Soluble immune checkpoint molecules in patients with antineutrophil cytoplasmic antibody-associated vasculitis

Abstract

Immune checkpoint molecules balance immune effector responses with regulatory reactions. We speculated that soluble immune checkpoint molecules are involved in dysregulation of the immune response and autoimmunity. We evaluated the association between soluble immune checkpoint molecules and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). A total of 56 patients with AAV from a prospective observational cohort and 40 healthy controls (HCs) were analyzed. Soluble PD-1, PD-L1, PD-L2, CTLA-4, CD28, CD80, CD86, ICOS, TIM-3, BTLA, CD40, LAG-3, TLR-2, and CD27 were measured in stored sera using the Milliplex MAP assay. Paired analyses were performed before and after the treatment. AAV-specific indices, including Birmingham vasculitis activity score, five factor score , vasculitis damage index, and blood samples, were collected. Patients with AAV had higher levels of sPD-L1, sCD28, sCD80, sCD86, sICOS, sTIM-3, sLAG-3, sTLR-2, and sCD27 and lower level of sCTLA-4 than HCs (p < 0.05). Patients with AAV had higher serum sCD28, sCD80, sTIM-3, and sCD27 levels than HCs at baseline and decreased after treatment. Furthermore, the serum levels of sCD28 and sTIM-3 were significantly correlated with disease activity. This study demonstrated altered concentrations of serum soluble immune checkpoint molecules in patients with AAV. In particular, sCD28 and sTIM-3 may act as surrogate markers of AAV disease activity.

Targeting immune checkpoints in anti-neutrophil cytoplasmic antibodies associated vasculitis: the potential therapeutic targets in the future

“…The same results were observed in patients with active MPO-AAV ( 19 ) and Behcet’s disease ( 73 ). In patients with active AAV, the serum concentration of soluble ICOS was also higher than HCs ( 57 ). In addition, the production of pro-inflammatory factors was decreased by blocking the ICOS signal ( 73 ).…”

“…Elevated soluble CD28(sCD28) levels was observed in sera samples in patients with active AAV. Such increase in was significantly positively correlated with disease activity markers, such as the Birmingham Vasculitis Activity Score, C-reactive protein, and erythrocyte sedimentation rate ( 57 ). Noteworthy, sCD28 level decreased when AAV patients from the active state became inactive after treatment ( 57 ), suggesting that sCD28 might play a potential immunopathological role in AAV and could be a novel biomarker to evaluate disease activity.…”

“…Soluble ICs in PD-1 signaling pathway also play an important role in AAV. It was observed that although the serum concentration of soluble PD-L2 in active AAV was lower than that in HCs, its level was significantly increased after treatment ( 57 ). In addition, the levels of serum soluble PD-1 (sPD-1) was higher in MPO-AAV ( 133 ).…”

“…Further explorations might be needed to assess the expression of TIM-3 on Th and Treg cells. Studies have shown that the serum concentrations of soluble TIM-3 correlated with the diseases state of AAV ( 57 , 133 ), i.e. it was increased in active AAV ( 57 ), and could predict the relapse in PR3-AAV with rituximab treatment ( 133 ).…”

“…Studies have shown that the serum concentrations of soluble TIM-3 correlated with the diseases state of AAV ( 57 , 133 ), i.e. it was increased in active AAV ( 57 ), and could predict the relapse in PR3-AAV with rituximab treatment ( 133 ). However, the specific mechanism of soluble TIM-3 in AAV remains to be further examined before considering as a therapeutic target.…”