Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis
Haidong Dong, … , Colin L.W. Driscoll, Lieping Chen
Haidong Dong, … , Colin L.W. Driscoll, Lieping Chen
Published February 1, 2003
Citation Information: J Clin Invest. 2003;111(3):363-370. https://doi.org/10.1172/JCI16015.
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Article Immunology

Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis

Abstract

A pathogenic hallmark of rheumatoid arthritis (RA) is persistent activation of self-reactive CD4+ T cells. The cause of this aberrant activity remains elusive. We report here detection of autoantibodies against B7-H1, a recently described member of the B7 family, in 29% of patients with RA versus 4% of healthy donors. High-level expression of cell surface B7-H1 are found on activated human CD4+, CD8+, and CD45RO+ T cells. Immobilized autoantibodies to B7-H1 are capable of costimulating the proliferation of CD4+ T cells in vitro, and the presence of these autoantibodies correlates with active disease status. Using immobilized B7-H1 mAb’s and programmed death 1Ig, we demonstrate that engagement of B7-H1 on CD4+ T cells costimulates proliferation and secretion of IL-10, and subsequently leads to programmed cell death, accompanied with upregulated expression of TNF-related apoptosis–inducing ligand and activation of caspase-3. Taken together with our previous findings, these data indicate a bidirectional signaling role of B7-H1 in T cell costimulation and apoptosis and implicate B7-H1 autoantibodies as contributing to the progression of RA by inducing aberrant T cell responses.

Authors

Haidong Dong, Scott E. Strome, Eric L. Matteson, Kevin G. Moder, Dallas B. Flies, Gefeng Zhu, Hideto Tamura, Colin L.W. Driscoll, Lieping Chen

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Detection, costimulatory function, and disease association of B7-H1 auto...
Detection, costimulatory function, and disease association of B7-H1 autoantibodies in RA patients. CD4+ T cells were cultured with immobilized (a) or soluble (b) sera IgG at the initiated dose of 20 μg/ml in the presence of suboptimal anti-CD3 mAb. The titers of RA 1 and RA 2 patients are 0.32 and 0.25 (OD450), respectively. (c) For blockade, the control (ctl) Ig, PD-1Ig, or B7-H1Ig at 3 μg/ml were added before the addition of CD4+ T cells. The growth of T cells was detected after 72 hours of culture. (d) To examine specificity of RA sera binding to B7-H1, diluted sera were preincubated with PBS, 2 μg/ml of soluble B7-H1Ig or control Ig (mIgG2a). (e) Diluted sera of 63 patients with RA and 54 healthy donors were tested for binding to B7-H1Ig by ELISA. Samples with OD450 values greater than 0.123 were considered positive. P value for differences between cohorts is shown (t test). (f) The sera at 1:1,000 dilution were examined for binding to B7-1Ig–coated vs. B7-H1Ig–coated ELISA plates. (g) Mock/624mel or B7-H1/624mel cells were stained with diluted (1:5) sera from 16 ELISA-positive RA patients. The inset bar shows the average percentage of positive staining. A typical histogram of FACS assay is shown on the left. (h) Sixty-three RA patients were sorted according to the active status of their disease, and the presence of B7-H1 autoantibodies. Statistical analysis of the correlation was performed as P = 0.0179 in a Fisher exact test.