Abstract
Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV).Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3+CD4−CD8−. To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied.Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3+CD4−CD8−). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC.Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.
Highlights
Anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by the presence of autoantibodies directed against myeloperoxidase (MPO) or Proteinase-3 (PR3) expressed by neutrophils [1]
In quiescent AAV patients (AAV-r), the B- and T-Lymphocyte Attenuator (BTLA) expression did not differ from HC on peripheral T-cells (AAV-r vs. HC, CD3+ T-cells: %BTLApos, 85.2 ± 1.7% vs. 86.6 ± 2.4%, p = 0.19, Figure 1). the same was found for T-helper cells (Th cells, AAV-r vs. HC, %BTLApos within CD3+CD4+ T-cells: 91.5 ± 1.2% vs. 92.2 ± 1.4%, p = 0.21), memory Th cells (AAV-r vs. HC, %BTLApos within CD3+CD4+CD45RA− Tcells: 90.1 ± 1.1 vs. 92.3 ± 1.6%, p = 0.2), and cytotoxic Tcells (AAV-r vs. HC, %BTLApos within CD3+CD8+ T-cells: 84.9 ± 2.5% vs. 81.6 ± 3.7%, p = 0.54)
On double negative T-cells (DN, CD3+CD4−CD8−) the expression of BTLA was significantly decreased in AAV (AAV-r vs. HC, %BTLApos within CD3+CD4−CD8− T-cells: 64.9 ± 3.6% vs. 84.0 ± 2.7%, p < 0.001, Figure 1)
Summary
Anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by the presence of autoantibodies directed against myeloperoxidase (MPO) or Proteinase-3 (PR3) expressed by neutrophils [1]. T-cells have an important role in the pathogenesis of AAV and persistent T-cell activation is frequently observed [2, 3]. Co-inhibitory signals may induce anergy or cell death of T-cells [12, 13] These mechanisms are important to maintain immune tolerance. Dysfunctional co-stimulation and co-inhibition promote the break of tolerance and are associated with autoimmunity. A defective co-inhibitory PD1/PDL-1 axis is associated with a number of autoimmune diseases such as systemic lupus erythematosus and AAV [14, 15]. BTLA as a co-inhibitor is scarcely studied in human autoimmune diseases and its role in disease pathogenesis is unclear.
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