The Co-inhibitor BTLA Is Functional in ANCA-Associated Vasculitis and Suppresses Th17 Cells

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 Band 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.

Association of baseline soluble immune checkpoints with the risk of relapse in PR3-ANCA vasculitis following induction of remission

“…Similarly, lower expression levels of mTim-3 have been associated with enhanced inflammation and thus correlated with an unfavourable clinical course in human autoimmune diseases 24. In line with our observation as higher sBTLA concentrations are linked to sustained remission, relapse rate was lower in patients with AAV with mBTLA-positive double-negative T cells (CD3 + CD4 - CD8 - ) 25. The immune-suppressive role of mBTLA is also supported by reduced rates of acute allograft rejection and prolonged graft survival in mBTLA high rates on organ transplantation 26.…”

“…It is worth mentioning that participants in the RAVE trial received high cumulative CYC doses,2 7 and there is no information on relapse risk in those receiving CYC intravenously 34. In this respect, cumulative CYC doses correlated with mBTLA expression on double-negative T cells in AAV 25. Follow-up investigations are urgently needed to investigate the potential of sICP concentrations to predict long-term remission following either RTX- or CYC-based induction regimens, including also patients receiving lower cumulative CYC doses.…”

A Predictive Disease Risk Model for Ankylosing Spondylitis: Based on Integrated Bioinformatic Analysis and Identification of Potential Biomarkers Most Related to Immunity

“…Costimulatory and coinhibitory receptors, as well as their ligands, shape and regulate the immune response in fundamental ways. Costimulation and coinhibition regulate T cell functions, and an imbalance between them might cause tolerance to break down, leading to autoimmune disorders [ 47 , 48 ]. The immunoglobulin superfamily (Ig-SF) and TNF receptor superfamily (TNFR-SF) contain the majority of costimulatory and coinhibitory molecules.…”

Stimulation of Immune Checkpoint Molecule B and T-Lymphocyte Attenuator Alleviates Experimental Crescentic Glomerulonephritis

“…Clinical data show a dysregulation of BTLA in patients with lupus erythematodes as well as ANCA-associated vasculitis. 36,37 Furthermore, preclinical data from murine transplant models suggest that BTLA may prevent acute kidney rejection. 26,27 Our own study now extends these findings and proposes antibody-based modulation of BTLA as a potential treatment strategy for acute GN.…”