Higher frequency of peripheral blood follicular regulatory T cells in patients with new onset ankylosing spondylitis

Abstract

Follicular helper T (TFH) cells and B cells are linked to the pathogenesis of ankylosing spondylitis (AS). Follicular regulatory T (TFR) cells suppress TFH cell and germinal center B cell numbers in vivo. The role of TFR cells in AS is unknown. The frequency of peripheral blood inducible FOXP3+CXCR5+CD4+TFR cells and CXCR5+CD4+TFH cells were taken from 20 onset AS patients and 10 healthy controls, and were examined by flow cytometry, their disease activity were measured by the Bath Ankylosing Spondylitis Disease Activity Index. The concentrations of serum interleukin (IL)-21, immunoglobulin G, immunoglobulin A, immunoglobulin M and C-reactive protein were examined, and the values of erythrocyte sedimentation rate were measured. The frequency of peripheral blood FOXP3+CXCR5+CD4+TFR cells, CXCR5+CD4+TFH cells, the ratio of FOXP3+CXCR5+CD4+TFR/CXCR5+CD4+TFH cells and the concentration of serum IL-21 in the AS patients were significantly higher than those in the healthy controls (P < 0.0001, P = 0.0027, P < 0.0001, P = 0.0039, respectively). The frequency of FOXP3+CXCR5+CD4+TFR cells and the ratio of FOXP3+CXCR5+CD4+TFR/CXCR5+CD4+TFH cells still significantly rose in those patients after standard treatment (P = 0.0006, P < 0.0001), the concentration of serum IL-21 decreased after treatment (P = 0.0049), accompanied by significantly minimized disease activities. Furthermore, the TFR cells were negatively correlated with serum immunoglobulin A in those patients before treatment (r = -0.582, P = 0.0071), and the frequency of TFR cells was negatively correlated with that of TFH cells and the concentration of serum IL-21 after treatment (r = -0.550, P = 0.046; r = -0.581, P = 0.0371). TFR cells might participate in the pathogenesis of AS, and might be responsible for controlling the autoantibodies, the frequency and function of TFH cells to inhibit the development of AS.

T follicular regulatory (Tfr) cells: Dissecting the complexity of Tfr‐cell compartments

“…[155][156][157][158] However, a higher frequency of bTfr cells was found in patients with ankylosing spondylitis, systemic lupus erythematosus, and Sjögren's syndrome (SS). [159][160][161][162][163] Importantly, most of the literature describes studies where what is defined as Tfh cells contain both Tfh and CXCR5 + Tfr cells, likewise many other studies identify as Treg cells a mixture of conventional Treg cells together with Tfr cells. 15 An accurate assessment of the balance of Tfh to Tfr/ Treg populations requires quantification of the different subsets.…”

T follicular regulatory cells in the regulation of B cell responses

“…Although in depth studies are lacking, diminished Tfr cells have been correlated with extent of autoantibody production in several settings. Altered Tfr:Tfh cell ratios have been implicated in autoimmunity in induced [51, 53] and spontaneous lupus-like disease settings [43, 44], in murine arthritis models [76, 77], in human patients with ankylosing spondylitis [78] and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX)-like disease[79]. …”

Follicular regulatory T cells: a novel target for immunotherapy?

“…81 Percentages of cTfr cells and cTfh cells are significantly higher in patients with AS. 68 In addition, the frequency of cTfr cells is negatively associated with serum IgA in AS patients before treatment and is negatively associated with cTfh cells and the level of serum IL-21 after 1 month of standard treatment in drug responders. 68 IL-10 + -producing cTfr cells are increased in patients with IgG4-RD.…”

“…68 In addition, the frequency of cTfr cells is negatively associated with serum IgA in AS patients before treatment and is negatively associated with cTfh cells and the level of serum IL-21 after 1 month of standard treatment in drug responders. 68 IL-10 + -producing cTfr cells are increased in patients with IgG4-RD. 69 In addition, the frequency of cTfr cells is positively correlated with serum IgG4, ratio of IgG4/IgG, number of organs involved and soluble IL-2 receptor in IgG4-RD patients.…”

“…Altered frequencies and/or the suppressive capacity of cTfr cells have been elucidated in a multitude of AIDs, including systemic AIDs and organ‐specific AIDs (shown in Table ). Systemic AIDs involve rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), ankylosing spondylitis (AS), IgG4‐related disease (IgG4‐RD) and common variable immune deficiency (CVID) . Organ‐specific AIDs involve multiple sclerosis (MS), myasthenia gravis (MG), Hashimoto's thyroiditis (HT), primary biliary cholangitis (PBC), type 1 diabetes (T1D) and ulcerative colitis (UC) .…”