Mapping the global research landscape and trends of autoimmune encephalitis: A bibliometric analysis.

Background: Autoimmune encephalitis (AE) is a neuroautoimmune disease featured by the presence of antibodies targeting neuronal surface, synaptic, or intracellular antigens. An increasing number of articles on its clinical manifestations, treatments, and prognosis have appeared in recent years. The objectives of this study were to summarize this growing body of literature and provide an overview of hotspots and trends in AE research using bibliometric analysis. Methods: We retrieved AE-related articles published between 1999 and 2022 from the Web of Science Core Collection. Using bibliometric websites and software, we analyzed the data of AE research, including details about countries, institutions, authors, references, journals, and keywords. Results: We analyzed 3348 articles, with an average of 32.83 citations per article and an H-index of 141. The USA (1091, 32.587%), China (531, 15.860%), Germany (447, 13.351%), England (266, 7.945%), and Japan (213, 6.362%) had the greatest numbers of publications. The top five institutions by numbers of publications were Oxford (143, 4.271%), the Udice French Research Universities (135, 4.032%), the University of Pennsylvania (135, 4.032%), l'Institut National de la Sante de la Recherche Medicale Inserm (113, 3.375%), and the University of Barcelona (110, 3.286%). The most productive authors were J. Dalmau (98, 2.927%), A. Vincent (65, 2.479%), H. Pruess (64, 1.912%), C. G. Bien (43, 1.284%), and F. Graus (43, 1.284%). "autoimmune encephalitis" was the most frequently used keyword (430), followed by "antibodies" (420), "NMDA receptor encephalitis" (383), and "limbic encephalitis" (368). In recent years, research hotspots have focused on the diagnosis and immunotherapy of NMDAR encephalitis and on limbic encephalitis. Conclusion: Developed Western countries have made significant contributions to this field. China has shown a steady increase in the number of publications in recent years, but the quality and influence of these articles warrant efforts at improvement. Future directions in AE research lie in two key areas: (i) the clinical manifestations, prevalence, and prognosis of AE (enabled by advances in diagnosis); and (ii) the efficacy and safety of targeted, individualized immunotherapy.

Mitochondrial and metabolic dysfunction of peripheral immune cells in multiple sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction has been implicated in the pathogenesis of MS, as studies have shown abnormalities in mitochondrial activities, metabolism, mitochondrial DNA (mtDNA) levels, and mitochondrial morphology in immune cells of individuals with MS. The presence of mitochondrial dysfunctions in immune cells contributes to immunological dysregulation and neurodegeneration in MS. This review provided a comprehensive overview of mitochondrial dysfunction in immune cells associated with MS, focusing on the potential consequences of mitochondrial metabolic reprogramming on immune function. Current challenges and future directions in the field of immune-metabolic MS and its potential as a therapeutic target were also discussed.

Unique association of anti-GABAA receptor encephalitis and myasthenia gravis in a patient with type A thymoma.

Association between anti-GABAAR encephalitis and myasthenia gravis is extremely rare with few reported cases. Herein, we report a case of a female patient diagnosed with anti-GABAAR encephalitis and thymoma at the first admission. She was administered glucocorticoids for long-term immunotherapy, and thymectomy with biopsy demonstrated a type A thymoma. After 4 months, the symptoms of encephalitis were relieved, but she then developed post-thymectomy myasthenia gravis with anti-AChR and anti-titin dual positivity. Antibodies to connective tissue (anti-ANA, anti-PCNA) and those characteristics of paraneoplastic syndrome (anti-Ma2/Ta) were also positive. She received oral glucocorticoids and tacrolimus as immunosuppressive therapy, and myasthenic symptoms were stable during a 2-year follow-up. Our case revealed that anti-GABAAR encephalitis and myasthenia gravis can appear in patient with type A thymoma at different periods, which alerts physicians to take long-term follow-up for anti-GABAAR encephalitis with thymoma, even after thymectomy. Concurrent positivity for more than one antibody after thymectomy is rarely observed, and their contribution to the clinical course and treatment decision remains to be further investigated.

Lymphoplasmapheresis versus plasma exchange in severe myasthenia gravis: a retrospective cohort study.

Background: Lymphoplasmapheresis (LPE) is a new therapy developed on the basis of traditional plasma exchange (PE) in combination with leukapheresis. Currently, it remains unclear whether PE and LPE show differences in efficacy for severe MG. Methods: A retrospective analysis was conducted on 198 MG patients, 75 in the PE group and 123 in the LPE group, and the patients' Myasthenia Gravis Foundation of America (MGFA) Clinical Classification was Class IV. The treatment outcome was the change in Quantitative Myasthenia Gravis Score (QMGS) from baseline to the end of treatment. Propensity score matching (PSM) was applied for the balance of confounders between the two groups. Results: In this study cohort, the safety profile of LPE and PE was good and no serious adverse events were observed. Based on PSM, 62 patients treated with LPE and 62 patients treated with PE were entered into a comparative efficacy analysis. In the PE group, patients underwent a total of 232 replacements, with a mean of 3.74. PE significantly improved the patients' QMGS performance, with the mean QMGS decreasing from 22.98 ± 4.03 points at baseline to 18.34 ± 5.03 points after treatment, a decrease of 4.68 ± 4.04 points (p < 0.001). A decrease of ≥3 points in QMGS was considered a significant improvement, with a treatment response rate of 67.7% in the PE group. In the LPE group, patients received a total of 117 replacements, with a mean of 1.89. The patients' mean QMGS was 23.19 ± 4.11 points at baseline and was 16.94 ± 5.78 points after treatment, a decrease of 6.26 ± 4.39 points (p < 0.001). The improvement in QMGS was more significant in patients treated with LPE compared to the PE group (p = 0.039). The treatment response rate in the LPE group was 79%, which was not significantly different compared to the PE group (p = 0.16). The LEP group had a shorter mean length of stay compared to the PE group (10.86 ± 3.96 vs. 12.14 ± 4.14 days), but the difference was not statistically significant (p = 0.13). During the 2-month follow-up period, LPE may be associated with better functional outcomes for patients, with lower QMG score and relapse rate. LPE and PE were both effective in reducing the levels of inflammatory cytokines (TNF-α, IL-1ß, and IL-6) and AChR-Ab. Compared to PE, LPE was superior in the reduction of AChR-Ab titer. Conclusion: In severe MG, LPE may be a more preferred treatment option than PE. It achieves treatment outcomes that are not inferior to or even better than PE with fewer replacements. This study provides further evidence to support the application of LPE as a new treatment option for MG.

Analysis of LAP+ and GARP+ Treg subsets in peripheral blood of patients with neuromyelitis optica spectrum disorders.

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a group of antibody-mediated inflammatory demyelinating central nervous system diseases. T lymphocytes participate in NMOSD pathogenesis, with regulatory T cells (Treg) being the core in maintaining immune homeostasis. Studies have revealed that different Treg subsets play different roles in autoimmune diseases. The distribution of LAP+ or GARP+ Treg subsets in NMOSD may help us deeply understand their immune mechanism. METHODS: This study reviewed 22 NMOSD patients and 20 normal controls. Flow cytometric analysis was utilized to detect subsets of Treg cells expressing Foxp3, Helios, LAP, or GARP in peripheral blood. ELISA was used to detect plasma TGF-ß1 and IL-10. In addition, changes in the proportion of Treg cell subsets before and after glucocorticoid treatment in 10 patients were analyzed. RESULTS: Compared with healthy controls, LAP and GARP expressions were significantly downregulated in the peripheral blood of NMOSD patients. TGF-ß1 expression in NMOSD patients was lower and was positively correlated with the ratio of CD4+GARP+ Treg cells. After treatment with glucocorticoid, LAP and GARP expressions in the peripheral blood of NMOSD patients were upregulated. CONCLUSIONS: The proportion of Treg cells expressing LAP and GARP is downregulated, implying that Treg cells with the best inhibitory function are insufficient to maintain autoimmune homeostasis in NMOSD patients. Upregulation of Treg cells expressing LAP and GARP in NMOSD patients may be one of the mechanisms of glucocorticoid treatment.

Application of lymphoplasmapheresis in the treatment of severe myasthenia gravis.

Background: Lymphoplasmapheresis (LPE) is a treatment that combines traditional plasma exchange and lymphocyte removal technique. It has been applied to treat a variety of autoimmune diseases, but its application value in the treatment of severe myasthenia gravis (MG) is not yet clear. Therefore, the aim of this study was to investigate the efficacy and safety of LPE in severe MG. Methods: Clinical data of 123 severe patients with MG (Myasthenia Gravis Foundation of America Clinical Classification, Class IV) who received LPE treatment were included in a retrospective analysis. Efficacy was evaluated by the change of Quantitative Myasthenia Gravis score (QMGS) before and after treatment. Univariate and multivariate logistic regression analysis was used to explore clinical factors affecting efficacy. Results: A total of 220 replacements were performed in 123 patients, with an average of 1.79 replacements per patient. The overall safety of LPE was good, and no serious adverse reactions occurred. After treatment, the mean QMGS of patients decreased significantly, from 23.40 ± 4.25 points before treatment to 17.93 ± 5.61 points after treatment, a decrease of 5.47 ± 4.16 points. 75.6% of patients experienced remission of clinical symptoms. During a 2-month follow-up of 64 patients, a progressive improvement in QMGS was found. Each muscle group involved in MG responded well to LPE treatment. In addition, LPE significantly reduced the levels of AChR-Ab and inflammatory cytokines in patients. Age ≥ 50 years and co-infection were unfavorable factors affecting the efficacy. Conclusions: In this study cohort, LPE is safe for the treatment of severe MG and achieves good treatment outcome with fewer replacements. In patients with MG, the avoidance and timely control of infection are necessary. Our study provides a potential new treatment option for severe MG.

Risk factors associated with adverse pregnancy outcomes and postpartum exacerbation in women with myasthenia gravis.

PROBLEM: Myasthenia gravis (MG), an autoimmune neuromuscular disease affecting women of childbearing age, exerts an impact on pregnancy, and vice versa. The purposes of the study were to evaluate adverse pregnancy outcomes and postpartum exacerbation in a cohort of Asian MG women, and to explore the predictors for these outcomes. METHODS OF STUDY: Thirty-seven MG pregnancies of 33 women followed in Xiangya and the second Xiangya hospitals between January 2012 and January 2022, were included in this study. Baseline maternal data, maternal complications, and neonatal outcomes were extracted from medical records. MG courses were evaluated during pregnancy and postpartum 1 year. RESULTS: In 5.4% of cases, MG exacerbation was reported during gestation, mostly in the third trimester, and in 38.9% in the postpartum period. Maternal complications were measured in 59.5% of women, gestational diabetes mellitus (GDM) taking the lead (29.7%) followed by premature rupture of membranes (PROMs) (18.9%). Transient neonatal MG (TNMG) and hyperbilirubinemia (HB) were seen in 24.3% of newborns. Body mass index (BMI) was the only independent predictor for maternal obstetric complications (p = .017), while thyroid disorders for GDM (p = .006). Younger mothers tended to give birth to babies with TNMG (p = .015). Primipara was the only risk factor for HB (p = .015). Higher gestational BMI gain (GBG) (p = .049) and without thyroid disorder (p = .017) were independent risk factors for puerperal exacerbation. Activated partial thromboplastin time and thyroid-stimulating hormone levels could be reliable to predict puerperal exacerbation. CONCLUSIONS: Most MG patients have unaffected courses during pregnancy but face a higher rate of maternal and fetal complications. Risk factors identified in our study aid the management of pregnancy in MG women.

Lymphoplasma Exchange Improves Myasthenia Gravis Exacerbations: A Retrospective Study in a Chinese Center.

Background: Lymphoplasma exchange (LPE), a technique combining plasma exchange with leukapheresis, is emerging as promising treatment for autoimmune diseases. Data on the efficacy and safety of LPE in myasthenia gravis (MG) therapy are scarce. In this study, we aimed to comprehensively review the clinical efficacy, safety, and immunological characteristics of LPE therapy in MG patients. Study Design and Methods: A Chinese cohort of 276 generalized MG patients in state of exacerbation, including impeding crisis, myasthenia crisis, and preparation for thoracic exsection between January 2014 and December 2020, were evaluated in this study. Results: A total of 276 patients with a median age of 45.5 ± 16.7 years underwent a total of 635 LPE sessions. Clinical scales of Quantitative Myasthenia Gravis (QMG) scores, Myasthenia Gravis Specific Manual Muscle Testing (MMT) scores, activities of daily living (ADL) scores, and quality of life (QOL) scores were improved during 4 weeks' follow-up. Adverse effects occurred in 20 out of 276 patients, with 14 patients having one adverse event each. Independent predictive factors for good response to LPE therapy were symptom onset before LPE therapy ≤3 days and age on LPE therapy <50 years of age. LPE decreased the serum levels of antibodies, immunoglobulins, and complements 4 weeks after the first replacement, with decreased levels of interleukin (IL)-17A and interferon (IFN)-γ and increased level of IL-10. Conclusion: LPE is an effective treatment for MG patients in state of exacerbation and preparation for thymectomy. Early use of LPE on early-onset MG may have good therapeutic effects. The potential mechanism for LPE is the polarization of cytokines from IL-17A, IFN-γ, into IL-10.

Case Report: Isolated facial and trigeminal nerve palsy without ataxia in anti-GQ1b antibody syndrome secondary to Mycoplasma pneumonia.

The presence of anti-GQ1b antibodies in serum or cerebrospinal fluid is a diagnostic indicator of the Miller-Fisher variant of Guillain-Barré syndrome (GBS), whereas anti-GQ1b antibody syndrome is rarely presented as acute bilateral pain in the cheeks and masticatory muscle fatigue without ophthalmoplegia, ataxia, or limb weakness. Here, we report a case of a female patient diagnosed with GBS characterized only by the involvement of the facial and trigeminal nerves who was positive for serum anti-GQ1b antibodies secondary to Mycoplasma pneumoniae infection. The patient was treated with macrolide antibiotics and neurotrophic drugs, and her symptoms were significantly alleviated after 1 month. This case indicates a new clinical presentation of GBS and anti-GQ1b antibody syndrome with a differential diagnosis of multiple cranial nerve damage of which neurological physicians should be aware. Positive anti-GQ1b antibodies secondary to infection were observed in this case, and antibiotic treatment resulted in a favorable prognosis. The specific underlying mechanism requires further investigation.

Soluble glucocorticoid-induced tumor necrosis factor receptor regulates Helios expression in myasthenia gravis.

BACKGROUND: Helios is important for functional and phenotype stability of regulatory T cells (Tregs). However, the role of Helios in autoimmune diseases and its regulation remains unclear. This study aimed to investigate the role of Helios+ Tregs in myasthenia gravis (MG) and glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) in the modulation of Helios. METHOD: Multicolor flow cytometry was performed to analyze Helios+ Tregs in peripheral blood from MG patients and healthy donors (HDs). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of soluble GITRL/GITR in plasma. Tregs were isolated via magnetic separation and treated with recombinant GITRL and GITR-Fc. Membrane GITRL on Tregs and expression of Helios and other markers (FOXP3, CD25, CD39, CTLA-4, PD-L1 and IL-10) involved in immunosuppressive activity were determined by flow cytometry. RESULT: Both Helios+ Tregs and soluble GITR were decreased in generalized MG (GMG) patients (n = 14), compared with HDs (n = 14) and ocular MG (OMG) patients (n = 16). Helios+ Tregs possessed greater immunosuppressive capacity compared to Helios- Tregs. Further analysis indicates soluble GITR was negatively correlated with quantitative MG score and promoted Helios expression and enhanced function of Tregs independently of membrane GITRL. CONCLUSION: This work demonstrates abnormal changes in Helios+ Tregs and soluble GITR in MG, as well as direct regulation of Helios by GITR in the context of Tregs. This work provides new insight into the role of GITR in the regulatory pathway of Helios and pathogenesis of MG.

Akt-1 and Akt-2 Differentially Regulate the Development of Experimental Autoimmune Encephalomyelitis by Controlling Proliferation of Thymus-Derived Regulatory T Cells.

Akt isoforms play key roles in multiple cellular processes; however, the roles of Akt-1 and Akt-2 isoforms in the development of T cell-mediated autoimmunity are poorly defined. In this study, we showed that Akt1-/- mice develop ameliorated experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, whereas Akt2-/- mice develop exacerbated EAE, compared with wild-type mice. At the cellular level, Akt-1 appears to inhibit proliferation of thymus-derived regulatory T cells (tTregs), which facilitates Ag-specific Th1/Th17 responses. In a sharp contrast to Akt-1, Akt-2 potentiates tTreg proliferation in vitro and in vivo and suppresses Ag-specific Th1/Th17 responses. Furthermore, treating mice with established EAE with a specific Akt-1 inhibitor suppressed disease progression. Our data demonstrate that Akt-1 and Akt-2 differentially regulate the susceptibility of mice to EAE by controlling tTreg proliferation. Our data also indicate that targeting Akt-1 is a potential therapeutic approach for multiple sclerosis in humans.

Immature Exosomes Derived from MicroRNA-146a Overexpressing Dendritic Cells Act as Antigen-Specific Therapy for Myasthenia Gravis.

Myasthenia gravis (MG) is a neurological autoimmune disease characterized by fluctuating weakness of certain voluntary muscles. Current treatments for MG are largely directed at suppressing the whole immune system by using immunosuppressants or glucocorticoids and often cause several side effects. The ideal therapeutic methods for MG should suppress aberrant immunoactivation specifically, while retaining normal function of the immune system. In this study, we first produced exosomes from microRNA-146a overexpressing dendritic cells (DCs). Then, we observed suppressive effects of those exosomes in experimental autoimmune myasthenia gravis (EAMG) mice. Results showed that exosomes from microRNA-146a overexpressing DCs expressed decreased levels of CD80 and CD86. In experimental autoimmune MG, exosomes from microRNA-146a overexpressing DCs suppressed ongoing clinical MG in mice and altered T helper cell profiles from Th1/Th17 to Th2/Treg both in serum and spleen, and the therapeutic effects of those exosomes were antigen-specific and partly dose dependent. All the findings provide experimental basis for antigen-specific therapy of MG.

The increased expression of CD21 on AchR specified B cells in patients with myasthenia gravis.

CD21, a major complement receptor expressed on B cells, is associated with autoimmune disorders. In the present study, we investigated the role of CD21 in pathogenesis of myasthenia gravis (MG) in relationship to anti-acetylcholine receptor (AchR) IgG (anti-AchR IgG) secretion. We detected increased surface expression of CD21 on AchR specified B cells as well as decreased surface expression of CD21 on total B cells in peripheral blood of patients with generalized MG (gMG). In addition, the serum concentrations of soluble secreted CD21 (sCD21) were decreased in patients with gMG. We also found that the level of CD21(+) AchR specified B cells correlated positively with serum anti-AchR IgG level, while the serum concentration of soluble CD21 correlated negatively with serum anti-AchR IgG level. Our data suggests that CD21 might facilitate its function on AchR specified B cell activation, resulting in the secretion of anti-AchR IgG.

Immature dendritic cell-derived exosomes: a promise subcellular vaccine for autoimmunity.

Exosomes, 60-90-nm-sized vesicles, are produced by a large number of cell types, including tumor cells, neurons, astrocytes, hemocytes, intestinal epithelial cells, and so on. Dendritic cell (DC), the most potent professional antigen-presenting cell in the immune system, produces exosomes in the course of maturation. Mature DCs produce exosomes with the ability to elicit potent immunoactivation, resulting in tumor eradication and bacterial or virus elimination. Given the notion that exosomes are stable and easy to be modified artificially, autologous mature DC-derived exosomes have been vaccinated into patients with malignant diseases. In clinical trials utilizing exosomes as therapeutic approaches, researchers observed considerable curative effect with little side effect. However, immature or suppressive DC-derived exosomes harbor anti-inflammatory properties distinct from mature DC-derived exosomes. In murine models of autoimmune disease and transplantation, immature DC-derived exosomes reduced T cell-dependent immunoactivation, relieved clinical manifestation of autoimmune disease, and prolonged survival time of transplantation. Although the exact mechanism of how immature DC-derived exosomes function in vivo is still unclear, and there are no clinical trials regarding application of exosome vaccine into patients with autoimmune disease, we will analyze the promise of immature DC-derived exosomes as a subcellular vaccine in autoimmunity in this review.

[Congenital myopathy with type 1 fiber predominance in two children].

Non-progressive congenital myopathy is a group of muscle diseases occurring at birth or during teenage years. A number of new reports of congenital myopathy, such as homogeneous bodies myopathy, muscle quality control myopathy and type 1 fiber predominance have recently been reported, but they lack of sufficient quantity and constant clinico-pathologic manifestations. This paper reports two cases of congenital myopathy with type 1 fiber predominance confirmed by muscle biopsy. The clinical manifestations of the two children (a 4.5-year-old girl and an 11-year-old boy) included non-progressive symptoms of muscle weakness, skeletal deformities and other clinical features of congenital myopathy. The physical examinations showed a long face or figure and funnel chest or kyphosis/scoliosis, high palatal arch and wing-like shoulder. Serum levels of creatine kinase were normal but slightly elevated serum lactate dehydrogenase levels were noted in the two children. The skeletal muscle biopsy by ATPase staining showed that type 1 fibers accounted for more than 90% of the total number of muscle fibers. No other abnormal pathological changes, such as central cores, muscle tube and central nuclei, were found in the two children.

[Expression of IL-21 in the peripheral blood of myasthenia gravis patients and its correlation with anti-AChR-Ab class switch].

OBJECTIVE: To explore the role of IL-21 in the pathogenesis of myasthenia gravis (MG) and its influence on the the class switch of anti-AChR antibodies. METHODS: Blood was taken from 26 patients and 18 healthy controls, and the expression of IL-21R mRNA in peripheral blood mononuclear cells (PBMCs) was detected by RT-PCR. The expression of IL-21R on B lymphocytes was measured by flow cytometry, while the concentrations of serum IL-21 and the levels of anti-AChR-IgG and its isotype IgG(1), IgG(2), and IgG(3) were tested by ELISA. RESULTS: The serum concentration of IL-21 in the MG group was higher than that in the control group (31.686±8.499 pg/mL, 15.147±6.366 pg/mL) and the difference was significant (P<0.01). IL-21R mRNA expressed on PBMCs in the MG group was higher than that in the control group (0.139±0.052, 0.101±0.022), and the difference was significant (P<0.05). There was no difference between ocular MG and generalized MG subgroup (P>0.05). Compared with the control group, the expression of IL-21R on B lymphocytes also increased in the MG group (P<0.05). In the anti-AChR-Ab positive MG group, the serum concentration of IL-21 showed positive correlation with anti-AChR-IgG(P<0.05),but no correlation with its isotype IgG(1), IgG(2), and IgG(3), respectively(P>0.05). Expression of IL-21R mRNA in the PBMCs showed no correlation with the level of serum anti-AChR-IgG and its isotype IgG(1), IgG(2), and IgG(3), respectively(P>0.05); however the expression of IL-21R in B lymphocytes showed positive correlation with anti-AChR-IgG and it's isotype IgG(1) and IgG(3) (P<0.05,P<0.01,P<0.05), but no correlation with IgG(2) (P>0.05). CONCLUSION: IL-21 might induce the class switch of anti-AChR antibodies to IgG(1) and IgG(3) isotype through IL-21R on B lymphocytes which promotes the pathogenesis of the MG.