The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris suis Ova Immunotherapy.

Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.

EBNA1 antigen-specific CD8+ T cells in cerebrospinal fluid of patients with multiple sclerosis.

Epidemiological data suggests that Epstein-Barr virus may be involved in the pathogenesis of Multiple Sclerosis (MS). We aimed to determine the frequency of CD8+ T cells specific for one EBNA1-derived epitope (HPVGEADYFEY) in cerebrospinal fluid (CSF) and blood of patients with MS and other inflammatory neurological diseases (OIND). The frequency of specific CD8+ T cells was assessed by HLA-class-I-binding pentamers restricted to HLA-B35. The frequency of HPVGEADYFEY-specific CD8+ T cells did neither differ significantly in blood nor CSF in MS compared to OIND, but was consistently higher in CSF compared to blood regardless of diagnosis.

Toxoplasma gondii seropositivity is negatively associated with multiple sclerosis.

BACKGROUND: Toxoplasma (T.) gondii is a ubiquitous intracellular parasitic protozoan that was recently associated with various autoimmune diseases. OBJECTIVES: We aimed to investigate the prevalence of T. gondii IgG and IgM antibodies between MS patients and healthy controls. METHODS: Sera from 163 MS, 91 clinically isolated syndrome cases and 178 age and gender matched controls were evaluated for the prevalence of T. gondii IgG antibodies utilizing chemiluminescent immunoassay (ARCHITECT). RESULTS: MS-patients showed a significantly lower prevalence for T. gondii IgG antibodies compared to controls (33.3% vs. 47.9%; p=0.011, OR=1.8 (95% CI 1.2-3.2)). CONCLUSION: The results demonstrate a negative association between an infection with the parasite T. gondii and the presence of MS.

Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis.

IMPORTANCE: Some patients with multiple sclerosis (MS) can either present with or develop severe cognitive impairment during the course of their disease. However, the mechanisms underlying severe cognitive dysfunction in MS are not well understood. OBSERVATIONS: We report on a woman who was diagnosed as having MS at age 33 years and who after giving birth at age 37 years developed cognitive impairment with severe memory dysfunction as the leading symptom. Treatment with different immunotherapies, including cyclophosphamide and natalizumab, did not improve her cognitive deficits, necessitating admission to a nursing home at age 39 years. During a thorough reevaluation at age 43 years, analysis of current and stored cerebrospinal fluid and serum samples demonstrated an intrathecal synthesis of IgG antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor, that is, the characteristic laboratory finding of anti-N-methyl-D-aspartate receptor encephalitis. Although the patient initially stabilized under therapy with corticosteroids, plasma exchange, and mitoxantrone, severe cognitive impairment persisted and she eventually died from the sequelae of her disease. CONCLUSIONS AND RELEVANCE: This report suggests that the occasional occurrence of severe cognitive impairment in patients with MS may, in some cases, be related to a superimposed antibody-mediated autoimmune encephalitis.

Multiple sclerosis: the elevated antibody response to Epstein-Barr virus primarily targets, but is not confined to, the glycine-alanine repeat of Epstein-Barr nuclear antigen-1.

Patients with multiple sclerosis (MS) have elevated antibodies against Epstein-Barr virus (EBV), but data on the epitope-resolved specificity of these antibodies are scarce. Using a peptide microarray containing 1465 peptides representing 8 full-length EBV proteins, we identified higher (p<0.001) antibody reactivities to 39 EBV-peptides in MS patients (n=29) compared to healthy controls (n=22). Seventeen of the 39 peptides were from EBNA-1 and 13 located within the glycine-alanine repeat of EBNA-1. Further reactivities were directed against EBNA-3, EBNA-4, EBNA-6, VP26, and LMP1. Thus, antibodies against EBV in MS patients primarily target, but are not confined to, the glycine-alanine repeat of EBNA-1.

Identical lesion morphology in primary progressive and relapsing-remitting MS--an ultrahigh field MRI study.

Potential differences between primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g., perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.

Serum levels of brain-derived neurotrophic factor (BNDF) in multiple sclerosis patients with Trichuris suis ova therapy.

We previously analysed clinical and immunological parameters under Trichuris suis ova (TSO) therapy in four patients with secondary progressive multiple sclerosis. The serum Brain-derived neurotrophic factor (BDNF) levels of these four patients were assessed before, during and after therapy with TSO and showed significant decrease of BDNF during TSO therapy (p < 0.05).

Trichuris suis ova in relapsing-remitting multiple sclerosis and clinically isolated syndrome (TRIOMS): study protocol for a randomized controlled trial.

BACKGROUND: Trichuris suis ova is a probiotic treatment based on the hygiene hypothesis. It has been demonstrated as safe and effective in autoimmune inflammatory bowel diseases and clinical trials indicate that helminth infections also have an immunomodulatory effect in multiple sclerosis.We hypothesize that administering 2,500 Trichuris suis ova eggs orally every two weeks for 12 months is--due to its immunomodulatory and anti-inflammatory effect--significantly more effective than oral placebo in preventing new T2 and Gd+ lesions, as quantified by cerebral MRI and clinical examination, in relapsing-remitting multiple sclerosis and clinically isolated syndrome. METHODS/DESIGN: Fifty patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome with clinical activity, not undergoing any standard therapies, will be randomized 1:1 to Trichuris suis ova 2,500 eggs every two weeks or matching placebo. The safety, tolerability and effect on disease activity and in vivo mechanisms of action of Trichuris suis ova in MS will be assessed by neurological, laboratory and immunological exams and magnetic resonance imaging throughout the 12-month treatment period and over a follow-up period of 6 months. Various immunological analyses will be used to assess the overall patient immune response prior to and at varying time points following treatment with Trichuris suis ova. DISCUSSION: We anticipate that Trichuris suis ova will be well tolerated and more effective than the placebo in preventing new T2 and Gd+ lesions, as quantified by MRI. We also expect the Th1/Th17 proinflammatory response to shift towards the more anti-inflammatory Th2 response. This study has important clinical implications and will involve extensive research on the immunology of helminth therapy. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01413243.

Proresolution lipid mediators in multiple sclerosis - differential, disease severity-dependent synthesis - a clinical pilot trial.

BACKGROUND: The severity and longevity of inflammation is controlled by endogenous counter-regulatory signals. Among them are long-chain polyunsaturated fatty acid (PUFA)-derived lipid mediators, which promote the resolution of inflammation, an active process for returning to tissue homeostasis. OBJECTIVE: To determine whether endogenous production of lipid-derived resolution agonists is regulated differentially in patients with highly active and less active multiple sclerosis (MS). DESIGN: Matched-pairs study in University hospital Neurology department. PATIENTS: Based on clinical (relapse frequency) and paraclinical (MRI lesions, contrast enhancement) criteria, 10 pairs of age- and sex-matched patients with relapsing-remitting MS were assigned either to a group with highly active or less active MS. Lipid mediators were quantified in serum and cerebrospinal fluid using LC-MS/MS-based lipidomics. RESULTS: Levels of the key arachidonic (ω-6) and docosahexaenoic acid (ω-6)-derived mediators prostaglandins (PG), leukotrienes, hydroxyeicosatetraenoic acids (HETE) and resolution agonists lipoxin A(4) (LXA(4)), resolvin D1 (RvD1) and neuroprotectin D1 (NPD1) were quantified. In the patient group with highly active MS, 15-HETE and PGE(2) were increased, which are products of the 15-lipoxygenase and cyclooxygenase pathways. The proresolution mediator RvD1 was significantly upregulated and NPD1 was detected in the highly active group only. LXA(4) levels were not increased in patients with highly active MS. CONCLUSIONS: Lipid mediator pathways are regulated differentially in the cerebrospinal fluid of MS patients, depending on disease severity. Non-exhaustive or possibly 'delayed' resolution pathways may suggest a defective resolution program in patients with highly active MS. Longitudinal analyses are required to hetero-typify this differential resolution capacity, which may be associated with disease progression, longevity and eventual termination.

Breastfeeding is associated with lower risk for multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease with known genetic and environmental susceptibility factors. Breastfeeding has been shown to be protective in other autoimmune diseases. OBJECTIVE: This case-control study analyzed the association of breastfeeding in infancy on the risk of developing MS. METHODS: A case-control study was performed in Berlin of 245 MS patients and 296 population-based controls, who completed a standardized questionnaire on their history and duration of breastfeeding in infancy and demographic characteristics. Univariable and multivariable logistic regression analysis was performed to investigate the association between breastfeeding and MS. The multivariate model was adjusted for age, gender, number of older siblings, number of inhabitants in place of domicile between ages 0 and 6 (categorized in each case), and daycare attendance between ages 0 and 3. RESULTS: In multivariable analysis, breastfeeding showed an independent association with MS (adjusted OR 0.58; p = 0.028). However, with no breastfeeding as reference, the protective effect only emerges after four months of breastfeeding (multivariable analysis for ≤ four months adjusted OR 0.87; p = 0.614 and for > four months OR 0.51; p = 0.016). CONCLUSION: The results of this case-control study support the hypothesis that breastfeeding is associated with a lower risk of MS. These results are in line with findings of previous studies on other autoimmune diseases, in which breastfeeding was shown to have protective effects.

Measles IgG antibody index correlates with T2 lesion load on MRI in patients with early multiple sclerosis.

BACKGROUND: B cells and humoral immune responses play an important role in the pathogenesis and diagnosis of multiple sclerosis (MS). A characteristic finding in patients with MS is a polyspecific intrathecal B cell response against neurotropic viruses, specifically against measles virus, rubella virus, and varicella zoster virus, also known as an MRZ reaction (MRZR). Here, we correlated from the routine clinical diagnostics individual IgG antibody indices (AIs) of MRZR with magnetic resonance imaging (MRI) findings in patients with first MS diagnosis. METHODS/RESULTS: MRZR was determined in 68 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting MS (RRMS). Absolute AI values for measles virus, rubella virus, and varicella zoster virus were correlated with T2 lesion load and gadolinium enhancing lesions on cerebral MRI (cMRI) and cMRI combined with spinal MRI (sMRI). Measles virus AI correlated significantly with T2 lesion load on cMRI (p = 0.0312, Mann-Whitney U test) and the sum of lesions on cMRI and sMRI (p = 0.0413). Varicella zoster virus AI also showed a correlation with T2 lesion load on cMRI but did not reach statistical significance (p = 0.2893). CONCLUSION: The results confirm MRZR as part of the polyspecific immune reaction in MS with possible prognostic impact on MRI and clinical parameters. Furthermore, the data indicate that intrathecal measles virus IgG production correlates with disease activity on cMRI and sMRI in patients with early MS.

Environmental factors in early childhood are associated with multiple sclerosis: a case-control study.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with increasing incidence mainly in high-income countries. One explanation of this phenomenon may be a higher prevalence of allergic and autoimmune diseases in industrialized countries as a consequence of otherwise beneficial advances in sanitation (hygiene hypothesis). We investigated environmental factors in early childhood associated with MS. METHODS: A case-control study was performed of 245 MS patients and 296 population-based controls in Berlin. The study participants completed a standardized questionnaire on environmental factors in childhood and youth, including aspects of personal and community hygiene. Multivariable logistic regression analysis was performed to investigate factors in childhood and youth associated with the occurrence of MS. RESULTS: Mean age was 46 years (range, 20-80) in the MS group and 42 years (range 18-80) in the control group, of which 73.9% in the MS and 61.5% in the control group were female. The multivariable analysis showed that having at least two older siblings (OR 0.54; p = 0.05, for individuals with two older siblings compared to individuals without older siblings), attending a day-care center (OR 0.5; p = 0.004) and growing up in an urban center with more than 100, 000 inhabitants (OR 0.43; p = 0.009) were factors independently associated with a lower chance for MS. CONCLUSIONS: The hygiene hypothesis may play a role in the occurrence of MS and could explain disease distribution and increasing incidence.

Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis.

Multiple sclerosis is a chronic inflammatory and demyelinating disorder of the CNS with an unknown aetiology. Although intrathecal immunoglobulin G (IgG) synthesis is a key feature of the disease, little is still known about the B cell response in the CNS of multiple sclerosis patients. We analysed the phenotype and kinetics of different B cell subsets in patients with multiple sclerosis, infectious disease (IND) and non-inflammatory neurological disease (NIND). B cells were detected in the CSF of multiple sclerosis and IND patients, but were largely absent in NIND patients. In the CSF, the majority of B cells had a phenotype of memory B cells and short-lived plasma blasts (PB); plasma cells were absent from the compartment. The proportion of PB was highest in multiple sclerosis patients and patients with acute CNS infection. While PB disappeared rapidly from the CSF after resolution of infection in IND patients, these cells were present at high numbers throughout the disease course in multiple sclerosis patients. CSF PB numbers in multiple sclerosis patients strongly correlated with intrathecal IgG synthesis and inflammatory parenchymal disease activity as disclosed by MRI. This study identifies short-lived plasma blasts as the main effector B cell population involved in ongoing active inflammation in multiple sclerosis patients.

The role of the polio virus receptor and the herpesvirus entry mediator B genes for the development of MS.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS). Although the cause of MS is still uncertain, it is well accepted that both genetic and environmental factors are important for the development of disease. In this study, we focused on the Polio Virus Receptor (PVR) and Herpesvirus entry mediator B (HVEB) receptor genes, which are located on chromosome 19q13, a region previously linked to MS. Both receptors are expressed in the brain and immune system and play an important role for inter-cellular adhesion and entry of neurotropic viruses to the brain. We identified four new polymorphisms in the PVR gene, which were located in the promoter region and three different exons. All exonic polymorphisms altered the amino acid sequence of the receptor. No new polymorphisms were found in the HVEB gene, but we confirmed a previously identified intronic polymorphism. We analyzed the frequency of the polymorphisms by RFLP analysis in sporadic MS patients, MS families, and healthy controls and determined the surface expression of HVEB and PVR on peripheral blood monocytes. We did not find differences in the frequency of the polymorphisms or surface expression between MS patients and controls. Overall, our findings do not support a role of HVEB and PVR genes in the development of MS.

Myositis in a patient with large granular leukocyte leukemia.

We describe the case of a 58-year-old patient with subacute progressive weakness in both legs accompanied by recurrent opportunistic infections. White cell count was normal, but immunophenotyping revealed an increased number of CD8(+) T cells and deficiency of natural killer cells, B cells, and CD4(+) T cells in the peripheral blood. Large granular leukocyte (LGL) leukemia was diagnosed based on a clonal T-cell receptor rearrangement. Muscle biopsy demonstrated severe myositis with extensive CD8(+) T-cell infiltrates. Since no evidence of microbial muscle infection was found, autoimmune myositis was diagnosed. Immunosuppressive treatment resulted in clinical improvement and normalization of creatine kinase (CK) serum levels. The immunological phenotype of the patient and the positive response to treatment adds further to the concept that CD8(+) T cells mediate disease in autoimmune myositis.

Effects of taurine and glycine on epileptiform activity induced by removal of Mg2+ in combined rat entorhinal cortex-hippocampal slices.

PURPOSE: The imbalance between neuronal inhibition and excitation contributes to epileptogenesis. Inhibition in the central nervous system (CNS) is mediated by gamma-aminobutyric acid (GABA) and glycine. Recent studies indicate the expression of glycine receptor (GlyR) in hippocampus and neocortex. However, the function of GlyR in these regions is not clarified completely. The aim of this study was to investigate whether the GlyR agonists glycine and taurine promote an anticonvulsive effect. METHODS: We induced epileptiform discharges by reducing extracellular Mg2+ concentration in combined rat entorhinal cortex-hippocampal slices (400 micro m). Epileptiform discharges were detected by using extracellular recording techniques. RESULTS: Seizure-like events were suppressed by taurine, exhibiting a half-maximal inhibitory effect (IC50) of 0.9 mM. Suppression of late recurrent discharges in the medial entorhinal cortex and recurrent short discharges in the hippocampus was obtained at an IC50 value of 1.6 and 2.1 mM, respectively. Strychnine at concentrations <1 micro M abolished these effects. Likewise glycine, after an initial proconvulsant effect, suppressed epileptiform discharges. CONCLUSIONS: These findings show that GlyR agonists, in particular taurine, could serve as potential anticonvulsants and suggest an important role of GlyR in cortical function and dysfunction.

The immune response at onset and during recovery from Borrelia burgdorferi meningoradiculitis.

BACKGROUND: Borrelia burgdorferi causes a wide range of neurologic syndromes. In Europe, acute meningoradiculitis is the most common manifestation. OBJECTIVE: To address the nature of the immune response during the course of B burgdorferi meningoradiculitis, with special respect to the early and late changes in cerebrospinal fluid (CSF). METHODS: Serial immunophenotyping was performed and cytokine measurements were obtained in the peripheral blood and CSF of 12 European patients with definite B burgdorferi meningoradiculitis. RESULTS: Early during infection and before initiation of treatment, we observed high levels of interleukin (IL) 10, IL-6, and IL-8, and large numbers of B cells and plasma cells in the CSF of most patients. At the same time, we found a mainly unspecific intrathecal antibody synthesis. During resolution of the infection, cytokine levels normalized rapidly and plasma cells disappeared from the CSF. In parallel, the percentage of B cells in the CSF increased over several months, accompanied by rising levels of intrathecally produced B burgdorferi-specific antibodies. CONCLUSIONS: Our findings demonstrate that the early phase of B burgdorferi meningoradiculitis is characterized by a well-coordinated immune response involving specific cytokine release and plasma cell recruitment, followed by a long-lasting, antigen-specific B-cell response in the central nervous system.