| Background:Multiple sclerosis(MS) is a relapse and remission autoimmune disease in the central nervous system, resulting in damage to the myelin and axons of the brain and spinal cord. Neuromyelitis optica(NMO) is an autoimmune disease characterized by severe optic neuritis and transverse myelitis. NMO spectrum disorders(NMOSD) are limited forms of NMO. Both MS and NMO/NMOSD are usually followed by relapse and a poor prognosis, finally leading to neurological disability.Nowadays, the accurate mechanisms underlying MS and NMO/NMOSD are not completely understood, and there is no specific cure. So, it is urgent to explore the pathogenesis of MS and NMO/NMOSD. MS is considered as a T cell-mediated autoimmune disease; nonetheless, a lot of groups have shown that humoral immunity participates in the pathogenic process of MS. NMO/NMOSD is a complicated immunological disorder mainly involving humoral immunity. T cells also participate in the development of NMO/NMOSD. However, how T cell immunity regulates humoral responses during the pathogenesis of MS and NMO/NMOSD has not been clarified.Follicular helper T(Tfh) cells play a key role in humoral immunity deriving from their ability to provide help for B cell differentiation into plasma cells and memory cells, and antibody production. Current studies showed that the dysregulation of Tfh cells may participate in the development of systemic lupus erythematosus(SLE), rheumatoid arthritis(RA), myasthenia gravis(MG) and so on. There are circulating Tfh cells which share similar properties of GC Tfh cells. Most circulating Tfh cells are memory Tfh cells. Immune memory is the hallmark of acquired immune response. After a primary response, most effector T cells undergo apoptosis, whereas a small proportion survive and become memory T cells. Memory T cells induce a potent and quick secondary response upon antigen re-challenge and participate in the pathogenesis of recurrent autoimmune diseases, hypersensitivity, and vaccination. However, it is unclear whether the expression and roles of memory Tfh cells are changed in MS and NMO/NMOSD patients.In conclusion, it is of great importance to explore the roles of memory Tfh cells in the development of MS and NMO/NMOSD. Objective:The study is aimed at examining the potential roles of circulating memory Tfh cells in the pathogenesis of MS and NMO/NMOSD. Materials and Methods:The numbers of different subsets of circulating memory Tfh cells in MS and NMO/NMOSD before and after treatment as well as HC were examined by flow cytometry. The levels of plasma and CSF IL-21 in both MS and NMO/NMOSD patients, as well as the levels of AQP4-Ig G in plasma and CSF of NMO/NMOSD patients were measured by ELISA. We sorted circulating memory Tfh cells from MS patients, NMO/NMOSD patients and HC, as well as CD19+ B cells from HC through flow cytometry. Memory Tfh cells from MS patients, NMO/NMOSD patients and HC were cultured with CD19+ B cells from HC, respectively. The percentages of memory B cells and plasma cells in co-cultured cells were examined by flow cytometry. Also, the levels of Ig G, Ig M and Ig A in co-cultured supernatants were measured by ELISA. Results:(1) The numbers of memory Tfh cells and ICOS+ memory Tfh cells in MS patients before treatment were significantly greater than that in HC. In addition, the numbers of CCR7+ memory Tfh and CCR7+ICOS+ memory Tfh cells in MS patients before treatment were significantly higher than that in HC.(2) The levels of plasma IL-21 were higher in MS patients before treatment than that in HC. Moreover, the levels of CSF IL-21 were significantly higher in MS patients before treatment than in NND patients.(3) The numbers of ICOS+ memory Tfh cells were positively correlated with the EDSS scores and the levels of plasma IL-21 in MS patients before treatment. Furthermore, the numbers of CCR7+ICOS+ memory Tfh cells were positively correlated with the EDSS scores, the levels of plasma IL-21, the levels of CSF IL-21, the levels of CSF Ig G, the levels of CSF MBP-Ab and CSF MOG-Ab in MS patients before treatment.(4) The isolated circulating memory Tfh cells from MS patients before treatment or HC were incubated with CD19+ B cells from HC. The percentages of CD27+CD19+ B cells, Ig D-CD27+CD19+ B cells and CD38+CD19+ B cells in CD19+ B cells, as well as the levels of Ig M and Ig G in the co-culture systems comprising MS patients’ memory Tfh cells and CD19+ B cells from HC were significantly greater compared with that of HC’s memory Tfh cells and CD19+ B cells from HC.(5) After treatment with methylprednisolone, the numbers of memory Tfh, ICOS+ memory Tfh, CCR7+ memory Tfh and CCR7+ICOS+ memory Tfh cells in MS patients who achieved CR(MS-CR) were significantly lower than those before treatment. The levels of plasma IL-21 in MS-CR after treatment significantly decreased, as compared with that before treatment.(6) After treatment with methylprednisolone, no decreased trend was found in the numbers of memory Tfh, ICOS+ memory Tfh, CCR7- memory Tfh, CCR7-ICOS+ memory Tfh, CCR7+ memory Tfh or CCR7+ICOS+ memory Tfh cells in patients with PR(MS-PR) post-treatment compared with that pre-treatment. In addition, no decreased trend was detected in the levels of plasma IL-21 in MS-PR before and after treatment.(7) The percentages of circulating memory Tfh, ICOS+ memory Tfh, CCR7-memory Tfh, CCR7-ICOS+ memory Tfh, CCR7+ memory Tfh and CCR7+ICOS+ memory Tfh cells among CD4+ T cells in NMO/NMOSD patients before treatment were significantly greater than that in the HC. In line with these results, the numbers of circulating memory Tfh cells, ICOS+ memory Tfh, CCR7- memory Tfh, CCR7-ICOS+ memory Tfh, CCR7+ memory Tfh and CCR7+ICOS+ memory Tfh cells were significantly higher in patients before treatment than in HC.(8) There was no difference in the percentages and numbers of circulating memory Tfh, ICOS+ memory Tfh, CCR7- memory Tfh, CCR7-ICOS+ memory Tfh, CCR7+ memory Tfh or CCR7+ICOS+ memory Tfh cells between AQP4-Ig G seronegative patients and AQP4-Ig G seropositive patients.(9) The levels of plasma IL-21 were higher in NMO/NMOSD patients before treatment than in HC. Moreover, the levels of CSF IL-21 were also greater in NMO/NMOSD patients before treatment than in NND patients.(10) The percentages of CCR7- memory Tfh and CCR7-ICOS+ memory Tfh cells were positively correlated with ARR and the levels of plasma IL-21 in the NMO/NMOSD patients before treatment. Among AQP4-Ig G seropositive patients before treatment, the percentages of CCR7- memory Tfh and CCR7-ICOS+ memory Tfh cells were positively correlated with the levels of plasma AQP4-Ig G. In addition, the percentages of CCR7+ memory Tfh and CCR7+ICOS+ memory Tfh cells were positively correlated with CSF WBC counts, CSF protein levels, and CSF IL-21 levels in NMO/NMOSD patients before treatment.(11) The isolated circulating memory Tfh cells from NMO/NMOSD patients before treatment and HC were incubated with CD19+ B cells from HC, respectively. The percentages of CD27+CD19+ B cells, Ig D-CD27+CD19+ B cells and CD38+CD19+ B cells in CD19+ B cells, as well as the levels of Ig M and Ig G in the co-culture systems comprising NMO/NMOSD patients’ memory Tfh cells and CD19+ B cells from HC were significantly greater compared with that of HC’s memory Tfh cells and CD19+ B cells from HC.(12) After treatment with methylprednisolone, the numbers of CCR7-ICOS+ memory Tfh and CCR7+ICOS+ memory Tfh cells in NMO/NMOSD patients who achieved PR(NMO/NMOSD-PR) were significantly lower than those before treatment. What’s more, the levels of plasma IL-21 in NMO/NMOSD-PR after treatment significantly decreased, as compared with that before treatment.(13) After treatment with methylprednisolone, no difference was found in the numbers of CCR7-ICOS+ memory Tfh or CCR7+ICOS+ memory Tfh cells in NMO/NMOSD patients with NR(NMO/NMOSD-NR) post-treatment compared with that pre-treatment. In addition, no evident change was found in the levels of plasma IL-21 between NMO/NMOSD-NR before and after treatment. Conclusion:(1) The expression of different subsets of circulating memory Tfh cells and the levels of IL-21 in MS and NMO/NMOSD patients were greater than that in HC. Circulating memory Tfh cells in MS and NMO/NMOSD patients have a greater ability to promote the differentiation of B cells and antibody production compared with HC. Circulating memory Tfh cells may be associated with the development of MS and NMO/NMOSD and may serve as a new therapeutic target.(2) In MS patients, circulating CCR7+ICOS+ memory Tfh cells may play a crucial role in the autoimmune inflammation lesions in the CNS and may serve as a new biomarker for evaluating the disease activity and severity in patients with relapsed MS.(3) In NMO/NMOSD patients, CCR7- memory Tfh and CCR7-ICOS+ memory Tfh cells may serve as new biomarkers for evaluating disease relapse and may participate in the AQP4-Ig G production in the periphery. CCR7+ memory Tfh and CCR7+ICOS+ memory Tfh cells may play an instrumental role in the autoimmune inflammation lesions in the CNS.(4) Corticosteroids can adjust the abnormal expression of circulating memory Tfh cells and IL-21 in some MS and NMO/NMOSD patients, leading to the recovery of immune homeostasis. |
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