Tg) mice. Insulin-specific B cells are rare in the periphery of nonautoimmune VH125Tg/C57BL/6 mice and WT/NOD autoimmune mice, whereas they clearly populate 1% of mature B-cell subsets in VH125Tg/NOD mice. Autoantigen upregulates CD86 in anti-insulin B cells, suggesting they are competent to interact with T cells. Endogenous insulin occupies anti-insulin BCR beginning with antigen commitment in bone marrow parenchyma, as identified by a second anti-insulin monoclonal antibody. Administration of this monoclonal antibody selectively eliminates insulin-reactive B cells in vivo and prevents disease in WT/NOD mice. Unexpectedly, developing B cells are less amenable to depletion, despite increased BCR sensitivity. These findings exemplify how a critical type 1 diabetes B-cell specificity escapes immune tolerance checkpoints. Disease liability is corrected by eliminating this B-cell specificity, providing proof of concept for a novel therapeutic approach for autoimmune disease.
Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee, USA.
Rachel A
RA
Henry
Peggy L
PL
Kendall
James W
JW
Thomas
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D051940:B7-2 Antigen / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007328:Insulin / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D007328:Insulin; D011947:Receptors, Antigen, B-Cell