Peripheral Blood Lymphocyte Subgroups in Patients Undergoing Hemodialysis with Medium Cut-Off Membranes and High-Flux Membranes: THE SHE Continuation Study.

INTRODUCTION: Chronic kidney disease (CKD) poses a significant global health burden, with increasing prevalence and high morbidity and mortality rates, particularly in end-stage kidney disease (ESKD). While traditional risk factors contribute, the exact mechanisms remain elusive, with inflammation playing a pivotal role. Medium cut-off (MCO) membranes offer promise in improving dialysis outcomes by efficiently clearing uremic toxins without substantial albumin loss. We aimed to elucidate the impact of MCO and high-flux (HF) membranes on peripheral blood lymphocyte subpopulations in hemodialysis patients. METHODS: Twenty-four ESKD patients underwent 36 sessions each with MCO and HF membranes. Immunophenotyping by flow cytometry was performed to analyze lymphocyte subsets. RESULTS: NK cell percentages significantly increased with MCO, returning to baseline with HF. Th1 cells decreased post-HF, while Th2 and TFH cells increased with MCO and persisted. Treg cells remained stable with MCO but decreased with HF. CONCLUSION: MCO dialysis induced an anti-inflammatory shift, evidenced by increased Th2 and TFH cells and stable Treg cells. NK cells also responded favorably to MCO. These findings underscore MCO membranes' potential to modulate immune responses and improve patient outcomes in ESKD.

The Association Between Serum Levels of Glial Biomarkers, Clinical Severity and Electro-encephalography Features in Idiopathic West and Lennox-Gastaut Syndromes.

Introduction: Although the contribution of enhanced glial activity in seizure induction is increasingly recognized, the role of glia-induced neuroinflammation in the physiopathology of epileptic encephalopathy (EE) has been scarcely investigated. Methods: To delineate the contribution of glial activity in EE, we measured levels of glia-derived mediators with previously described biomarker value, including glial fibrillary acidic protein (GFAP), high mobility group box 1 (HMGB1), chitinase-3-like protein 1 (CHI3L1), soluble CD163 (sCD163) and triggering receptor expressed on myeloid cells 2 (TREM2) by ELISA in sera of patients with idiopathic West syndrome (WS, n=18), idiopathic Lennox-Gastaut syndrome (LGS, n=13) and healthy controls (n=31). Results: Patients with EE showed significantly higher CHI3L1 levels compared to healthy controls. Levels of HMGB1, CHI3L1, sCD163 and TREM2 were higher in LGS patients than WS patients and/or healthy controls. One or more of the investigated mediators were associated with treatment responsiveness, disease severity and presence of pathological features on electroencephalography (EEG). Conclusions: To our knowledge, our findings provide the initial patient-based evidence that astrocyte- and microglia-mediated neuroinflammation might be involved in the pathogenesis of LGS and WS. Moreover, glial mediators may serve as prognostic biomarkers in patients with idiopathic EE.

Distinctive sleep complaints and polysomnographic findings in antibody subgroups of autoimmune limbic encephalitis.

INTRODUCTION: Sleep disturbances are being increasingly recognized in association with autoimmune encephalitis (AIE). We investigated the prevalence of sleep-related symptoms and polysomnographic features of patients with AIE and the long-term outcomes in these patients in a multi-center, prospective study from Turkey. METHODS: We prospectively evaluated patients with definite AIE in a common database including demographics, AIE-related and sleep-related symptomatology. Maximum and latest modified Rankin scores (mRS) and Liverpool Outcome Score (LOS) were noted. RESULTS: Of 142 patients, 87 patients (61.3%) fulfilled the criteria for definite AIE (mean age, 46.8+18.8 years; 51.7% women; mean disease duration, 21.0+38.4 months). 78.9% of patients had at least one or more new onset or worsened sleep-related symptomatology: insomnia (55.3%), excessive daytime sleepiness (EDS, 28.0%), sleep apnea (18.7%), REM sleep behavior disorder (RBD, 17.3%), restless legs syndrome (10.7%) and oneiric stupor (9.3%). Sleep efficiency, N3 and REM sleep were decreased and N1 sleep was increased in patients with Ab[+] AIE. LOS points were highest in those with insomnia and sleep apnea, and lowest in those with EDS, RBD and oneiric stupor. RBD and sleep apnea were more common in anti-LG1 Ab[+] group than anti-NMDAR Ab[+] group. Index of periodic leg movements was highest in anti-LG1 Ab[+] group. Patients with EDS and oneiric stupor had more common memory problems. Maximum and latest mRS scores were positively correlated with EDS and oneiric stupor. EDS, RBD and oneiric stupor were negatively correlated with LOS points. CONCLUSION: Our study emphasizes the presence and importance of early diagnosis of sleep disturbances in AIE in regard to their deteriorative influences on disease prognosis.

Altered Cerebrospinal Fluid Neurofilament Light Chain but Not Neurogranin Levels Are Associated with Response to Ocrelizumab Treatment in Relapsing-Remitting Multiple Sclerosis: A Preliminary Study.

INTRODUCTION: Ocrelizumab is a CD20-targeting monoclonal antibody used for treatment of multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) neurofilament light (NFL) chain levels are reduced in MS patients under ocrelizumab treatment indicating a preventive action against neuro-axonal degeneration. Our aim, in this preliminary study, was to explore the impact of ocrelizumab treatment on synaptic integrity through assessment of neurogranin levels. METHODS: Thirteen relapsing-remitting multiple sclerosis (RRMS) patients resistant to first-line immunomodulating agents were enrolled and followed up for 24 months under ocrelizumab treatment. Disease activity was monitored by periodic EDSS, MSSS, and cranial-spinal MRI assessments. No evidence of disease activity (NEDA)-3 was determined, and CSF levels of NFL (marker of neuro-axonal integrity) and neurogranin (marker of synaptic integrity) were measured by ELISA at baseline and 12-month ocrelizumab treatment. RESULTS: Seven RRMS patients, who preserved NEDA-3 status during 24-month follow-up, showed ≥30% NFL level decrease, whereas 6 patients with stable/increased NFL levels displayed relapse, MRI lesion, or disability progression. Although most RRMS patients exhibited increased CSF levels of neurogranin under ocrelizumab treatment, patients with and without neurogranin level increase did not differ in terms of clinical features and NEDA-3 status. Baseline neurogranin levels negatively correlated with baseline EDSS scores. CONCLUSION: Our results confirm that NFL effectively monitors treatment response of RRMS patients under ocrelizumab treatment. Neurogranin does not appear to exhibit a similar benefit in screening of RRMS disease activity. Nevertheless, lower neurogranin levels are associated with increased disability in RRMS indicating a potential disease activity biomarker function.

Effects of Transcranial Direct Current Stimulation on Clinical Outcomes, Calcitonin Gene-Related Peptide, and Pituitary Adenylate Cyclase-Activating Polypeptide-38 Levels in Menstrual Migraine.

OBJECTIVES: Transcranial direct current stimulation (tDCS) has been suggested as an alternative treatment option for migraine. The present study aimed to evaluate the efficacy of tDCS on clinical outcomes in addition to calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide 38 (PACAP-38) levels in individuals with menstrual-related migraine (MRM) for the first time. MATERIALS AND METHODS: In this parallel study, 58 female patients between the ages of 18 and 45 years, including 36 with MRM and 22 with nonmenstrual migraines (nMM), were recruited. Sessions of 2-mA 20-minute anodal tDCS were administered over the left dorsolateral prefrontal cortex within three consecutive days (1:1 active and sham stimulation). Migraine attack frequency, severity, analgesic usage, CGRP, and PACAP-38 levels of the patients were evaluated before and one month after tDCS. RESULTS: After tDCS, in the active group compared with the sham group, the frequency (p = 0.031), the severity of attacks (p = 0.003), the number of days with headache (p = 0.004), and the analgesic usage (p = 0.024) were all decreased. In both MRM and nMM groups, the frequency and severity of attacks and analgesic usage were decreased in those receiving active stimulation (p < 0.001 for each). CGRP and PACAP-38 levels were no different in the active group and the sham group after tDCS. CONCLUSIONS: tDCS was shown to be efficacious in migraine prophylaxis and a valuable option for migraine and MRM treatment. The absence of changes in serum CGRP and PACAP-38 levels suggests that tDCS efficacy may stem from distinct cerebral electrophysiological mechanisms.

Autoimmune Encephalitis with Antibodies Against A-Amino-3hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor and γ-Aminobutyric Acid-Beta Receptor: Case Report.

Introduction: Limbic encephalitis is a rapidly progressing disease that presents with seizures, psychiatric symptoms, and recent memory loss. Detection of more than one autoantibody is a rare condition in this disease where an underlying autoantibody is frequently detected. Although different autoantibodies have been reported in the literature, no case has been reported regarding the association of anti-γ-aminobutyric acid-beta-receptor (anti-GABABR) and anti-α-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (anti-AMPAR). Case: In this presentation, a 46-year-old female patient with subacute development of short-term memory loss and behavioral symptoms will be described. Anti-GABABR and anti-AMPAR were positive in the anti-neuronal antibody panel sent from the cerebrospinal fluid and serum. Small cell lung cancer was detected as a result of malignancy screening tests. The patient's complaints and autoantibody positivity regressed after immunotherapy. Conclusion: In this case report, a case with coexistence of anti-GABABR and anti-AMPAR antibodies, which has not been previously reported in the literature, is described. As more cases with the coexistence of these two antibodies are detected, knowledge on clinical aspect, laboratory and treatment will increase.

Electrodiagnostic methods to verify Guillain-Barré syndrome subtypes in Istanbul: A prospective multicenter study.

BACKGROUND AND AIMS: This study aimed to identify the clinical characteristics and electrodiagnostic subtypes of Guillain-Barré syndrome (GBS) in Istanbul. METHODS: Patients with GBS were prospectively recruited between April 2019 and March 2022 and two electrodiagnostic examinations were performed on each patient. The criteria of Ho et al., Hadden et al., Rajabally et al., and Uncini et al. were compared for the differentiation of demyelinating and axonal subtypes, and their relations with anti-ganglioside antibodies were analyzed. RESULTS: One hundred seventy-seven patients were included, 69 before the coronavirus disease 2019 pandemic (April 2019-February 2020) and 108 during the pandemic (March 2020-March 2022), without substantial changes in monthly frequencies. As compared with the criteria of Uncini et al., demyelinating GBS subtype diagnosis was more frequent according to the Ho et al. and Hadden et al. criteria (95/162, 58.6% vs. 110/174, 63.2% and 121/174, 69.5%, respectively), and less frequent according to Rajabally et al.'s criteria (76/174, 43.7%). Fourteen patients' diagnoses made using Rajabally et al.'s criteria were shifted to the other subtype with the second electrodiagnostic examination. Of the 106 analyzed patients, 22 had immunoglobulin G anti-ganglioside antibodies (14 with the axonal subtype). They had less frequent sensory symptoms (54.5% vs. 83.1%, p = 0.009), a more frequent history of previous gastroenteritis (54.5% vs. 22.9%, p = 0.007), and a more severe disease as compared with those without antibodies. INTERPRETATION: Serial electrodiagnostic examinations are more helpful for accurate subtype diagnosis of GBS because of the dynamic pathophysiology of the disease. We observed no significant increase in GBS frequency during the pandemic in this metropolis.

Peripheral blood regulatory B and T cells are decreased in patients with focal epilepsy.

Patients with focal epilepsy of unknown cause (FEoUC) may display T cell infiltration in post-surgery brain specimens and increased serum levels of pro-inflammatory cytokines produced by B and T cells, indicating potential involvement of adaptive immunity. Our study aimed to investigate the peripheral blood distribution of B and T cell subgroups to find clues supporting the distinct organization of adaptive immunity in FEoUC. Twenty-two patients with FEoUC and 25 age and sex matched healthy individuals were included. Peripheral blood mononuclear cells were immunophenotyped by flow cytometry. Expression levels of anti-inflammatory cytokines and FOXP3 were measured by real-time PCR. Carboxyfluorescein succinimidyl ester (CFSE) proliferation assay was conducted using CD4+ T cells. Patients with FEoUC showed significantly decreased regulatory B (Breg), B1a, plasmablast and regulatory T (Treg) cell percentages, and increased switched memory B and Th17 cell ratios. Moreover, CD4+CD25+CD49d- Tregs of FEoUC patients displayed significantly reduced TGFB1 and FOXP3, but increased IL10 gene expression levels. CD4+ helper T cells of patients with FEoUC gave more exaggerated proliferation responses to phytohemagglutinin, anti-CD3 and anti-CD28 stimulation. Patients with FEoUC display increased effector lymphocyte, decreased regulatory lymphocyte ratios, and impaired Treg function and enhanced lymphocyte proliferation capacity. Overall, this pro-inflammatory phenotype lends support to the involvement of adaptive immunity in FEoUC.

Disease activity in chronic inflammatory demyelinating polyneuropathy: association between circulating B-cell subsets, cytokine levels, and clinical outcomes.

Chronic inflammatory demyelinating polyneuropathy (CIDP), a common and treatable autoimmune neuropathy, is frequently misdiagnosed. The aim of this study is to evaluate the relationship between immunological markers and clinical outcome measures in a mixed cohort of patients with typical CIDP and CIDP variants at different disease stages. Twenty-three typical, 16 multifocal and five distal CIDP patients were included. Twenty-five sex and age-matched healthy controls and 12 patients with Charcot-Marie-Tooth type 1A (CMT1A) disease served as controls. Peripheral B-cell populations were analyzed by flow cytometry. IL6, IL10, TNFA mRNA and mir-21, mir-146a, and mir-155-5p expression levels were evaluated by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMC) and/or skin biopsy specimens. Results were then assessed for a possible association with clinical disability scores and intraepidermal nerve fiber densities (IENFD) in the distal leg. We detected a significant reduction in naive B cells (P ≤ 0.001), plasma cells (P ≤ 0.001) and regulatory B cells (P < 0.05), and an elevation in switched memory B cells (P ≤ 0.001) in CIDP compared to healthy controls. CMT1A and CIDP patients had comparable B-cell subset distribution. CIDP cases had significantly higher TNFA and IL10 gene expression levels in PBMC compared to healthy controls (P < 0.05 and P ≤ 0.01, respectively). IENFDs in the distal leg showed a moderate negative correlation with switched memory B-cell ratios (r = -0.51, P < 0.05) and a moderate positive correlation with plasma cell ratios (r = 0.46, P < 0.05). INCAT sum scores showed a moderate positive correlation with IL6 gene expression levels in PBMC (r = 0.54, P < 0.05). Altered B-cell homeostasis and IL10 and TNFA gene expression levels imply chronic antigen exposure and overactivity in the humoral immune system, and seem to be a common pathological pathway in both typical CIDP and CIDP variants.

Silencing of FCRLB by shRNA ameliorates MuSK-induced EAMG in mice.

INTRODUCTION: Muscle specific kinase (MuSK) antibody positive myasthenia gravis (MG) often presents with a severe disease course and resistance to treatment. Treatment-refractory patients may respond to B cell depleting treatment methods. Our aim was to investigate whether inhibition of Fc receptor-like B (FCRLB) could effectively suppress autoimmunity without diminishing B cell counts in animal model of MG, a classical antibody-mediated autoimmune disease. METHODS: Experimental autoimmune MG was induced in Balb/C mice with two s.c. immunizations with recombinant human MuSK in complete Freund's adjuvant. FCRLB was silenced with a lentiviral particle transported shRNA in myasthenic mice with a single i.p. injection during second MuSK-immunization. Control immunized mice received scrambled shRNA or saline. Mice were observed for clinical parameters for 28 days and at termination, anti-MuSK IgG, neuromuscular junction (NMJ) deposits, muscle AChR expression and lymph node B and T cell ratios were assessed by ELISA, immunofluorescence, immunoblotting and flow cytometry, respectively. RESULTS: FCRLB shRNA-treated mice showed no muscle weakness or weight loss at termination. Also, they exhibited higher grip strength and muscle AChR levels, lower anti-MuSK IgG and NMJ IgG/C3 levels than control mice. Flow cytometry analysis showed that ratios of major effector lymph node B and T cell populations were not altered by FCRLB silencing. However, regulatory T and CD19 + CD5+ B cell ratios were decreased in FCRLB shRNA-group. CONCLUSION: Our results provide evidence regarding involvement and therapeutic value of FCRLB in MuSK-MG. Silencing of FCRLB appears to substantially inhibit antibody production without interfering with survival of major lymphocyte populations.

Therapeutic Effect of C-Vx Substance in K18-hACE2 Transgenic Mice Infected with SARS-CoV-2.

C-Vx is a bioprotective product designed to boost the immune system. This study aimed to determine the antiviral activity of the C-Vx substance against SARS-CoV-2 infection. The effect of C-Vx in K18-hACE2 transgenic mice against the SARS-CoV-2 virus was investigated. For this purpose, ten mice were separated into experimental and control groups. Animals were infected with SARS-CoV-2 prior to the administration of the product to determine whether the product has a therapeutic effect similar to that demonstrated in previous human studies, at a histopathological and molecular level. C-Vx-treated mice survived the challenge, whereas the control mice became ill and/or died. The cytokine-chemokine panel with blood samples taken during the critical days of the disease revealed detailed immune responses. Our findings showed that C-Vx presented 90% protection against the SARS-CoV-2 virus-infected mice. The challenge results and cytokine responses of K18-hACE2 transgenic mice matched previous scientific studies, demonstrating the C-Vx's antiviral efficiency.

Chloride intracellular channel protein-1 (CLIC1) antibody in multiple sclerosis patients with predominant optic nerve and spinal cord involvement.

INTRODUCTION: Antibodies to cell surface proteins of astrocytes have been described in chronic inflammatory demyelinating disorders (CIDD) of the central nervous system including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Our aim was to identify novel anti-astrocyte autoantibodies in relapsing remitting MS (RRMS) patients presenting predominantly with spinal cord and optic nerve attacks (MS-SCON). METHODS: Sera of 29 MS-SCON patients and 36 healthy controls were screened with indirect immunofluorescence to identify IgG reacting with human astrocyte cultures. Putative target autoantigens were investigated with immunoprecipitation (IP) and liquid chromatography-mass/mass spectrometry (LC-MS/MS) studies using cultured human astrocytes. Validation of LC-MS/MS results was carried out by IP and ELISA. RESULTS: Antibodies to astrocytic cell surface antigens were detected in 5 MS-SCON patients by immunocytochemistry. LC-MS/MS analysis identified chloride intracellular channel protein-1 (CLIC1) as the single common membrane antigen in 2 patients with MS-SCON. IP experiments performed with the commercial CLIC1 antibody confirmed CLIC1-antibody. Home made ELISA using recombinant CLIC1 protein as the target antigen identified CLIC1 antibodies in 9/29 MS-SCON and 3/15 relapsing inflammatory optic neuritis (RION) patients but in none of the 30 NMOSD patients, 36 RRMS patients with only one or no myelitis/optic neuritis attacks and 36 healthy controls. Patients with CLIC1-antibodies showed trends towards exhibiting reduced disability scores. CONCLUSION: CLIC1-antibody was identified for the first time in MS and RION patients, confirming once again anti-astrocytic autoimmunity in CIDD. CLIC1-antibody may potentially be utilized as a diagnostic biomarker for differentiation of MS from NMOSD.

Distribution of peripheral blood mononuclear cell subtypes in patients with West syndrome: Impact of synacthen treatment.

BACKGROUND: West Syndrome (WS) is an epileptic encephalopathy that typically occurs in infants and is characterized by hypsarrhythmia, infantile spasms, and neurodevelopmental impairment. Demonstration of autoantibodies and cytokines in some WS patients and favorable response to immunotherapy have implicated inflammation as a putative trigger of epileptiform activity in WS. Our aim was to provide additional support for altered inflammatory responses in WS through peripheral blood immunophenotype analysis. METHODS: Eight WS cases treated with synacthen and 11 age- and sex-matched healthy volunteers were included. Peripheral blood mononuclear cells (PBMC) were isolated and immunophenotyping was performed in pre-treatment baseline (8 patients) and 3 months post-treatment (6 patients) samples. The analysis included PBMC expressing NFκB transcription and NLRP3 inflammasome factors. RESULTS: In pre-treatment baseline samples, switched memory B cells (CD19+IgD-CD27+) were significantly reduced, whereas plasma cells (CD19+CD38+CD138+) and cytotoxic T cells (CD3+CD8+) were significantly increased. Regulatory T and B cell ratios were not significantly altered. Synacthen treatment only marginally reduced helper T cell ratios and did not significantly change other T, B, NK and NKT cell and monocyte ratios. CONCLUSIONS: Our findings lend further support for the involvement of inflammation-related mechanisms in WS. New-onset WS patients are inclined to display increased plasma cells in the peripheral blood. Synacthen treatment does not show a beneficial effect on most effector acquired and innate immunity subsets.

Serum CXCL5 as a biomarker in multiple sclerosis and neuromyelitis optica spectrum disorder.

OBJECTIVE: Our aim was to determine whether serum C-X-C motif chemokine 5 (CXCL5) may serve as a diagnostic biomarker for relapsing-remitting multiple sclerosis (RRMS) as well as a marker that can be used to predict treatment response. METHODS: CXCL5 levels were measured by ELISA in sera of 20 RRMS patients under fingolimod treatment, 10 neuromyelitis optica spectrum disorder (NMOSD) patients, 15 RRMS patients presenting predominantly with spinal cord and optic nerve attacks (MS-SCON), and 14 healthy controls. RESULTS: Fingolimod treatment significantly reduced CXCL5 levels. CXCL5 levels were comparable among NMOSD and MS-SCON patients. CONCLUSION: Fingolimod might regulate the innate immune system. Serum CXCL5 measurement does not differentiate between RRMS and NMOSD.

Ocrelizumab Treatment Modulates B-Cell Regulating Factors in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Antibodies to CD20 efficiently reduce new relapses in multiple sclerosis (MS), and ocrelizumab has been shown to be effective also in primary progressive MS. Although anti-CD20 treatments efficiently deplete B cells in blood, some B cells and CD20- plasma cells persist in lymphatic organs and the inflamed CNS; their survival is regulated by the B cell-activating factor (BAFF)/A proliferation-inducing ligand (APRIL) system. The administration of a soluble receptor for BAFF and APRIL, atacicept, unexpectedly worsened MS. Here, we explored the long-term effects of ocrelizumab on immune cell subsets as well as on cytokines and endogenous soluble receptors comprising the BAFF-APRIL system. METHODS: We analyzed immune cell subsets and B cell-regulating factors longitudinally for up to 2.5 years in patients with MS treated with ocrelizumab. In a second cohort, we determined B-cell regulatory factors in the CSF before and after ocrelizumab. We quantified the cytokines BAFF and APRIL along with their endogenous soluble receptors soluble B-cell maturation antigen (sBCMA) and soluble transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (sTACI) using enzyme-linked immunosorbent assays (ELISAs). In addition, we established an in-house ELISA to measure sTACI-BAFF complexes. RESULTS: Ocrelizumab treatment of people with MS persistently depleted B cells and CD20+ T cells. This treatment enhanced BAFF and reduced the free endogenous soluble receptor and decoy sTACI in both serum and CSF. Levels of sTACI negatively correlated with BAFF levels. Reduction of sTACI was associated with formation of sTACI-BAFF complexes. DISCUSSION: We describe a novel effect of anti-CD20 therapy on the BAFF-APRIL system, namely reduction of sTACI. Because sTACI is a decoy for APRIL, its reduction may enhance local APRIL activity, thereby promoting regulatory IgA+ plasma cells and astrocytic interleukin (IL)-10 production. Thus, reducing sTACI might contribute to the beneficial effect of anti-CD20 as exogenous sTACI (atacicept) worsened MS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that endogenous sTACI in blood and CSF is decreased after ocrelizumab treatment.

Elevated sTREM2 and NFL levels in patients with sepsis associated encephalopathy.

PURPOSE: Sepsis-associated encephalopathy (SAE) is a common manifestation of sepsis that may lead to cognitive decline. Our aim was to investigate whether the neurofilament light chain (NFL) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) could be utilized as prognostic biomarkers in SAE. MATERIALS AND METHODS: In this prospective observational study, baseline serum levels of sTREM2 and cerebrospinal fluid (CSF) levels of sTREM2 and NFL were measured by ELISA in 11 SAE patients and controls. Patients underwent daily neurological examination. Brain magnetic resonance imaging (MRI) and standard electroencephalography (EEG) were performed. Cognitive dysfunction was longitudinally assessed after discharge in 4 SAE patients using the Mini-Mental State Examination (MMSE) and Addenbrooke's Cognitive Examination-Revised (ACE-R) tests. RESULTS: SAE patients showed higher CSF sTREM2 and NFL levels than controls. sTREM2 and NFL levels were not correlated with the severity measures of sepsis. Three months after discharge, 2 SAE patients displayed ACE-R scores congruent with mild cognitive impairment (MCI), persisting in one patient 12 months after discharge. SAE patients with MCI showed higher CSF NFL levels, bacteremia, and abnormal brain MRI. Patients with increased serum/CSF sTREM2 levels showed trends towards displaying poorer attention/orientation and visuo-spatial skills. CONCLUSIONS: sTREM2 and NFL levels may serve as a prognostic biomarker for cognitive decline in SAE. These results lend further support for the involvement of glial activation and neuroaxonal degeneration in the physiopathology of SAE.

Cerebrospinal fluid level of neurofilament light chain is associated with increased disease activity in neuro-Behçet's disease.

BACKGROUND: Clinical exacerbations characterized with neurological symptoms are observed in around 10% of Behçet's disease (BD) patients and may culminate in severe disability. Although certain immunological factors have been associated with disease activity in neuro-Behçet's disease (NBD), biomarkers for monitoring the clinical outcome of NBD have not been properly investigated. METHODS: Levels of neurofilament light chain (NFL), homeobox protein Hox-B3 (HoxB3), and YKL-40 were measured in cerebrospinal fluid (CSF) samples of 23 parenchymal (n = 16) and nonparenchymal (n = 7) NBD patients obtained during NBD attacks by ELISA. Parameters of clinical progression and outcome were assessed for an average follow-up period of 3.9 ± 1.3 years. RESULTS: Parenchymal NBD patients showed elevated CSF levels of NFL, HoxB3, and YKL-40 as compared to nonparenchymal patients. NBD patients showing an increase in modified Rankin score (mRS) values during follow-up had significantly higher CSF NFL levels. Patients with relatively lower CSF NFL levels (<1000 ng/L) did not develop attacks or cognitive impairment interfering with daily life activities during follow-up. NFL levels correlated with disease duration and mRS at the last follow-up visit, while HoxB3 levels correlated with a number of attacks during follow-up. DISCUSSION: CSF level of NFL appears to predict the prospective somatic and cognitive disability in NBD patients and may thus be potentially used as a biomarker of clinical outcome in this disease.

Serum 3-phenyllactic acid level is reduced in benign multiple sclerosis and is associated with effector B cell ratios.

BACKGROUND: 3-phenyllactic acid (PLA) is produced by both intestinal bacteria and the human host. PLA exists in its D- and L- chiral forms. It modulates human immune functions, thereby acting as a mediator of bacterial-host interactions. We aim to determine the amount and potential influence of PLA on clinical and immunological features of MS. METHODS: We measured D- and L-PLA levels in bacterial supernatants and in sera of 60 MS patients and 25 healthy controls. We investigated potential associations between PLA levels, clinical features of MS, serum cytokine levels and ratios of peripheral blood lymphocyte subsets. RESULTS: Multiple gut commensal bacteria possessed the capacity to generate D- and L-PLA. MS patients with benign phenotype showed markedly lower PLA levels than healthy controls or other MS patients. Fingolimod resistant patients had higher PLA levels at baseline. Furthermore, MS patients with higher PLA levels tended to display increased memory B and plasma cell ratios, elevated IL-4 levels and increased ratios of IL-4 and IL-10 producing T cell subsets. CONCLUSION: Collectively, our work indicates that reduced serum levels of PLA could be associated with a favorable clinical course in MS and possibly be used as a biomarker.

The modulatory action of C-Vx substance on the immune system in COVID-19.

The modulatory effect of C-Vx, a novel therapeutic agent, on the immune system of COVID-19 patients was investigated. The functions of T and NK cells of COVID-19 patients with different disease severity were evaluated by flow cytometry in response to C-Vx stimulation. The levels of pro- and anti-inflammatory cytokines were detected by multiplex assay in supernatants after cell culture with C-Vx. Bradykinin, IRF3, and IFN-α levels were also measured by ELISA in the presence or absence of C-Vx stimulation. As a result, increased CD107a expression was observed on NK cells in response to C-Vx addition. The proliferation of T cell subsets was increased by C-Vx, decreasing by disease severity. IL-4 and IL-10 levels were elevated while IFN-γ and IL-17 levels were reduced in T cells following C-Vx stimulation. However, the levels of pro-inflammatory IL-1ß, IL-6, IL-8, IFN-γ and GM-CSF were significantly increased upon C-Vx stimulation. IFN-α levels tended to increase after incubation with C-Vx. These findings support an immunomodulatory action of C-Vx on the immune system of patients with a mild and moderate phase of COVID-19.