Autoantigen-Specific B-Cell Depletion Overcomes Failed Immune Tolerance in Type 1 Diabetes

  1. James W. Thomas1,2
  1. 1Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University, Nashville, Tennessee
  2. 2Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee
  3. 3Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University, Nashville, Tennessee
  1. Corresponding author: James W. Thomas, james.w.thomas{at}vanderbilt.edu.

Abstract

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.

  • Received December 13, 2011.
  • Accepted March 9, 2012.

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  1. Diabetes vol. 61 no. 8 2037-2044
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