Expression of TRAF6 in peripheral blood B cells of patients with myasthenia gravis.

BACKGROUND: Tumor necrosis factor receptor-associated factor 6 (TRAF6) can regulate the activation of inflammatory signaling pathways by acting as an E3 ubiquitin ligase, which enhances B cell activation. This study aimed to evaluate the expression of TRAF6 in the peripheral blood B cells of myasthenia gravis (MG) patients and analyze the relationships between TRAF6 expression and clinical characteristics. METHOD: In our study, the expression level of TRAF6 in peripheral blood B cells of 89 patients was measured by flow cytometry compared with that of healthy subjects. The effects of disease severity, MG classification and immunotherapy on TRAF6 expression level were also analyzed. RESULTS: In our study, TRAF6 expression was elevated in CD19+ B cells and CD19+CD27+ memory B cells in generalized MG (GMG) patients compared with ocular MG (OMG) patients (p = 0.03 and p = 0.03, respectively). There was a significant positive correlation between the TRAF6 expression level and disease severity in both OMG patients and GMG patients (CD19+ B cells: OMG: p < 0.001, r = 0.89; GMG: p = 0.001, r = 0.59; CD29+CD27+ B cells: OMG: p = 0.001, r = 0.80; GMG: p = 0.048, r = 0.38). TRAF6 expression was significantly elevated in CD19+ B cells and CD19+CD27+ memory B cells in GMG with acute aggravation compared with GMG in MMS (p = 0.009 and p = 0.028, respectively). In the eleven MG patients who were followed, TRAF6 expression in B cells and memory B cells was significantly decreased after treatment (p = 0.03 and p < 0.01, respectively). CONCLUSION: TRAF6 is potentially a useful biomarker of inflammation in patients with MG, and might be used to evaluate the effectiveness of treatment.

The prevalence of anti-neurofascin-155 antibodies in patients with neuromyelitis optica spectrum disorders.

Anti-neurofascin-155 (NF155) antibodies have been observed in two cases with neuromyelitis optica spectrum disorders (NMOSD). This study investigated the prevalence of anti-NF155 antibodies in patients with NMOSD and the clinical features of anti-NF155 antibody-positive patients. Sera from 129 patients with NMOSD were screened with anti-NF155 antibodies by cell-based assay (CBA) and re-examined using immunostaining of teased mouse sciatic nerve fibres. Fifty-six patients with multiple sclerosis (MS) and 50 healthy controls (HC) were also enrolled for detecting anti-NF155 antibodies. A total of 12.40% (16 of 129) of patients with NMOSD were positive for anti-NF155 antibodies confirmed by both CBA and immunostaining. Immunoglobulin (Ig) G1 was the predominant subclass. However, none of 56 MS patients or 50 HC were positive for anti-NF155 antibodies. Anti-NF155 antibody-positive NMOSD patients had a higher proportion of co-existing with autoimmune diseases (p < 0.001) and higher positive rates of serum non-organ-specific autoantibodies, including anti-SSA antibodies (p < 0.001), anti-SSB antibodies (p = 0.008), anti-Ro-52 antibodies (p < 0.001) and rheumatoid factor (p < 0.001). Five anti-NF155 antibody-positive NMOSD patients who took part in the nerve conduction study showed mildly abnormal results. Differences in some nerve conduction study parameters were observed between anti-NF155 antibody-positive and negative patients. Anti-NF155 antibodies occurred in a small proportion of NMOSD patients. Anti-NF155 antibody-positive NMOSD patients tended to co-exist with autoimmune diseases.

Increased serum IL-36γ levels are associated with disease severity in myasthenia gravis patients.

BACKGROUND: Interleukin 36 (IL-36), as a gradually recognized cytokine, is involved in the occurrence and evolution of autoimmune diseases. Nevertheless, the relationship between myasthenia gravis (MG) and IL-36 is rarely reported. METHODS: We evaluated the serum levels of IL-36 (IL-36α, IL-36ß and IL-36γ) by enzyme-linked immunosorbent assay (ELISA). Further, clinical parameters in 97 MG patients and 49 healthy controls (HCs) were carefully measured. RESULTS: Serum IL-36γ levels were significantly elevated in the MG patients compared with the HCs (p < 0.0001). Compared to those in remission, patients in the acute phase exhibited higher levels of IL-36α and IL-36γ (p = 0.038 and p = 0.011, respectively). Furthermore, patients with generalized MG (GMG) exhibited markedly higher serum IL-36γ levels than those with ocular MG (OMG) (p = 0.003). CONCLUSIONS: The serum levels of IL-36γ in patients with MG were increased and positively correlated with disease severity and may thus have potential as a serological MG marker.

Behavioural thermoregulation by the endangered crocodile lizard (Shinisaurus crocodilurus) in captivity.

Understanding the factors that may affect behavioural thermoregulation of endangered reptiles is important for their conservation because thermoregulation determines body temperatures and in turn physiological functions of these ectotherms. Here we measured seasonal variation in operative environmental temperature (Te), body temperature (Tb), and microhabitat use of endangered crocodile lizards (Shinisaurus crocodilurus) from a captive population, within open and shaded enclosures, to understand how they respond to thermally challenging environments. Te was higher in open enclosures than in shaded enclosures. The Tb of lizards differed between the open and shaded enclosures in summer and autumn, but not in spring. In summer, crocodile lizards stayed in the water to avoid overheating, whereas in autumn, crocodile lizards perched on branches seeking optimal thermal environments. Crocodile lizards showed higher thermoregulatory effectiveness in open enclosures (with low thermal quality) than in shaded enclosures. Our study suggests that the crocodile lizard is capable of behavioural thermoregulation via microhabitat selection, although overall, it is not an effective thermoregulator. Therefore, maintaining diverse thermal environments in natural habitats for behavioural thermoregulation is an essential measure to conserve this endangered species both in the field and captivity.

Increased serum IL-36ß and IL-36γ levels in patients with neuromyelitis optica spectrum disorders: association with disease activity.

BACKGROUND: Interleukin 36 (IL-36) cytokines belong to the IL-1 family and play an important role in some autoimmune diseases. However, the relationship between IL-36 and neuromyelitis optica spectrum disorders (NMOSD) remains unclear. METHODS: We determined serum IL-36α, IL-36ß and IL-36γ levels and assessed correlations with clinical characteristics in 50 NMOSD patients and 30 healthy controls (HC). RESULTS: The concentrations of serum IL-36ß and IL-36γ were significantly higher in patients with NMOSD than in HCs and decreased during remission. Serum IL-36ß levels were positively correlated with the annual relapse rate (ARR), spinal cord lesion length and Expanded Disability Status Scale (EDSS) scores. CONCLUSIONS: Serum IL-36ß and IL-36γ levels were related to disease activity in NMOSD patients and may be important biomarkers of NMOSD.

Neuromyelitis optica spectrum disorders with and without connective tissue disorders.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) often coexist with connective tissue disorders (CTD). The aim of this study was to investigate and compare the features of NMOSD with and without CTD. METHODS: NMOSD patients with (n = 18) and without CTD (n = 39) were enrolled, and the clinical, laboratory, and magnetic resonance imaging (MRI) features of the two groups were assessed. RESULTS: Most of the demographic and clinical features examined were similar between NMOSD patients with and without CTD. Serum immunoglobulin G (IgG), percentage of γ-globulin and seropositivity for several other autoantibodies were significantly elevated in NMOSD patients with CTD (P < 0.05). NMOSD with CTD was marked by longer spinal cord lesions and a lower frequency of short transverse myelitis (TM) than NMOSD without CTD (P < 0.05). NMOSD with CTD also featured more T1 hypointensity and T2 bright spotty lesions (BSLs) on MRI than NMOSD without CTD (P = 0.001 and 0.011, respectively). There were no other differences in laboratory, MRI and clinical characteristics between different NMOSD subtypes. CONCLUSIONS: A few characteristics differed between NMOSD with and without CTD. NMOSD patients with CTD had higher serum IgG, longer spinal cord lesions, a lower frequency of short TM and more T1 hypointensity and T2 BSLs on spinal MRI than NMOSD patients without CTD.

Augmentation of Circulating Follicular Helper T Cells and Their Impact on Autoreactive B Cells in Myasthenia Gravis.

Myasthenia gravis (MG) is a chronic humoral immunity-mediated autoimmune disorder of the neuromuscular junction characterized by muscle weakness. Follicular helper T (Tfh) cells may be the key Th cell subset that promotes MG development, as their major function is helping B cell activation and Ab production. Aberrance of thymus-derived Tfh cells might be implicated in autoimmune diseases including MG; just how circulating Tfh cells, especially those from patients with a normal thymus, contribute to MG pathogenesis remains to be uncovered. In this article, we characterize a population of circulating CD4(+)CXCR5(+)PD-1(+) Tfh cells in ocular and generalized MG patients without thymic abnormalities and demonstrate that the circulating Tfh cells are significantly enriched in generalized MG patients but not in ocular MG patients compared with healthy subjects, whereas a proportion of follicular regulatory T cells decreased in MG patients. In addition, the frequency of plasma cells and B cells was higher and the serum levels of IL-6/IL-21 were also elevated in these MG patients. The activated Tfh1 and Tfh17 in Tfh cells are the major source for IL-21 production in MG patients. A strong correlation between Tfh cells and the plasma cell frequency and anti-acetylcholine receptor Ab titers was evident in generalized MG patients. In particular, we found that Tfh cells derived from MG patients promoted B cells to produce Abs in an IL-21 signaling-dependent manner. Collectively, our results suggest that circulating Tfh cells may act on autoreactive B cells and thus contribute to the development of MG in patients without thymic abnormalities.

Recent developments in nanomedicine for melanoma treatment.

Melanoma is a most aggressive skin cancer with limited therapeutic options and its incidence is increasing rapidly in recent years. The discovery and application of new targeted therapy agents have shown significant benefits. However, adverse side-effects and resistance to chemotherapy remain formidable challenges in the clinical treatment of malignant melanoma. Nanotherapeutics offers an important prospect of overcoming these drawbacks. The anti-tumoral applications of nanomedicine are varied, including those in chemotherapy, RNA interference, photothermal therapy, and photodynamic therapy. Furthermore, nanomedicine allows delivery of the effector structures into the tumor site via passive or active targeting, thereby allowing increased therapeutic specificity and reduced side effects. In this review, we summarize the latest developments in the application of nanocarrier-mediated targeted drug delivery to melanoma and nanomedicine-related clinical trials in melanoma treatment. We also discuss existing problems and opportunities for future developments, providing direction and new thoughts for further studies.

Distinctive characteristics of early-onset and late-onset neuromyelitis optica spectrum disorders.

OBJECTIVES: Little is known about patients with neuromyelitis optica spectrum disorders (NMOSD) as defined by onset age. This study aimed to analyze the different demographic, clinical, laboratory, and magnetic resonance imaging (MRI) characteristics in early-onset (≤50 years) NMOSD (EONMOSD) and late-onset (>50 years) NMOSD (LONMOSD). MATERIALS AND METHODS: We enrolled 142 patients with NMOSD from Tianjin Medical University General Hospital, Tianjin, China, and categorized them into two groups according to the age of onset: EONMOSD and LONMOSD. Demographic, clinical, laboratory, and MRI characteristics were collected and compared between the two groups. Serum aquaporin-4 (AQP4) antibody levels were determined by cell-based assay and fluorescence immunoprecipitation assays. RESULTS: Among the patients studied, 83 had early onset (≤50 years) and 59 had late onset (>50 years) of NMOSD. As compared with LONMOSD, EONMOSD patients had more severe visual disability according to functional scores in clinical parameters, significantly lower C3 and C4 serum levels, more frequent cervical lesions, and more lesions around the fourth ventricle, but fewer lesions in hemispheric white matter. LONMOSD patients suffered more motor and sensory disability than EONMOSD patients. CONCLUSIONS: In NMOSD, the clinical, laboratory, and MRI features differ according to age of onset, suggesting that differences in pathogenesis and treatment should be further investigated.

[Determination of eight components in Lamiophlomis rotate by UPLC method and preliminary study on influencing factors of contents].

To establish a method for simultaneous determination of the contents of sesamoside, menthyl chloride, chlorogenic acid, caffeic acid, 8-O-acetyl-phloridzin methyl ester, forsythiaside B, luteolin, and ergosterol, the LIPLC analysis was performed on a Kinetex XB-C18 (4.6 mm×50 mm,2.6 µm)column with acetonitrile (A)-0.1% phosphoric acid solution (B) as the mobile phase. The flow rate is 1.0 mL min⁻¹. The detection wavelength was 238, 320 and 350 nm and column temperature was 30 ℃. The results showed that the eight components could be completely separated with good linear relationships (r≥0.999 8) in the linear range. The average recoveries were 96.61%-100.4%. The method was simple with strong specificity and high precision. It can be used for the identification and quality evaluation of the Lamiophlomis rotate.The results also showed that there was a correlation between the various components, and the habitat was the main factor affecting the content of the eight components. However, the degradation gradient had no obvious effect on the contents, while the content of sesamoside was significantly decreased after one year of storage.

DNA methylation and histone acetylation regulate the expression of MGMT and chemosensitivity to temozolomide in malignant melanoma cell lines.

Malignant melanoma is an aggressive, highly lethal dermatological malignancy. Chemoresistance and rapid metastasis limit the curative effect of multimodal therapies like surgery or chemotherapy. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes adducts from the O6-position of guanine to repair DNA damage. High MGMT expression is associated with resistance to therapy in melanoma. However, it is unknown if MGMT is regulated by DNA methylation or histone acetylation in melanoma. We examined the effects of the DNA methylation inhibitor 5-Aza-2'-deoxycytidine and histone deacetylase inhibitor Trichostatin A alone or in combination on MGMT expression and promoter methylation and histone acetylation in A375, MV3, and M14 melanoma cells. This study demonstrates that MGMT expression, CpG island methylation, and histone acetylation vary between melanoma cell lines. Combined treatment with 5-Aza-2'-deoxycytidine and Trichostatin A led to reexpression of MGMT, indicating that DNA methylation and histone deacetylation are associated with silencing of MGMT in melanoma. This study provides information on the role of epigenetic modifications in malignant melanoma that may enable the development of new strategies for treating malignant melanoma.

[Study on DNA Fourier infrared spectroscopy of three kinds of Nicotiana tabacum L].

The aim is analyzing genetic reLationship and identifying varieties by detecting DNA differences of three kinds of Nicotiana tabacum L. using Fourier infrared spectrum (FTIR). Results show that DNA FTIR of three kinds of Nicotiana tabacum L. is relatively similar. They all have four obvious characteristic peaks. 1 105 cm(-1) beLongs to symmetrical stretching vibration of phosphodiester bond, 1 250 cm(-1) is unsymmetrical stretching vibration of phosphodiester bond, 1 400 cm(-1) is contributed to glucosidic bond, and 1 622 cm(-1) belongs to C4-C5=C6 stretching vibration of cytosine. DNA FTIR data was handled by smoothing, standardizing, second derivative, principal component analysis and Hierarchical cluster analysis. The standard model of Hierarchical cluster combined with principal component of the second derivative was set up. The correct rate of identification is 100%. Yunyan 87 and K326 were clustered into one by using the model. The distance coefficient is 0.003, and DNA similarity is 99.7%, Hongda was clustered into one by itself. The correct rate of cluster is 100%. The study provides a reference for Nicotiana tabacum L. variety identification and genetic breeding.

4-Octyl itaconate inhibits inflammation via the NLRP3 pathway in neuromyelitis optica spectrum disorders.

OBJECTIVE: Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene-1 (IRG1) and the IRG1-itaconic acid-NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4-octyl itaconate (4-OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute-onset NMOSD and to investigate the inhibitory effects of 4-OI on NLRP3 inflammasome activation via the IRG1-itaconic acid-NLRP3 pathway in monocytes and macrophages by using in vitro models. METHODS: Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3-related inflammatory factors. Subsequently, the effects of 4-OI on the IRG1-itaconic acid-NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP-1 cells) via in vitro experiments. RESULTS: Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4-OI inhibited the activation of the IRG1-itaconic acid-NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD. INTERPRETATION: 4-OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD-derived PBMCs and in a human macrophage model. Thus, 4-OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future.

A Simple Score (MOG-AR) to Identify Individuals at High Risk of Relapse After MOGAD Attack.

BACKGROUND AND OBJECTIVES: To identify predictors for relapse in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to develop and validate a simple risk score for predicting relapse. METHODS: In China National Registry of Neuro-Inflammatory Diseases (CNRID), we identified patients with MOGAD from March 2023 and followed up prospectively to September 2023. The primary endpoint was MOGAD relapse, confirmed by an independent panel. Patients were randomly divided into model development (75%) and internal validation (25%) cohorts. Prediction models were constructed and internally validated using Andersen-Gill models. Nomogram and relapse risk score were generated based on the final prediction models. RESULTS: A total of 188 patients (comprising 612 treatment episodes) were included in cohorts. Female (HR: 0.687, 95% CI 0.524-0.899, p = 0.006), onset age 45 years or older (HR: 1.621, 95% CI 1.242-2.116, p < 0.001), immunosuppressive therapy (HR: 0.338, 95% CI 0.239-0.479, p < 0.001), oral corticosteroids >3 months (HR 0.449, 95% CI 0.326-0.620, p < 0.001), and onset phenotype (p < 0.001) were identified as factors associated with MOGAD relapse. A predictive score, termed MOG-AR (Immunosuppressive therapy, oral Corticosteroids, Onset Age, Sex, Attack phenotype), derived in prediction model, demonstrated strong predictive ability for MOGAD relapse. MOG-AR score of 13-16 indicates a higher risk of relapse (HR: 3.285, 95% CI 1.473-7.327, p = 0.004). DISCUSSION: The risk of MOGAD relapse seems to be predictable. Further validation of MOG-AR score developed from this cohort to determine appropriate treatment and monitoring frequency is warranted. TRIAL REGISTRATION INFORMATION: CNRID, NCT05154370, registered December 13, 2021, first enrolled December 15, 2021.

Clinical features of COVID-19 infection in patients with myasthenia gravis: a real-world retrospective study.

Objective: We investigated the risk factors associated with severe or critical Coronavirus disease 2019 (COVID-19) infection due to the Omicron variant in patients with myasthenia gravis (MG) and determined the potential effect of COVID-19 on myasthenic exacerbation during the Omicron pandemic. Methods: This retrospective study included 287 patients with MG in Tianjin, China. Clinical data of the patients were collected using electronic questionnaires, databases, and clinical records. Results: The overall infection rate was 84.7%. Advanced age, comorbidities, generalized phenotype, and MG instability were drivers of COVID-19 severity, and post-COVID-19 myasthenic exacerbation. The concurrent use of a steroid-sparing agent did not affect COVID-19 susceptibility or severity. It did lower the risk of myasthenic exacerbation after COVID-19 infection. Patients with severe COVID-19 experienced myasthenic exacerbation earlier than patients with non-severe infection (p < 0.001). The severity of COVID-19 (Hazards Ratio = 3.04, 95% CI: 1.41-6.54, p = 0.004) and the clinical phenotype (Hazards Ratio = 3.29, 95% CI: 1.63-6.63, p < 0.001) emerged as independent risk factors for early MG exacerbation. Conclusion: Generally, patients with MG appear to be susceptible to the Omicron strains. Immunotherapy for MG did not increase COVID-19 susceptibility or severity. We do not advocate an immediate cessation of ongoing immunosuppressive treatments once a COVID-19 infection is diagnosed. Instead, a judicious evaluation of the risks and benefits, tailored to each individual, is recommended.

Parylene-based implantable platinum-black coated wire microelectrode for orbicularis oculi muscle electrical stimulation.

A novel and simple process was proposed to fabricate a parylene-based platinum-black coated wire microelectrode for orbicularis oculi muscle electrical stimulation. Compared with conventional microelectrodes, wire microelectrodes would enable smaller wounds, increased ease of implantation, and improved cosmesis. Meanwhile, the circumferential electrode sites of this wire microelectrode fabricated by lift-off process would contribute to fully contact with tissue and reduction of electrode-tissue interface impedance. The width and the amount of electrode sites could be decided by the thickness and the amount of sacrificial layer, respectively. The platinum-black coatings were electroplated on electrode sites by applying a current pulse train in chloroplatinic acid solution with ultrasonic bath for further electrode-tissue interface impedance reduction and good mechanical stability of coatings. Electrode impedance at 1 kHz has been significantly reduced by 90%, and the cathodic charge storage capacity (CSCc) has been increased by 13 times. In addition, hematoxylin-eosin (HE) staining section of muscle demonstrated the good biocompatibility of this electroplated platinum-black. By applying a charge imbalanced biphasic stimulation waveform for orbicularis oculi muscle stimulation, the rabbits with facial paralysis rehabilitated the function of closing eyes. This kind of microelectrode will be promising for neuromuscular applications.

Multi-Level Analyses of Genome-Wide Association Study to Reveal Significant Risk Genes and Pathways in Neuromyelitis Optica Spectrum Disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system and it is understandable that environmental and genetic factors underlie the etiology of NMOSD. However, the susceptibility genes and associated pathways of NMOSD patients who are AQP4-Ab positive and negative have not been elucidated. METHODS: Secondary analysis from a NMOSD Genome-wide association study (GWAS) dataset originally published in 2018 (215 NMOSD cases and 1244 controls) was conducted to identify potential susceptibility genes and associated pathways in AQP4-positive and negative NMOSD patients, respectively (132 AQP4-positive and 83 AQP4-negative). RESULTS: In AQP4-positive NMOSD cases, five shared risk genes were obtained at chromosome 6 in AQP4-positive NMOSD cases by using more stringent p-Values in both methods (p < 0.05/16,532), comprising CFB, EHMT2, HLA-DQA1, MSH5, and SLC44A4. Fifty potential susceptibility gene sets were determined and 12 significant KEGG pathways were identified. Sixty-seven biological process pathways, 32 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained from the GO annotations of the 128 pathways identified. In the AQP4 negative NMOSD group, no significant genes were obtained by using more stringent p-Values in both methods (p < 0.05/16,485). The 22 potential susceptibility gene sets were determined. There were no shared potential susceptibility genes between the AQP4-positive and negative groups, furthermore, four significant KEGG pathways were also identified. Of the GO annotations of the 165 pathways identified, 99 biological process pathways, 37 cellular-component pathways, and 29 molecular-function pathways with a p-Value of <0.05 were obtained. CONCLUSION: The potential molecular mechanism underlying NMOSD may be related to proteins encoded by these novel genes in complements, antigen presentation, and immune regulation. The new results may represent an improved comprehension of the genetic and molecular mechanisms underlying NMOSD.

Elevated cerebrospinal fluid ß2-microglobulin levels in patients with neuromyelitis optica spectrum disorders.

Cerebrospinal fluid (CSF) ß2-microglobulin (ß2-MG) levels elevated in patients with multiple sclerosis (MS). We examined the levels of ß2-MG in serum and cerebrospinal fluid (CSF) from 46 patients with neuromyelitis optica spectrum disorders (NMOSD), in serum from 21 healthy controls (HC), in CSF from 25 disease controls with non-inflammatory neurological diseases (NIND) with normal CSF results. CSF ß2-MG levels were significantly higher in patients with NMOSD than controls and with weak association with the number of white blood cells, protein and lactate levels in CSF. CSF ß2-MG is thus one more, non-specific indicator of inflammation in NMOSD.

Positive association of herpes simplex virus-IgG with multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS), and whether herpes simplex virus (HSV) infection is associated with the development of MS remains controversial. We aimed to investigate potential associations between MS or clinically isolated syndrome (CIS) and the prevalence of IgG and DNA for HSV in the clinical samples. METHODS: A systematic search of English databases (PubMed, Embase and Cochrane Library) was performed. The prevalence of IgG against herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) and DNA for HSV-1 or HSV-2 in clinical samples were pooled and compared between patients with MS/CIS and controls using Stata 12.0. RESULTS: A total of 1756 patients with MS/CIS and 6429 controls from eight studies were included. The pooled results showed a significantly statistical difference in the seroprevalence of IgG against HSV-2 (OR 1.764, 95% CI [1.410 to 2.206], P = 0.000) between patients with MS/CIS and controls. However, no significantly statistical difference was shown in the seroprevalence of IgG against HSV-1 (OR 1.166, 95% CI [0.737 to 1.845], P = 0.512) between patients with MS/CIS and controls. Similarly, there was no significantly statistical difference in the prevalence of HSV-1 DNA (OR 0.957, 95% CI [0.310 to 2.949], P = 0.938) and HSV-2 DNA in cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMC) (OR 0.506, 95% CI [0.022 to 11.416], P = 0.668) between patients with MS/CIS and controls. Subgroup analysis suggested that mean age at sampling might be a source of heterogeneity, and the seroprevalence of IgG against HSV-1 was significantly increased in the pediatric patients with MS/CIS (OR 1.488, 95% CI [1.130 to 1.959], P = 0.005), compared with the controls. CONCLUSIONS: The study demonstrated that prior HSV-1 infection might relate to the onset of pediatric MS/CIS and might not play a role in the development of adult MS. Furthermore, prior HSV-2 infection might have a correlation with MS/CIS. The mechanism remains to be further studied.