Immune Skew of Circulating Follicular Helper T Cells Associates With Myasthenia Gravis Severity

Abstract

ObjectiveTo clarify functional alterations of follicular helper T cells (Tfh) in myasthenia gravis (MG) because Tfh play important roles in helping B cells generate antibody-producing cells.MethodsA total of 24 immunotherapy-naive patients with anti–acetylcholine receptor (AchR) antibody–positive MG and 18 age-matched healthy subjects (HS) were enrolled. Samples from 6 patients were available for posttreatment analysis. Subsets of circulating Tfh (cTfh) and B cells were identified by flow cytometry analysis of surface molecules. Cytokine production by isolated cTfh subsets from 5 patients with MG and 5 HS was measured in vitro. Analysis was performed to examine the correlation between the frequency of cTfh subsets and that of plasmablasts and between cTfh subsets and the quantitative MG score.ResultscTfh increased with elevated expression of inducible T-cell costimulator (ICOS) in patients with MG. cTfh shifted to Th2 and Th17 over Th1 in MG. ICOShighcTfh produced significantly higher levels of interleukin (IL)-21, IL-4, and IL-17A than ICOSlow cTfh only in patients with MG. The frequency of cTfh within CD4 T cells was more closely associated with disease severity than the serum anti-AchR antibody titer and frequency of plasmablasts within B cells. Abnormalities of cTfh were improved after immunotherapy in parallel with clinical improvement.ConclusionsAlternation of cTfh is a key feature in the development of MG and may become a biomarker for disease severity and therapeutic efficacy.Classification of EvidenceThis study provides Class II evidence that the level of cTfh is associated with disease severity in patients with MG.

Circulating plasmablasts and follicular helper T-cell subsets are associated with antibody-positive autoimmune epilepsy

“…ICOS is preferentially expressed on Tfh; it is required for active regulation of B cell responses by interacting with ICOS ligands on B cells and is involved in IgG production ( 34 , 35 ). Although ICOS high cTfh has been reported to be elevated in myasthenia gravis and idiopathic thrombocytopenic purpura ( 16 , 36 ), elevated ICOS high cTfh levels in autoimmune epilepsy found in this study may reflect a common immunological feature of these diseases. Notably, cTfh was shifted to cTfh17 in the present study.…”

“…cTfh17 is characterized by the production of the cytokine IL-17 and expression of the transcription factor ROR-gt, which has been shown to have a potent stimulatory effect on plasmablasts that produce IgG in autoimmune diseases, such as dermatomyositis (15). Several reports have shown that cTfh shifts to a subset of cTfh17 or cTfh2 in autoantibody-associated autoimmune diseases (16)(17)(18)(19) that is consistent in patients with AE/Ab(+). Moreover, the cTfh17/cTfh1 cells ratio correlates with enhanced humoral immune response (20).…”

“…The cTfh2 and cTfh17 classes switch naive B cells to promote IgG production ( 15 ). In several antibody-associated autoimmune diseases, cTfh shift to cTfh17 or cTfh2 ( 16 – 20 ) and increase the cTfh17/cTfh1 cells ratio ( 21 ). Notably, the expression of inducible T-cell co-stimulator (ICOS) in cTfh and subset changes in cTfh have been identified as factors that promote B cell differentiation and antibody production ( 15 , 22 , 23 ).…”

The CXCL13/CXCR5 Immune Axis in Health and Disease—Implications for Intrathecal B Cell Activities in Neuroinflammation

“…It is similarly true for autoimmunity, as increased frequencies of cTfh cells occur in a vast spectrum of both autoantibody-mediated and autoantibody-associated autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), autoimmune thyroid diseases, myasthenia gravis (MG), neuromyelitis spectrum disorders (NMOSD), type 1 diabetes (T1D), and multiple sclerosis (MS) [ 26 , 27 , 59 ], frequently associated with a shift towards a higher Th2- plus Th17- to Th1-ratio, higher disease activity, disease severity, and elevated serum CXCL13 levels [ 9 , 27 , 28 , 29 , 73 , 74 ].…”

“…Circulating counterparts of Tfh cells (cTfh) have been detected in peripheral blood with increased frequencies in settings of acute and chronic immune activation [ 19 , 20 , 21 ]. Accumulating evidence revealing heterogeneities in subset differentiation and frequency distributions, and linking the activation states of certain subsets to antigen-specific high-affinity antibody responses, have made them hot topics in infection, vaccination, autoimmunity, and cancer research [ 19 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. Furthermore, CXCL13/CXCR5-associated immune activities occur in non-lymphoid tissues, where they contribute to organizing and shaping in situ adaptive immune responses via the formation of ELS [ 30 , 31 ] at chronic inflammatory sites during persistent infections, autoimmune diseases, and cancer [ 2 , 31 , 32 , 33 , 34 , 35 ].…”