Aryl hydrocarbon receptor (AHR) is a pivotal protein that belongs to PAS [PER (periodic circadian protein)-ARNT(AHR nuclear translocator)-SIM (single-minded protein)] domain-containing receptor superfamily. This group of proteins play a central role in regulating cellular homeostasis by sensing endogenous (e.g. redox status and oxygen partial pressure) and exogenous stimuli (e.g. toxic aromatic hydrocarbons), and AHR, in particular, is recently emerging as an important gear of the machinery that regulates inflammation in the gut-brain axis (see here). The endogenous ligands for AHR include, mostly, triptophan derivatives which are either produced by endogenous metabolic pathways or by the commensal microbiota, which -on the other hand- can also produce other distinct molecules that possess AHR agonistic activity and are involved in a series of immunoregolatory functions (e.g. they can limit intestinal inflammation).
The dire situation that UK scientific community has been fearing in these last two years is, quite probably, one of the consequences that people voting for brexit in 2016 failed to consider. Brexit, and in particular the catastrophic perspective of a no-deal exit from the EU - which last 15 january became more likely as the UK parliament fiercely rejected the last negotiations - would not only leave UK science without arrangements on european fundings (e.g. H2020), but would also have more direct consequences until new immigration rules are properly discussed (40% of the scientific workforce comes from other EU nations, as stated by Paul Nurse, director of the Francis Crick Institute in London). With this scenario in mind, UK scientists are starting to elaborate possible contingency plans in the event of a hard brexit.
B cells are involved in the pathogenesis of multiple sclerosis (MS) and, as a matter of fact, many drugs are designed to target CD20+ B cells as a treatment for this disease. However, many surprising evidences still suggest, to date, that our knowledge concerning the role of B cell axis in MS is still quite incomplete: for example, drugs targetting the plasma cells (PC) (the antibody-producing mature form of B cells) survival niches unexpectedly result in exacerbation of the disease. In light of these, more the involvement of antibody-secreting cells in immunomodulation during MS needs to be fully assessed. Interestingly, recent evidences show that IgA-producing PC possess antiinflammatory properties; plasma cells directed against tissue-specific antigens can be found way far from their mucosal origin and can be enriched in different organs, including the brain of MS patients. In light of this, Olga L. Rojas, Anne Katrin Probstel and Elisa A. Porfilio, as well as their many colleagues, sought to investigate a possible immunoregulatory role for IgA-producing cells in multiple sclerosis.
Il 22 febbraio 2019, l'Aula Magna Giorgio De Sandre del Policlinico Universitario G.B. Rossi, a Verona, ospiterà l'incontro "Antibody-associated CNS disorders and theri differential diagnosis", patrocinato da AINI.
T regulatory cells (Treg) have been reported to exert IL10-dependent beneficial effects during the aftermath of brain infarction, although their physiological role in this pathology has not been yet fully understood, mostly due to the fact that Treg cells are present only in low numbers around stroke area during the acute phase of the ischaemic episode (i.e. around one week later). According to this brief comunication, published on Nature last december, however, looking at a different time window might shed some light on the immunomodulatory role played by Tregs on ischaemic stroke.
Mandatory vaccination in Italy - a reaction mostly driven by the drop of immunization coverage threshold below 95% - has unleashed significant uproar in some political and social environment due to a spreading fear for adverse reactions, mostly fed by misinformation and populism. Although the vast majority of scientific community, as well as many other influential personalities, clinged together to convey the message of vaccines as a secure and well-validated prehemptive strategy to avoid some catastrophic pathologies and epidemies, clarifying that the risk of side effects is low and largely surpassed by that of infection-related complications (see here), many people are still reluctant to accept trustful scientifical evidences as a way to dissipate skepticism. In the perspective of promoting good information and avoid aberrant conducts driven by mythomania, however, the italian National Order of Biologists (Ordine Nazionale dei Biologi, ONB), seems to have preferred an "alternative", paradoxical path.
Harnessing the potential of gene editing-based therapies has been one of the long sought-after dreams of biology and medicine. New techniques such as CRISPR and ZFP, though still in need of being refined, have opened the possibility of manipulating genomes and, for example, target specific disease-associated genes. While the perspective of modifying organisms in order to make them less susceptible to certain conditions, either pathophysiological or infective, represents a rather fascinating scenario, many think that this approach still has to deal with our very limited knowledge of the way gene products work in the context of a complete organism, in relation with the other 21.000 protein-coding genes extimated to date, with the huge non-coding part of the genome and, quite importantly, environmental variables (a good example of this complexity is represented by the fact that less than a 2% DNA divergence accounts for the phenotypic differences existing between humans and chimps). As a matter of fact we might be able to modify human genes, but our knowledge of the full spectrum of effects exerted by a certain DNA sequence on living organisms is often scarce, and seldom predictable. It is no surprise, thus, that scientific comunity was profoundly shaken, a few weeks ago, when chinese scientist He Jiankui claimed that he had made the first couple of gene-edited twin babies carryinga mutation for CCR5 chemochine receptor that make them, theoretically, immune to HIV infection.
A widely -though a little bit simplistic paradigm of central tolerance, in immunology, is that thymocytes undergo a process of deletion, during their differentiation, as they express a TCR that shows high affinity or avidity for MHC that load self-antigens. This mechanism helps eliminating autoreactive T cells that might unleash autoimmunity. However, the host of T cell precursors in the thymus is also the source of T regulatory cells (Treg), a central gear of the machinery that modulates and shapes the immune system. In this sense, Treg existence and features exposed all the limits of a model of central tolerance based on TCR affinity for MHC: indeed this theoretical approach could only partially explain the huge variety of T cells we see circulating, especially in light of paradoxical evidences such as that of Tregs partly sharing their TCR repertoire with that of conventional T cells, or the fact that they can be induced by self-antigen recognition. As it turns out, things are way more difficult to explain and the system that, in the thymus, decides the fate of CD4 T cells is rather convoluted, as Ludger Klein, Ellen A Robey and Cyi- Song Hsieh explained so eminently in Nature Reviews Immunology, last week.
The cells characterizing healthy metazoa bodies are meant to share and maintain the same genome, with tissue diversity being originated by differential gene expression and alternative mRNA splicing during transcription. Few exceptions exist in this paradigm, the most prominent being that of B ant T cells, which are able to rearrange genomic DNA through somatic recombination and generate the huge variability of immunoglobulin and T cell receptor (TCR) repertoires.
On the other hand, the brains of patients affected by neurodegenerative diseases often display mosaicism -the presence of mutations and different copies of certain genes in the tissue cells- which does not depend on mutations inherited by parents: for examples, the neurons of patients with Alzheimer's disease (AD) display more DNA and different copies of the amiloid precursor protein (APP) gene, which is one of the causes of this condition. Although this feature is common in neurodegenerative pathologies, its mechanism is basically unknown. In this sense, the paper published this week on Nature by Lee et al represents an important milestone of molecular biology and neuroscience: it provides a mechanistic base for neuronal mosaicism of patients with AD and other neurodegenerative conditions, proving that neuron can indeed perform somatic recombination (a feature that to date was thought to be exclusive of immune cells), while it also lays new ground to understand neurodegeneration.
Brexit is possibly one of the most difficult situations ever faced by United Kingdom in recent times. Nobody has a clear prediction for what its long-term consequences are going to be for the country, should UK definitely decide to leave EU, but what has been pretty clear in these past months is that, among those who advocated Brexit, few saw the big picture and the full spectrum of the repercussion that this event would have had on the country's health, economy and, quite relevant to our cause, science.
Starting (and hopefully, ending) a PhD studentship is undoubtedly a thrilling -though demanding- task that is meant to teach students to cope with the hard work that is at the base of a research job. As someone new to several different duties -often performed at the same time- a PhD student can underestimate the magnitude of his tasks, and be overwhelmed by them.
Disfunctions of the gut-brain axis are increasingly emerging as an important factor in several pathologies, including neurodegenerative ones. These alterations are able to act on peripheral and central nervous system by disrupting physiological, immune and inflammatory. In particular, functional alterations in the gut have been linked, in the past, to the pathogenesis and prevalence of neurodegenerative conditions such as Parkinson's disease (PD), in which misfolded alpha-synuclein accumulates in the brain resulting, eventually, in the neuronal loss at the substantia nigra that is the basis of the motor impairment of this condition. Rather curiously, gastrointestinal alterations represent a quite common and often early symptom in PD, while the prevalence of this disease has been reported to be lower in patients that underwent gut surgical treatments such as partial vagotomy (the partial severing of a portion of the vagal nerve that innervates the gastroenteric tube, performed in the management of peptic ulcer); this led to the yet controversial theory that PD might harbour its seeds in the gut, before climbing its way up to the brain by propagating misfolded alpha-synuclein aggregates through the vagal nerve, in a sort of twisted "telephone game".
Peer reviewing is a pivotal part of scientific publication process, and it's meant to ensure that the data collected by researchers is properly scrutinized to find majour flaws or incoherences in the theory or methodology behind it. Nonetheless, nowaday, scientists receive little -if any- training in this, and most of the ability to analyze and review a scientific paper comes from raw experience.
The pathogenesis of multiple sclerosis (MS) lays its base on an self-directed attack of the immune system that goes haywire, as it attacks neuron myelin sheets and destroys them. This lack of capacity of the immune system of discriminating self antigens from microbial structures, which in turn unleashes auto-immunity, seems to be based on several factors, including the inheritance of particular HLA genes (HLA-DR15 is responsible, alone, for 60% of the genetic risk in MS), which govern T cell expansion, as well as a tendency of T and B cells to replicate independently of specific and direct antigen exposure. Among other things, an important pathogenetic event seems to be represented by the ability of T and B cells to engage in a HLA-TCR synapse that leads to autoproliferation of both lineages and eventually to IFN-gamma-dependent signals that, in turn, trigger macrophage-dependent myelin damage. In light of this, B and T cell proliferation, represents a central topic of interest in undestanding MS pathogenesis.
Glial cells are present in the brain roughly in an equal proportions to neurons, although such a ratio can vary significantly between different regions. They are central in several homeostatic and developmental aspects of the central nervous system and include oligodendrocytes progenitors and mature oligodendrocytes, astrocytes, and the "immune guests" of the CNS - the microglial cells, all of which display considerable morphological and functional variability, according to several recent investigations.
Homeopathy has been causing intense debates in Italy in the past years, mainly between its supporters and the scientists and clinicians pointing out its lack of effects in comparison to placebo treatments, at least according to the most recent and influent scientific literature. This was until last september 10th, when Dr Patil and colleagues published, on Scientific Reports a paper reporting the anti-inflammatory and pain-inhibiting effects of an homeopathic preparation in rats.
Two days ago, a monday no less, James P Allison and Tasuku Honjo have been abruptly awaken (by their colleagues and relatives, before the Royal Swedish Academy of Sciences, it would seem) by the greatest new that a scientist could possibly believe to receive on a random day of his or her life: they had been awarded with the 2018 Nobel Prize for physiology or medicine.
This week, Nature published two news that try to analyse the dire political, social and scientific situation that UK is facing now, six months away from the official exit from European Union. The scenario is far from encouraging and the lack, to date, of a defined agreement between Europe and Britain is, alone, causing trouble among several scientists inside and outside UK.
Microglia, the most abundant brain-resident immune cell, are specialized - highly heterogeneous tissue macrophages that control many functional and developmental features of the central nervous system (CNS). Their homeostatic population comes mostly by yolk sac precursors during embryogenesis and maintain a rather well-defined transcriptional signature that is maintained by cytokines of the brain environment (e.g. TGF-beta) and other environmental factors (e.g. microbiota); on the other hand, different cohort of cells, displaying a slightly different signature, is represented by perypheral monocyte-derived cells that enter the brain and differentiate in loco. Given the central role played by microglia in CNS homeostasis, these cells have long be connected to the processes that either trigger or avoid neurodegeneration.
The immune network, and the host of of its modulators, represent -alongside the central nervous system- the most complex entity in human biology, which makes the full contextualization of immune responses in health an disase one of the hardest tasks of research. This picture is further complicated by sex-based differences: indeed it is a well-known fact that males and females can differ significanlty when it comes to immune processes, as well as to the prevalence of autoimmune diseases, with women being more prone to develop conditions such as rheumatoid arthritis, lupus erythematosus and multiple sclerosis (MS). An important culprit of this difference has been found in the ormonal differences that lead to immune alterations (e.g. cytokine expression, generation of pathogenetic phenotypes of immuno cells), which, in turn, are thought to trigger the pathogenesis of autoimmune conditions. In this rather vast puzzle, a research group from Chicago School of Medicine might have recently found a new piece that helped clarifying how ormonal and immune differences between sexes have an impact in MS susceptibility and development.
Most of currently used high throughput-cell sorting techniques employ the analysis of low resolution data coming from the multiparametric measurements of the light peak intensities in the emission spectra of fluorochromes that are conjugated to antibodies binding to specific phenotypic cell markers. The use of more complex approaches, such as those that rely on the analysis of image-based informations, is basically limited by the highly demanding computational power that deep learning algorithms would require to quickly process the huge amount of informations confined in these dimensional data. Nao Nitta, and colleagues, however, proposed an interesting alternative.
Gut microbiota has been linked to several physiological and immune-related functions as well as it has been widely proven that the variety of microbes that inhabit human intestine can be influenced by social and dietary habits, as well as by chronical conditions such as diabetes. Furthermore, alterations or imbalances of the microbiota has often been theorized - although never unequivocally proven - as an important factor in the pathogenesis of several inflammatory conditions, including multiple sclerosis (SM); this fact, in particular, has been recently corroborated by the observation that the microbiota of MS patients differs significantly from that of their healthy counterpart.
Interleukin-2 (IL-2) is one of the most important cytokines of adaptive immunity. It was first identified as a principal autocrine mitogenic factor for T cells, as well as being the first product of recombinand DNA technology to be used as immuno-boosting treatment for human experimentation in pathologies in which immune modulation was a promising therapeutic strategy (e.g. cancer or AIDS). However, its role in adaptive immune response, as it was later discovered, goes well beyond that of a "mere" aspecific growth factor for T cells. Quite soon, in fact, researcers had to deal with the baffling evidence that patients with autoimmune disease displayed low production of IL-2, while mouse models with compromised IL-2 signal axis developed autoimmune conditions, a puzzle that was clarified only when Tregs were discovered.
The contact between T cell receptors (TCR), expressed by CD4 T lymphocytes, and the MHC on the surface of antigen presenting cells is crucial in leading the differentiation of naive T cells into effector cells that are required in the adaptive response against microbes. On the other hand, long-lasting immunity is guaranteed, in the aftermath of the fight against invading organisms, by memory T cells that emerge from a small population of effector T cells that survives the initial clonal expansion.
L'Associazione Italiana di Neuroimmunologia ha concesso il proprio patrocinio per le attività della Scuola quadriennale di Specializzazione post-laurea in Medicina e Chirurgia e in Psicologia dal titolo “Scuola di specializzazione in psicoterapia e neuroscienze orientata allo studio e al trattamento dei disturbi mentali e del comportamento nelle malattie neurologiche (PSICOMED)”.
B cells play a role in most autoimmune conditions mostly due faulty immune tolerance, both central and peripheral, that should instead be meant to keep autoreactive cells at bay. In multiple sclerosis (MS) B cell aggregates located in the meninges and spinal cord seem to be an important factor that contributes to the compartmentalized CNS inflammation that is typical of this disease. Despite our incomplete knowledge of the cellular and molecular mechanisms underlying MS pathogenesis, great advances have been made in this field by research.