CD4+CXCR5+PD-1+ T Follicular Helper Cells Play a Pivotal Role in the Development of Rheumatoid Arthritis

Abstract

Background T follicular helper (Tfh) cells are a subgroup of activated CD4 + T cells in the germinal centers of secondary lymphoid organs, they play critical roles in the development of many chronic autoimmune inflammatory diseases. The aim of this study was to investigate whether circulating Tfh cells contribute to the development of rheumatoid arthritis (RA). Material/Methods Thirty patients fulfilled the diagnosis criteria that was established by the American College of Rheumatology and 30 healthy controls were recruited. The frequency of Tfh cells in patients and collagen-induced arthritis (CIA) in DBA/1J mice were analyzed by flow cytometry. The serum IL-21 level was examined by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of Blimp-1 and Bcl-6 were detected by qRT-PCR. Results RA patients had more CD4 + PD-1 + CXCR5 + Tfh cells in peripheral blood compared with healthy controls, and CIA in DBA/1J mice showed similar results. Higher mRNA expression of Bcl-6 and lower Blimp-1 mRNA expression were observed in patients with RA compared to healthy controls, and the expression level of IL-21 was higher in RA patients, which was also seen in CIA mice. Furthermore, the spleen CD4 + ICOS + CXCR5 + Tfh cells in CIA mice show significantly higher frequency than that in the control mice. The percentage of CD4 + PD-1 + CXCR5 + Tfh cells was correlated positively with the values of erythrocyte sedimentation rate (ESR) (r=0.968, P <0.001), rheumatoid factor (RF) (r=0.962, P <0.001), C-reactive protein (CRP) (r=0.953, P <0.001), and anti-cyclic citrullinated peptide antibodies (ACPA) (r=0.966, P <0.001), and the level of serum interleukin (IL)-21 in RA patients showed positive correlation with ESR (r=0.982, P <0.001), RF (r=0.959, P <0.001), CRP (r=0.951, P <0.001), and ACPA (r=0.971, P <0.001) as well. Conclusions The activated Tfh cells in the peripheral blood may be responsible for the development of RA.

The Imbalance of Circulating Follicular Helper T Cells and Follicular Regulatory T Cells Is Associated With Disease Activity in Patients With Ulcerative Colitis

“…In rheumatoid arthritis, TFH is significantly elevated and Abbreviations: BFA, brefeldin A; CBC, complete blood cell count; CRP, Creactive protein; GALT, gut-associated lymphoid tissues; GC, germinal center; HC, healthy controls; Ig, immunoglobulin; IL, interleukin; PBMC, peripheral blood mononuclear cells; PMA, phorbol myristate acetate; SLE, systemic lupus erythematosus; SLEDAI, SLE Disease Activity Index; TFH, follicular helper T cells; TFR, follicular regulatory T cells; TIGIT, T cell Ig and ITIM domain; Treg, regulatory T cells; UC, ulcerative colitis; WBC, white blood cells; 5-ASA, 5-aminosalycilates. related to disease activity (15). In a DSS UC mouse model, TFH was significantly increased, and positively correlated with the amount of colonic lesions (16).…”

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

“…Blimp-1 in peripheral blood is upregulated in patients with IgG4-RD [14]. Compared with the healthy controls, higher expression of Bcl6 and lower Blimp-1 expression in the peripheral blood are observed in patients with rheumatoid arthritis (RA) [15].…”

Human follicular helper T lymphocytes critical players in antibody responses

“…The follicles in these tissues contain large numbers of Tfh cells, and it is thought that Tfh facilitate the formation and maintenance of ectopic follicles. ( 28 , 30 ) However, in RA and in other situations the outcome depends on the balance of Tfh and Treg cells. ( 31 )…”

“…Os folículos desses tecidos contêm grande número de linfócitos Tfh, e acredita-se que essas células facilitem a formação e a manutenção de folículos ectópicos. ( 28 , 30 ) Porém, na AR, assim como em outras situações, o resultado depende do equilíbrio entre linfócitos Tfh e Tfreg. ( 31 )…”