There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial ...composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twinderived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.
Neuromyelitis optica (NMO, Devic’s syndrome), long considered a clinical variant of multiple sclerosis, is now regarded as a distinct disease entity. Major progress has been made in the diagnosis and ...treatment of NMO since aquaporin-4 antibodies (AQP4-Ab; also termed NMO-IgG) were first described in 2004. In this review, the Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings. Testing of AQP4-Ab is essential and is the most important test in the diagnostic work-up of suspected NMO, and helps to distinguish NMO from other autoimmune diseases. Furthermore, AQP4-Ab testing has expanded our knowledge of the clinical presentation of NMO spectrum disorders (NMOSD). In addition, imaging techniques, particularly magnetic resonance imaging of the brain and spinal cord, are obligatory in the diagnostic workup. It is important to note that brain lesions in NMO and NMOSD are not uncommon, do not rule out the diagnosis, and show characteristic patterns. Other imaging modalities such as optical coherence tomography are proposed as useful tools in the assessment of retinal damage. Therapy of NMO should be initiated early. Azathioprine and rituximab are suggested as first-line treatments, the latter being increasingly regarded as an established therapy with long-term efficacy and an acceptable safety profile in NMO patients. Other immunosuppressive drugs, such as methotrexate, mycophenolate mofetil and mitoxantrone, are recommended as second-line treatments. Promising new therapies are emerging in the form of anti-IL6 receptor, anti-complement or anti-AQP4-Ab biologicals.
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system with a modest concordance rate in monozygotic twins, which strongly argues for involvement of ...epigenetic factors. We observe highly similar peripheral blood mononuclear cell-based methylomes in 45 MS-discordant monozygotic twins. Nevertheless, we identify seven MS-associated differentially methylated positions (DMPs) of which we validate two, including a region in the TMEM232 promoter and ZBTB16 enhancer. In CD4 + T cells we find an MS-associated differentially methylated region in FIRRE. Additionally, 45 regions show large methylation differences in individual pairs, but they do not clearly associate with MS. Furthermore, we present epigenetic biomarkers for current interferon-beta treatment, and extensive validation shows that the ZBTB16 DMP is a signature for prior glucocorticoid treatment. Taken together, this study represents an important reference for epigenomic MS studies, identifies new candidate epigenetic markers, and highlights treatment effects and genetic background as major confounders.
Neuromyelitis optica spectrum disorder (NMOSD) in people living with HIV (PLWH) is rare and its management can be difficult. Here we report a case of an HIV patient with bilateral vision loss, who ...was diagnosed with AQP4-IgG-positive NMOSD in 2020 during the COVID-19 pandemic. Rituximab treatment was initiated after attack therapy with corticosteroids and plasma exchange. NMOSD and HIV disease remained stable, but SARS-CoV-2 immune response after repeated vaccinations was insufficient. After switching immunotherapy due to the lack of vaccination response to satralizumab, peripheral B cells reoccurred and a humoral immune response was observed after reapplication of SARS-CoV-2 vaccination. This case illustrates the challenges associated with the treatment of NMOSD in PLWH.
We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4‐blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic ...resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T‐cell type MS. Quantitative next generation sequencing of T‐cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T‐cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294–300
Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF). The preclinical events leading to ...established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six "healthy" co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS patients but also from subjects with SCNI. In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells. The TRM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells.
Background:
Fingolimod is an effective treatment for active relapsing–remitting multiple sclerosis (MS). Discontinuation of therapy may be followed by recurrence of disease activity. Thus, female MS ...patients may be at risk of relapse during pregnancy after stopping fingolimod.
Objectives and methods:
To report the disease course during pregnancy of five women who interrupted therapy with fingolimod for pregnancy.
Results:
All patients experienced relapses during pregnancy and/or postpartum after stopping fingolimod.
Conclusion:
The risk of recurrence of disease activity during pregnancy after stopping fingolimod may be substantial. This should be considered and discussed with MS patients who are planning to become pregnant.
Objective
Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the central nervous system (CNS). We analyzed ...their pathogenic activity by affinity‐purifying these antibodies (Abs) from patients and transferring them to experimental animals.
Methods
Patients with Abs to MOG were identified by cell‐based assay. We determined the cross‐reactivity to rodent MOG and the recognized MOG epitopes. We produced the correctly folded extracellular domain of MOG and affinity‐purified MOG‐specific Abs from the blood of patients. These purified Abs were used to stain CNS tissue and transferred in 2 models of experimental autoimmune encephalomyelitis. Animals were analyzed histopathologically.
Results
We identified 17 patients with MOG Abs from our outpatient clinic and selected 2 with a cross‐reactivity to rodent MOG; both had recurrent optic neuritis. Affinity‐purified Abs recognized MOG on transfected cells and stained myelin in tissue sections. The Abs from the 2 patients recognized different epitopes on MOG, the CC′ and the FG loop. In both patients, these Abs persisted during our observation period of 2 to 3 years. The anti‐MOG Abs from both patients were pathogenic upon intrathecal injection in 2 different rat models. Together with cognate MOG‐specific T cells, these Abs enhanced T‐cell infiltration; together with myelin basic protein–specific T cells, they induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology.
Interpretation
MOG‐specific Abs affinity purified from patients with inflammatory demyelinating disease induce pathological changes in vivo upon cotransfer with myelin‐reactive T cells, suggesting that these Abs are similarly pathogenic in patients. Ann Neurol 2018;84:315–328
We describe a method for correlating the immunoglobulin (Ig) proteomes with the B cell transcriptomes in human fluid and tissue samples, using multiple sclerosis as a paradigm. Oligoclonal Ig bands ...and elevated numbers of clonally expanded B cells in the cerebrospinal fluid (CSF) are diagnostic hallmarks of multiple sclerosis. Here we compared the Ig transcriptomes of B cells with the corresponding Ig proteomes in CSF samples from four subjects with multiple sclerosis. We created individual Ig transcriptome databases that contained the subject-specific mutations introduced by V(D)J recombination and somatic hypermutation and then searched the CSF for corresponding characteristic peptides by mass spectrometry. In each sample, the Ig transcriptomes and proteomes strongly overlapped, showing that CSF B cells indeed produce the oligoclonal Ig bands. This approach can be applied to other organ-specific diagnostic fluid or tissue samples to compare the Ig transcripts of local B cells with the corresponding antibody proteomes of individual subjects.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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