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Inflammasomes are protein complexes that respond to a wide range of pathogens and cellular damage signals. Their activation prompts the caspase-1-mediated cleavage of the proinflammatory cytokines IL-1β and IL-18. Inflammasome dysregulation has been demonstrated to play a role in a range of diseases involving the adaptive immune system like multiple sclerosis, rheumatic diseases, and type 1 diabetes. Priming and activation of inflammasomes can be modulated by microRNAs (miRNAs), small noncoding RNAs that regulate gene expression posttranscriptionally. miRNAs, such as miR-223-3p, have been demonstrated to directly target the inflammasome components NLRP3, caspase-1, and caspase-8. Other miRNAs like miR-155-5p modulate TLR-, IL-1R-, TNFR-, and IFNAR-mediated signaling pathways upstream of the inflammasomes. In this study, we discuss how a more detailed elucidation of miRNA-driven inflammasome regulation helps in understanding the molecular processes underlying immune-mediated human diseases, holds potential for the identification of biomarkers and may offer novel targets for the development of future therapeutics., (Copyright © 2019 by The American Association of Immunologists, Inc.)

The complete DNA sequence of the human genome and of several related mammals are now available, due to the investments of enormous resources and advances in sequencing technology. Novel technologies have been developed to compare multiple genomes with each other, thus specifying regions of sequence similarity among mammals and with their pathogens. Larger blocks of sequence similarity (syntenic regions) have been determined and made publicly available. In many ways, novel insights can be gained by such data when combining external genetic or clinical information for these syntenic loci. These novel tools have proven to be successful in inferring functional equivalence between loci of multiple genomes. This review reports on the role of comparative genomics in research on autoimmune diseases, a field with strong dependencies on animal models of human diseases and the problem of an adequate information transfer between multiple organisms and research areas.

The analysis of the molecular basis of autoimmune diseases is currently under intense investigation. The identification of novel mechanisms underlying the pathogenesis of these diseases generates the possibility for the development of new therapeutic agents. In this review we summarize the results leading to novel insights concerning the molecular processes involved in the pathogenesis of rheumatoid arthritis, systemic lupus erythematodes, multiple sclerosis and diabetes type 1. We focus on the role of transcription factors such as nuclear factor kappa B, activator protein 1, peroxisome proliferator-activated receptor, vitamin D receptor and the glucocorticoid receptor that mediate pro- and anti-inflammatory effects and therefore represent direct or indirect targets for therapeutic intervention.

Several studies reported post-SARS-CoV-2-vaccination (PV) symptoms. Even people with multiple sclerosis (PwMS) have concerns about disease activity following the SARS-CoV-2 vaccination. We aimed to determine the proportion of PwMS with PV relapses, the PV annualized relapse rate (ARR), the time from vaccination to subsequent relapses, and identify sociodemographic/clinical risk factors for PV relapses. PwMS were surveyed several times at baseline and four follow-ups as part of a longitudinal observational study regarding the safety and tolerability of the SARS-CoV-2 vaccination. The inclusion criteria for this analysis were age ≥18 years, ≥1 SARS-CoV-2 vaccination, and ≥1-year observation period since initial vaccination. Of 2466 PwMS, 13.8% reported PV relapses (mostly after second [N = 147] or booster vaccination [N = 145]) at a median of 8.0 (first/third quantile: 3.55/18.1) weeks PV, with the shortest period following initial vaccination (3.95 weeks). The ARR was 0.153 (95% confidence interval: 0.138–0.168), with a median observation period since initial vaccination of 1.2 years. Risk factors for PV relapses were younger age, female gender, moderate-severe disability levels, concurrent autoimmune diseases, relapsing-remitting MS courses, no DMT, and relapses within the year prior to the first vaccination. Patients' health conditions before/during initial vaccination may play a more important role in PV relapse occurrence than vaccination per se. [ABSTRACT FROM AUTHOR]

In contrast to other diseases that go along with spasticity (e.g. spinal cord injury), spasticity in chronic autoimmune diseases involving the CNS is complicated by the ongoing damage of neuronal networks that leads to permanent changes in the clinical picture of spasticity. Multiple sclerosis (MS) is the most frequent autoimmune disease of the central nervous system (CNS) and spasticity is one of the most disabling symptoms. It occurs in more than 80% MS patients at some point of the disease and is associated with impaired ambulation, pain and the development of contractures. Besides causing cumulative structural damage, neuroinflammation occurring in MS leads to dynamic changes in motor circuit function and muscle tone that are caused by cytokines, prostaglandins, reactive oxygen species and stress hormones that affect neuronal circuits and thereby spasticity. The situation is complicated further by the fact that therapeutics used for the immunotherapy of MS may worsen spasticity and drugs used for the symptomatic treatment of spasticity have been shown to have the potential to alter immune cell function and CNS autoimmunity itself. This review summarizes the current knowledge on the immunologic pathways that are involved in the development, maintenance, dynamic changes and pharmacological modulation of spasticity in MS. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS). Methods: The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease. Results: The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS. Conclusion: We present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role. [ABSTRACT FROM AUTHOR]

Interferon-β is an established treatment for patients with multiple sclerosis (MS) but its mechanisms of action are not well understood. Viral infections are a known trigger of MS relapses. Toll-like receptors (TLRs) are key components of the innate immune system, which sense conserved structures of viruses and other pathogens. Effects of interferon-β on mRNA levels of all known human TLRs (TLR1-10) and the TLR adaptor molecule MyD88 were analyzed in peripheral blood mononuclear cells (PBMCs) of healthy donors by quantitative real-time PCR and by transcriptome analysis in PBMCs of 25 interferon-β-treated patients with relapsing-remitting MS. Regulation of TLR protein expression by interferon-β was investigated by flow cytometry of leukocyte subsets of healthy subjects and of untreated, interferon-β-, or glatiramer acetate-treated patients with MS. Interferon-β specifically upregulated mRNA expression of TLR3, TLR7, and MyD88 and downregulated TLR9 mRNA in PBMCs of healthy donors as well as in PBMCs of patients with MS. Plasmacytoid dendritic cells (pDCs) were identified as the major cell type responding to interferon-β with increased expression of TLR7 and MyD88 protein. In line with this, expression of TLR7 protein was increased in pDCs of interferon-β-treated, but not untreated or glatiramer acetate-treated patients with MS. Interferon-β-induced upregulation of TLR7 in pDCs is of functional relevance since pre-treatment of PBMCs with interferon-β resulted in a strongly increased production of interferon-α upon stimulation with the TLR7 agonist loxoribine. Flow cytometry confirmed pDCs as the cellular source of interferon-α production induced by activation of TLR7. Thus, upregulation of TLR7 in pDCs and a consequently increased activation of pDCs by TLR7 ligands represents a novel immunoregulatory mechanism of interferon-β. We hypothesize that this mechanism could contribute to a reduction of virus-triggered relapses in patients with MS. [ABSTRACT FROM AUTHOR]

Recent studies on Multiple Sclerosis (MS) pathology mention the involvement of “tertiary B cell follicles” in MS pathogenesis. This inflammatory process, which occurs with interindividually great variance, might be a link between MS pathology and headaches. The aim of this study was to detect the prevalence of headaches and of subtypes of headaches (migraine, cluster, tension-type headache [TTH]) in an unselected MS collective and to compile possibly influencing factors. Unselected MS patients (n = 180) with and without headache were examined by a semi-structured interview using a questionnaire about headache, depression and the health status. Additionally clinical MS data (expanded disability state score [EDSS], MS course, medication, disease duration) were gathered. N = 98 MS patients (55.4%) reported headaches in the previous 4 weeks. We subsequently grouped headache patients according to the IHS criteria and detected 16 (16.3%) MS patients suffering from migraine (migraine with aura: 2 [2%]; migraine without aura: 14 [14.3%]), 23 (23.5%) suffering from TTH and none with a cluster headache. Thus, headaches of 59 (60.2%) MS patients remained unclassified. When comparing MS patients with and without headaches significant differences in age, gender, MS course, physical functioning, pain and social functioning occurred. MS patients with headaches were significantly younger of age (p = 0.001), female (p = 0.001) and reported more often of a clinically isolated syndrome (CIS) and relapsing/remitting MS (RRMS) instead of secondary chronic progressive MS (SCP). EDSS was significantly lower in MS patients suffering from headaches compared to the MS patients without headaches (p = 0.001). In conclusion headache in MS patients is a relevant symptom, especially in early stages of the MS disease. Especially unclassified headache seems to represent an important symptom in MS course and requires increased attention. [ABSTRACT FROM AUTHOR]

Various types of experimental autoimmune encephalomyelitis (EAE) reflect some of the pathogenetic, clinical, and therapeutic features of the different forms of multiple sclerosis (MS), thereby, providing some, albeit limited, insight into the molecular and cellular basis of the human disease. Specific questions of MS therapy including the search for new therapeutic targets and strategies and their validation require investigations in different available EAE models. A survey is given of experimental therapeutic approaches that are currently under study with the most promising examples of monoclonal antibodies, gene therapy, stem cell transplantation and orally applied small molecular weight disease-modifying drugs. Reasons for therapy failure and adverse side-effects of some experimental trials are discussed. Precaution is advised, if results of new experimental approaches are translated into clinical practice. [ABSTRACT FROM AUTHOR]

Common complex polygenic diseases as autoimmune diseases have not been completely understood on a molecular level. While many genes are known to be involved in the pathways responsible for the phenotype, explicit causes for the susceptibility of the disease remain to be elucidated. The susceptibility to disease is thought to be the result of genetic epistatic interactions between common polymorphic genes. This polymorphism is mostly caused by single nucleotide polymorphisms (SNPs). Human subpopulations are known to differ in the susceptibility to the diseases and generally in the distribution of single nucleotide polymorphisms. The here presented approach retrieves SNPs with the most divergent frequencies for selected human subpopulations to help defining properties for the experimental verification of SNPs within defined regions. A web-accessible program implementing this approach was evaluated for multiple sclerosis (MS), a common human polygenic disease. A link to a summary of data from "The SNP Consortium" (TSC) with sex-dependencies of SNPs is available. Associations of SNPs to genes, genetic markers and chromosomal loci are retrieved from the Ensembl project. This tool is recommended to be used in conjunction with microarray analyses or marker association studies that link genes or chromosomal loci to particular diseases. [ABSTRACT FROM AUTHOR]

The article presents the authors' comments on a case study involving a woman with acute myelopathy in pregnancy. They discuss the intriguing facet brought by the case, which is the similarity of histological lesions in the spinal cord of patients with neuromyelitis optica and the placenta of the patient. They recommend plasmapheresis as a treatment option for autoimmune diseases during pregnancy. The authors also argue against the use of rituximab during pregnancy based on current available data.

Immunological changes during pregnancy influence the course of neurological autoimmune diseases in different ways. In case of pregnancy immunmodulatory standard therapies such as interferon-β, glatiramer acetate, monoclonal antibodies and cytostatics mostly should be discontinued. In those cases intravenous immunoglobulin (IVIg) therapy might be an alternative. In some diseases, contemporary publications describe positive therapeutic effects on the course of disease during or after pregnancy. [ABSTRACT FROM AUTHOR]

Abstract: The term neuroimmunology was first coined to refer to a generic involvement of the immune system in the pathogenesis of neurological diseases, particularly of the central nervous system. Since then, the neuroimmunology spectrum has steadily grown and currently spans from classical autoimmune diseases of the central and peripheral nervous systems to previously unsuspected conditions such as autism spectrum disorders or chronic fatigue syndrome. Multiple sclerosis remains the predominant entity in terms of research efforts and social pressure as well as a good model of organ-specific autoimmune disease with limited therapeutic options. While the fast-pace genome-wide association studies reported a number of genes to be significantly associated with multiple sclerosis, these currently explain only a minor part of disease susceptibility. Further, clinicians are continuously challenged with the clinical classifications of immune-mediated or autoimmune central and peripheral conditions and with other pragmatic questions such as the roles of vaccination and physical therapy. For these reasons the present collection of Autoimmunity Reviews is timely as it will address these major issues related to neuroimmunology. [Copyright &y& Elsevier]

Abstract: MicroRNA (miRNA) are small non-coding RNA molecules about 21–25 nucleotides long. They control gene regulation by translational repression and cleavage. Several studies have shown that many miRNA are associated with the etiology of different diseases. Recent developments in diverse miRNA profiling platforms like microarray and quantitative real-time PCR may enable the identification of specific miRNA as novel diagnostic and predictive markers for various diseases. MiRNAs could even be used as therapeutic drug targets. Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system. Dysregulated immune system processes result in demyelination of neurons and consequently, electrical impulses that travel along the nerves are disrupted resulting in the impairment of organs. In the past three years, there has been an increased interest in establishing miRNA-based biomarkers for MS. So far, there are six studies on miRNA expression in MS patients in which first miRNAs were discovered as potential disease markers. For instance, one study showed that blood levels of miR-145 can discriminate MS patients from healthy controls, and another showed that active lesions in the brain are characterized by a strong up-regulation of miR-155. Studies on experimental autoimmune encephalomyelitis (EAE), the animal model of MS, further support the significance of miRNA as e.g. mice with miR-155 deletion are highly resistant to EAE. Such investigations help to understand the molecular processes involved in the disease. The identification of miRNA markers that are associated with type of MS, individual disease activity or clinical progression under treatment may open new avenues for early diagnosis and optimized therapy of MS. [Copyright &y& Elsevier]