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Collectively, autoimmune diseases are among the most prevalent diseases in the U.S., affecting more than 23.5 million Americans. They are more common among women, and while some are more prevalent among white people, others are more common among African-Americans and Hispanics.1 Autoimmune diseases are becoming increasingly prevalent, for reasons unknown.
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Information Society website and facebook page bring all the news from many different sources to an unique place where people can place their opinions and get involved with everything that is happening around the globe.
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DNA Cell Biol. 2016 Sep;35(9):455-8. doi: 10.1089/dna.2016.3432. Epub 2016 Jul 27.
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Immune cell activation and differentiation occurs concurrently with metabolic reprogramming. This ensures that activated cells generate the energy and substrates necessary to perform their specified function. Likewise, the metabolic programs among different cells of the immune system vary. By targeting different metabolic pathways, these differences allow for selective regulation of immune responses. Further, the relative susceptibility of cells to a metabolic inhibitor is dictated by their metabolic demands; cellular selectivity is based on demand. Therefore, where differences exist in metabolic pathways between healthy and pathogenic cells, there is opportunity for selective regulation with agents lacking intrinsic specificity. There are now a host of studies demonstrating how inhibitors of metabolism (e.g., glycolysis, glutamine metabolism, and fatty acid oxidation) can regulate immune responses and treat immune-mediated pathogenesis. In this brief review we detail how inhibitors of metabolism can be employed to regulate immune responses in both autoimmunity and transplantation.
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The discovery that central nervous system (CNS)–targeted autoreactive T cells required a process of licensing in the lung revealed an unexpected relationship between these organs. The clinical and immunological significance of this finding is bidirectional in that it showed not only a mechanism by which T cells become pathogenic before entering the CNS, but also the potential for this process to influence lung immunity as well. Epidemiological studies have shown that people with multiple sclerosis (MS) suffer from increased morbidity and mortality from infectious diseases, independent of immunosuppressive therapies. Respiratory infections account for a large percentage of deaths of people with MS. In this study, to investigate the mechanisms responsible for this enhanced susceptibility, we established a comorbid model system in which mice with experimental autoimmune encephalomyelitis (EAE) were administered a sublethal dose of influenza. Whereas mice with either EAE alone or influenza alone survived, 70% of comorbid mice died as a result of uncontrolled viral replication. Immunological analyses revealed that the induction of EAE led to a surprising alteration of the lung milieu, converting an effective stimulatory influenza-reactive environment into a suppressive one. These results provide mechanistic information that may help to explain the unexpected immunological interactions.
Gilbert C FAURE's insight:
connected lung
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In October of 2015, the startup company ImmunArray announced the launch of a microarray platform – the iChip® – to profile repertoires of serum antibodi..
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Nature Reviews Rheumatology | doi:10.1038/nrrheum.2017.2
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Myasthenia gravis (MG) is a prototypical B cell-mediated autoimmune disease affecting 20–50 people per 100,000. The majority of patients fall into two clinically distinguishable types based on whether they produce autoantibodies targeting the acetylcholine receptor (AChR-MG) or muscle specific kinase (MuSK-MG). The autoantibodies are pathogenic, but whether their generation is associated with broader defects in the B cell repertoire is unknown. To address this question, we performed deep sequencing of the BCR repertoire of AChR-MG, MuSK-MG, and healthy subjects to generate ∼518,000 unique VH and VL sequences from sorted naive and memory B cell populations. AChR-MG and MuSK-MG subjects displayed distinct gene segment usage biases in both VH and VL sequences within the naive and memory compartments. The memory compartment of AChR-MG was further characterized by reduced positive selection of somatic mutations in the VH CDR and altered VH CDR3 physicochemical properties. The VL repertoire of MuSK-MG was specifically characterized by reduced V-J segment distance in recombined sequences, suggesting diminished VL receptor editing during B cell development. Our results identify large-scale abnormalities in both the naive and memory B cell repertoires. Particular abnormalities were unique to either AChR-MG or MuSK-MG, indicating that the repertoires reflect the distinct properties of the subtypes. These repertoire abnormalities are consistent with previously observed defects in B cell tolerance checkpoints in MG, thereby offering additional insight regarding the impact of tolerance defects on peripheral autoimmune repertoires. These collective findings point toward a deformed B cell repertoire as a fundamental component of MG.
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The interactions of the gut microbiota in children with typical diabetes autoantibodies differ from that in healthy children. The fact that these differences already exist before antibodies are detectable in the blood add
Gilbert C FAURE's insight:
in 2014
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Don’t delay going to the doctor, because treatment can make you feel better fast.
Gilbert C FAURE's insight:
PMR viewed by WPost
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Objectives
Patients with antiphospholipid syndrome (APS) are at risk for subclinical endothelial injury, as well as accelerated atherosclerosis. In the related disease systemic lupus erythematosus, there is a well-established defect in circulating endothelial progenitors, which leads to an accrual of endothelial damage over time. This defect has been at least partially attributed to exaggerated expression of type I interferons (IFNs). We sought to determine whether these pathways are important in APS. Methods We studied 68 patients with primary APS. Endothelial progenitors were assessed by flow cytometry and functional assay. Type I IFN activity was determined by a well-accepted bioassay, while peripheral blood mononuclear cells were scored for expression of IFN-responsive genes. Results Endothelial progenitors from patients with APS demonstrated a marked defect in the ability to differentiate into endothelial cells, a phenotype which could be mimicked by treating control progenitors with APS sera. Elevated type I IFN activity was detected in the circulation of patients with APS (a finding that was then replicated in an independent cohort). While IgG depletion from APS sera did not rescue endothelial progenitor function, the dysfunction was successfully reversed by a type I IFN receptor-neutralising antibody. Conclusions We describe, for the first time to our knowledge, an IFN signature in primary APS and show that this promotes impaired endothelial progenitor function. This work opens the door to novel approaches that may mitigate vascular damage in APS, such as anti-IFN drugs.
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We have previously shown that activated T cells have a much stronger proinflammatory effect in the development of experimental autoimmune uveitis than their nonactivated counterparts. Our present study explored T cell subsets are functionally distinct in autoimmune pathogenesis and determined the pathogenic contribution of biased V4+ T cell activation in this disease. By systematically comparing two major peripheral T cell subsets, the V1+ and the V4+ cells, we found that the V4+ cells were readily activated in B6 mice during experimental autoimmune uveitis development, whereas V1+ cells remained nonactivated. Cytokines that were abundantly found in the serum of immunized mice activated V4+, but did not activate V1+, cells. The V4+ cells had a strong proinflammatory activity, whereas the V1+ cells remained nonactivated when tested immediately after isolation from immunized mice. However, when the V1+ cells were activated in vitro, they promoted inflammation. Our results demonstrated that activation is a major factor in switching the enhancing and inhibiting effects of both V1+ and V4+ T cell subsets, and that T cell subsets differ greatly in their activation requirements. Whether the enhancing or inhibiting function of T cells is dominant is mainly determined by the proportion of the T cells that are activated versus the proportion not activated.
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Psychological health, access to care, expanded and personalized treatment options, and the tracking of hypoglycemia in people with diabetes are key areas emphasized in the American Diabetes Association’s (Association) new 2017 Standards of Medical Care in Diabetes (Standards). Produced annually by the Association, the guidelines focus on screening, diagnosis and treatment to provide better health outcomes for children, adults and older people with type 1, type 2 or gestational diabetes, and to improve the prevention and delay of type 2 diabetes.
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Inflammasomes are multiprotein complexes that critically control different aspects of innate and adaptive immunity. Among them we could highlight the release of pro-inflammatory cytokines that induces and maintains the inflammatory response. Usually, inflammasomes results from oligomerization of a nucleotide-binding domain-like receptor (NLR) after sensing different pathogenic or endogenous sterile dangerous signals; however other proteins as AIM2, RIG-I or Pyrin could also form inflammasome platforms. Inflammasome oligomerization leads to caspase-1 activation and the processing and release of the pro-inflammatory cytokines interleukin (IL)-1 and IL-18. Mutations in different inflammasomes are causative for multiple periodic hereditary syndromes or autoinflammatory diseases, characterized by acute systemic inflammatory flares not associated to infections, tumors or autoimmunity. This review focus on germline mutations that have been described in cryopyrin-associated periodic syndrome (CAPS) for NLRP3 or in familial Mediterranean fever (FMF) and Pyrin associated autoinflammation with neutrophilic dermatosis (PAAND) for MEFV. Besides the implication of inflammasomes in autoinflammatory syndromes, these molecular platforms are involved in the pathophysiology of different illnesses, including chronic inflammatory diseases, degenerative processes, fibrosis or metabolic diseases. Therefore, drug development targeting inflammasome activation is a promising field in expansion.
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Highly multiplexed point of care tests could improve diagnostic accuracy and differential diagnostic capacity in for instance emergency medicine and low resource environments. Available technology platforms for POC biomarker detection are typically simplex or low-plexed, whereas common lab-based microarray systems
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Gilbert C FAURE's insight:
Neovacs pipeline
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Brought to you by the American College of Gastroenterology.
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Diabetes Educ. 2016 Feb;42(1):23-33. doi: 10.1177/0145721715620019. Epub 2015 Dec 7. Research Support, N.I.H., Extramural
Gilbert C FAURE's insight:
health literacy for diabetes
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Arthritis Res Ther. 2017 Jan 19;19(1):8. doi: 10.1186/s13075-016-1213-9.
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The IL-17 family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti–IL-17A Abs were recently approved to treat human psoriasis. Little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. In this article, we show that the endoribonuclease MCP-1–induced protein 1 (MCPIP1; also known as regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency ( Zc3h12a +/−) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a +/− mice was associated with elevated expression of IL-17A– and IL-17C–dependent genes, as well as with increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a +/− mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in nonhematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a +/− Il17ra−/− mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a +/− Il17a−/− and Zc3h12a +/− Il17c−/− mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a −/− keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, to our knowledge, MCPIP1 is the first described negative regulator of IL-17C signaling.
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The most important feature of B cells is the production of Abs upon activation; additionally, B cells produce pro- and anti-inflammatory cytokines in response to certain stimuli. IL-10–producing B cells represent a major subset of regulatory B cells (Bregs) that suppress autoimmune and inflammatory responses. B cells play a crucial role in the development and maintenance of the chronic inflammatory autoimmune disease rheumatoid arthritis (RA); however, controversial data are available on IL-10– producing Bregs in RA. Our aim was to identify the optimal conditions that induce IL-10+ Bregs and, furthermore, to shed light on the signaling pathways that are responsible for their expansion. The results show that dual stimulation by CpG and CD40L for 48 h is optimal for IL-10 induction, and this can be synergistically boosted by IL-21. We identified the CD19+CD27+ memory B cell population as the major source of IL-10+ Bregs. We detected significantly fewer CD19+CD27+IL-10+ cells in RA patients compared with healthy controls, and these were functionally defective in suppressing IFN-γ production by CD4+ T cells in coculture. IL-21 drastically increased the number of IL-10+ Bregs within the CD19+CD27+ and CD19+CD27− populations; furthermore, it induced the appearance of IL-10+Blimp-1+ plasmablasts. Monitoring the phosphorylation of key signaling molecules revealed that activation of ERK, p38, and CREB is indispensable for the induction of IL-10 production, whereas phosphorylation of STAT3 further enhances IL-10 expression in human Bregs. We conclude that CREB and STAT3 are the key transcription factors responsible for the expansion and differentiation of human IL-10–producing Bregs.
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Thème : SAPL : De la physiopathologie à la prise en charge thérapeutique (incluant le syndrome catastrophique) Orateur : Denis WAHL
Gilbert C FAURE's insight:
à Nancy, avec MIEL
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Before a malignant tumor is developed, the immune system tries to fight against proteins that are altered during their formation, producing certain cancer antibodies.
Gilbert C FAURE's insight:
an old dream?
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Background
In 2012, a European initiative called Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate diagnostic and management regimens in Europe for children and young adults with rheumatic diseases. Juvenile dermatomyositis (JDM) is a rare disease within the group of paediatric rheumatic diseases (PRDs) and can lead to significant morbidity. Evidence-based guidelines are sparse and management is mostly based on physicians' experience. Consequently, treatment regimens differ throughout Europe. Objectives To provide recommendations for diagnosis and treatment of JDM. Methods Recommendations were developed by an evidence-informed consensus process using the European League Against Rheumatism standard operating procedures. A committee was constituted, consisting of 19 experienced paediatric rheumatologists and 2 experts in paediatric exercise physiology and physical therapy, mainly from Europe. Recommendations derived from a validated systematic literature review were evaluated by an online survey and subsequently discussed at two consensus meetings using nominal group technique. Recommendations were accepted if >80% agreement was reached. Results In total, 7 overarching principles, 33 recommendations on diagnosis and 19 recommendations on therapy were accepted with >80% agreement among experts. Topics covered include assessment of skin, muscle and major organ involvement and suggested treatment pathways. Conclusions The SHARE initiative aims to identify best practices for treatment of patients suffering from PRD. Within this remit, recommendations for the diagnosis and treatment of JDM have been formulated by an evidence-informed consensus process to produce a standard of care for patients with JDM throughout Europe.
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