TNF-α inhibitor therapy can improve the immune imbalance of CD4+ T cells and negative regulatory cells but not CD8+ T cells in ankylosing spondylitis

Abstract

Background: Studies into ankylosing spondylitis (AS) and its relationship with immune imbalance are controversial, and the correlation between the efficacy of TNF-α inhibitor and changes in immune imbalance is unclear. Methods: A total of 40 immune cells were tested with flow cytometry, and the results of 105 healthy control (HC) subjects, 177 active-stage AS patients, and 23 AS cases before and after 12 weeks of TNF-α inhibitor therapy (Anbainuo) were analyzed. Results: Compared with the HC group, the proportion of immune cells, such as naïve and central memory CD4+T cells, in AS increased (P < 0.0001), but effector memory and terminally differentiated CD4+T cells were decreased (P < 0.01 and 0.0001, respectively). Naïve, central memory, and effector memory CD8+T cells were increased (P < 0.0001, 0.001, and 0.01, respectively), but terminally differentiated CD8+T cells were decreased (P < 0.0001). Th1 cells (helper T cells-1), Tfh1 cells (follicular helper T cells-1), Tc1 cells (cytotoxic T cells-1), and Tregs (regulatory T cells) were lower (P < 0.01, 0.05, 0.0001, and 0.001, respectively), but Th17 cells, Tfh17 cells, and Tc cells were higher (P < 0.001, 0.0001, and 0.001, respectively). The proportions of total B cells and class-switched B cells were increased (P < 0.05), but non-switched B cells, plasma cells, memory B cells, and immature Bregs (regulatory B cells) were lower (P < 0.01, 0.0001, 0.0001, and 0.0001, respectively). After Anbainuo therapy, the percentage of naïve CD4+ T cells had decreased (P < 0.05) but Tregs and B10 cells (IL-10-producing regulatory B cells) had increased (P < 0.01 and 0.05, respectively), and the increase in Tregs was positively correlated with the decrease in C-reactive protein (CRP) (r = 0.489, P = 0.018). Conclusions: We found that active-stage AS patients have an immunity imbalance of frequency involving multiple types of immune cells, including CD4+T cells, CD8+T cells, Th cells, Tfh cells, Tc cells, Tregs, Bregs, and B cells. TNF-α inhibitor Anbainuo can not only help to inhibit disease activity but can also improve the immune imbalance of CD4+ T cells and negative regulatory cells in frequency. But CD8+ T cells have not been rescued.

Dynamics of Adaptive Immune Cell and NK Cell Subsets in Patients With Ankylosing Spondylitis After IL-17A Inhibition by Secukinumab

“…Recent studies have reported immune cell dysregulation related to inflammatory disorders play a significant role in the pathogenesis of AS (Fiorillo et al, 2019). We proved again that AS patients have altered CD4 + T cell and CD8 + T cell subsets at different stages of differentiation, revealing that both CD4 + T cells and CD8 + T cells were activated in disease processes (Yang et al, 2020). CD4 + T cell subgroups can transform to each other and play diverse roles under appropriate environments.…”

“…According to the ASAS/EULAR recommendations, biologic DMARD therapy, typically TNFi therapy, should be considered in patients with persistently high disease activity despite conventional treatments ( Noureldin and Barkham, 2018 ). We have reported AS patients have altered immune cell frequencies, including CD4 + T cells, CD8 + T cells and B cell, and found that anti-TNF-α therapy could improve the frequency of immune dysregulation of CD4 + T cells and negative regulatory cells ( Yang et al, 2020 ). Although most patients had improvement with TNFi therapy, there is an unmet need that not all patients respond well to or can tolerate TNFi treatment ( Noureldin and Barkham, 2018 ).…”

Imbalance of Peripheral Lymphocyte Subsets in Patients With Ankylosing Spondylitis: A Meta-Analysis

“…It has been reported that in patients with active AS, Tregs in peripheral blood fail to utilize IL-2 and cannot suppress naïve T cell proliferation ( 117 ). Moreover, application of TNF-α inhibitors can restore the proportion of Tregs, and the increase in Tregs is positively correlated with the decrease in CRP levels ( 94 ). Of note, different markers have been employed to identify the subgroup of Tregs, which may exert an influence on the proportions of Tregs measured in different studies, sometimes yielding contradictory results.…”

Modulatory Impact of Adipose-Derived Mesenchymal Stem Cells of Ankylosing Spondylitis Patients on T Helper Cell Differentiation

“…Between them, Th1, Th2, and Th17 cells contribute to the development of various autoimmune diseases, whereas Treg cells play a protective role [ 24 , 25 ]. In AS chronic activation of T lymphocytes leads to a quantitative imbalance between Th subsets and a significant increase in Th1/Th2 and Th17/Treg ratios [ 3 , 8 , 10 , 26 , 27 ]. Consistently, increased serum levels of the effector cytokines, IL-17, and IFNγ were reported [ 7 , 28 ].…”

“…Consistently, increased serum levels of the effector cytokines, IL-17, and IFNγ were reported [ 7 , 28 ]. These abnormalities are often associated with disease activity and normalize with clinical improvement [ 26 , 28 , 29 ]. The Th17 cells produce IL-17A and IL-17F, two structurally related members of the IL-17 family with overlapping pro-inflammatory activities that function as homo- and heterodimers (IL-17AF).…”