Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes.

Henry RA, Kendall PL, Thomas JW
Diabetes. 2012 61 (8): 2037-44

PMID: 22698916 · PMCID: PMC3402296 · DOI:10.2337/db11-1746

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.

MeSH Terms (13)

Animals Antibodies, Monoclonal Autoantigens B-Lymphocytes B7-2 Antigen Diabetes Mellitus, Type 1 Humans Immune Tolerance Insulin Mice Mice, Inbred NOD Mice, Transgenic Receptors, Antigen, B-Cell

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