Circulating CCR7^loPD-1^hi Follicular Helper T Cells Indicate Disease Activity and Glandular Inflammation in Patients with Primary Sjögren's Syndrome

Abstract

Since primary Sjögren's syndrome (pSS) is an autoummune disease of B cell hyperactivity and pathologic autoantibody response, follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells are suggested to be key players in pSS. We examined subsets of Tfh and Tfr cells from the blood in pSS patients, and whether these subsets represent disease activity, glandular inflammation, or autoantibody responses in pSS. Circulating Tfh and Tfr cells, along with their specific subsets, were identified from the peripheral blood of 18 pSS patients and 14 age- and sex-matched healthy controls (HCs) using flow cytometry analysis. Blood Tfr and Tfh cell ratios were increased in pSS patients compared with HCs. The CCR7 lo PD-1 hi subset of circulating Tfh cells was increased in pSS patients with high degree of focal lymphocytic sialadenitis; whereas circulating Tfh cells did not differ between pSS patients and HCs. The frequency of CCR7 lo PD-1 hi Tfh cells was significantly correlated with disease activity scores and differentiated B cells. PD-1 expression on blood Tfh and Tfr cells showed positive correlations with IL-21 in pSS. Increasing trend of blood Tfr cells was observed in pSS patients, and blood Tfr cells (particularly Th1 and Th17 subsets) represented hypergammaglobulinemia in pSS. In summary, circulating CCR7 lo PD-1 hi Tfh cells indicated disease activity and glandular inflammation in pSS. Circulating Tfr cells, shifted toward Th1 and Th17 subsets, indicated ongoing IgG production in pSS. Subsets of circulating Tfh or Tfr cells could be biomarkers for disease monitoring and patient stratification in pSS.

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

“…Tfh cells immunophenotyping is based on sustained surface expression of CXCR5 high , ICOS, and PD-1, intracellular expression of the essential transcription factor Bcl-6, and secretion of abundant IL-21 amounts, although some variations are dependent on their source and activated state [ 83 ]. Tfh cells are increased in peripheral blood of SS patients [ 83 , 84 ], and activated Tfh cells are associated with disease activity and have been considered as biomarker predictors of tissue damage [ 85 , 86 ]. Furthermore, circulating Tfh cells represent a heterogeneous population based on surface marker expression and cytokine production, existing distinct subpopulations acquiring different activities in supporting B cell response in several autoimmune disease [ 87 ].…”

“…For instance, there areTh17-like cells expressing markers for Tfh cells that have been detected significantly increased in pSS patients, correlating with humoral parameters and disease activity [ 84 ]. Strikingly, the CCR7 low PD1 high subset is a novel population of circulating Tfh cell that have been linked to Tfh as a partial effector phenotype, and their differentiation was suggested occurring before GC formation [ 86 , 89 ]. Moreover, this novel subset showed to mediate better B cell response than other CD4+CCR5+ T cell populations [ 89 ].…”

“…Moreover, this novel subset showed to mediate better B cell response than other CD4+CCR5+ T cell populations [ 89 ]. In regard to SS, the CCR7 low PD1 high subset was displayed increased in blood from pSS patients and their frequency significantly correlated with disease activity and SG inflammation [ 86 ].…”

Activated inducible co-stimulator-positive programmed cell death 1-positive follicular helper T cells indicate disease activity and severity in ulcerative colitis patients

“…Therefore, the expression of ICOS and PD-1 represents activated Tfh cells and plays an important role in helping B cell differentiation and antibody production. ICOS and PD-1 expression on Tfh is reported to be increased in several immune-related diseases, such as Sjögren's syndrome (SS) [23], multiple sclerosis (MS) [24] and primary biliary cirrhosis (PBC) [25], and further found to be positively correlated with diseases severity [23,25]. However, the changes and potential clinical significance of ICOS and PD-1 expression on Tfh cells in UC remain unclear.…”

Autoantibody-Mediated Dysfunction of Salivary Glands Leads to Xerostomia in SKG Mice

“…Sjögren's syndrome (SS) is a complex heterogeneous disease clinically defined by the presence of salivary and lacrimal gland dysfunction. In addition to sicca symptoms such as xerostomia and xerophthalmia, SS is characterized by autoimmune features including hypergammaglobulinemia and abundance of autoantibodies (1)(2)(3). Whether the presence of focal lymphocytic infiltrates in exocrine glands is a critical feature of SS is still the subject of debate, because of the fact that approximately 20% of patients with primary SS do not have such infiltrates (4).…”