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There is increasing evidence from animal and human studies that glaucoma is an autoimmune disease. Evidence for this hypothesis includes the fact that antibodies as well as T‐cell responses to heat‐shock proteins (HSPs) are detectable in some patients with glaucoma and in an animal model of the disease. As in the human disease, experimental animal models of glaucoma have been found to demonstrate neurodegenerative changes in the optic nerve associated with immunoglobulin and T‐cell infiltration. Although there is still insufficient evidence in humans to classify all cases of glaucoma as autoimmune diseases, the implications of this hypothesis have major impact on the diagnosis and treatment of glaucoma. In this paper, we discuss the concept that glaucoma is an autoimmune disease and review emerging evidence for this concept. There is increasing experimental data that some types of normal‐pressure glaucoma may involve immune mechanisms directed at self‐antigens, such as HSP, but proof of the concept that glaucoma is an autoimmune disease remains to be conclusively demonstrated. [ABSTRACT FROM AUTHOR]

As the amount of biomedical information available in the literature continues to increase, databases that aggregate this information continue to grow in importance and scope. The population of databases can occur either through fully automated text mining approaches or through manual curation by human subject experts. We here report our experiences in populating the National Institute of Allergy and Infectious Diseases sponsored Immune Epitope Database and Analysis Resource ( IEDB, http://iedb.org), which was created in 2003, and as of 2012 captures the epitope information from approximately 99% of all papers published to date that describe immune epitopes (with the exception of cancer and HIV data). This was achieved using a hybrid model based on automated document categorization and extensive human expert involvement. This task required automated scanning of over 22 million PubMed abstracts followed by classification and curation of over 13 000 references, including over 7000 infectious disease-related manuscripts, over 1000 allergy-related manuscripts, roughly 4000 related to autoimmunity, and 1000 transplant/alloantigen-related manuscripts. The IEDB curation involves an unprecedented level of detail, capturing for each paper the actual experiments performed for each different epitope structure. Key to enabling this process was the extensive use of ontologies to ensure rigorous and consistent data representation as well as interoperability with other bioinformatics resources, including the Protein Data Bank, Chemical Entities of Biological Interest, and the NIAID Bioinformatics Resource Centers. A growing fraction of the IEDB data derives from direct submissions by research groups engaged in epitope discovery, and is being facilitated by the implementation of novel data submission tools. The present explosion of information contained in biological databases demands effective query and display capabilities to optimize the user experience. Accordingly, the development of original ways to query the database, on the basis of ontologically driven hierarchical trees, and display of epitope data in aggregate in a biologically intuitive yet rigorous fashion is now at the forefront of the IEDB efforts. We also highlight advances made in the realm of epitope analysis and predictive tools available in the IEDB. [ABSTRACT FROM AUTHOR]

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Background: Autoantibody biomarkers are valuable tools used to diagnose and manage autoimmune diseases in dogs. However, prior publications have raised concerns over a lack of standardization and sufficient validation for the use of biomarkers in veterinary medicine. Objectives: Systematically compile primary research on autoantibody biomarkers for autoimmune disease in dogs, summarize their methodological features, and evaluate their quality; synthesize data supporting their use into a resource for veterinarians and researchers. Animals: Not used. Methods: Five indices were searched to identify studies for evaluation: PubMed, CAB Abstracts, Web of Science, Agricola, and SCOPUS. Two independent reviewers (AET and ELC) screened titles and abstracts for exclusion criteria followed by full‐text review of remaining articles. Relevant studies were classified based on study objectives (biomarker, epitope, technique). Data on study characteristics and outcomes were synthesized in independent data tables for each classification. Results: Ninety‐two studies qualified for final analysis (n = 49 biomarker, n = 9 epitope, and n = 34 technique studies). A high degree of heterogeneity in study characteristics and outcomes reporting was observed. Opportunities to strengthen future studies could include: (1) routine use of negative controls, (2) power analyses to inform sample sizes, (3) statistical analyses when appropriate, and (4) multiple detection techniques to confirm results. Conclusions: These findings provide a resource that will allow veterinary clinicians to efficiently evaluate the evidence supporting the use of autoantibody biomarkers, along with the varied methodological approaches used in their development. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Lechtman et al paper. To view this article, visit https://doi.org/10.1111/apt.16282 [ABSTRACT FROM AUTHOR]

Heat shock proteins ( HSPs) serve as molecular chaperones for diverse client proteins in many biological processes. In plant immunity, cytosolic HSP90s participate in the assembly, stability control and/or activation of immune receptor complexes. In this paper we report that in addition to the well-established positive roles that HSP90 isoforms play in plant immunity, they are also involved in the negative regulation of immune receptor accumulation. Point mutations in two HSP90 genes, HSP90.2 and HSP90.3, were identified from a forward genetic screen designed to isolate mutants with enhanced disease resistance. We found that specific mutations in HSP90.2 and HSP90.3 lead to heightened accumulation of immune receptors, including SNC1, RPS2 and RPS4. HSP90s may assist SGT1 in the formation of SCF E3 ubiquitin ligase complexes that target immune receptors for degradation. Such regulation is critical for maintaining appropriate levels of immune receptor proteins to avoid autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Recommendations on contraindications to allergen immunotherapy (AIT) have been independently developed by National and International Societies/Academies. AIT contraindications are mainly based on case reports, case‐series, or experts' opinion, while evidence‐based information is limited. The aim of the present review was to describe existing guidelines on contraindications to AIT and to highlight differences between them. Main body: An extended review of the literature regarding contraindications to AIT for respiratory allergy and venom hypersensitivity was performed. Furthermore, Societies and Academies registered in the World Allergy Organization and EAACI databases, were asked for additional information. Only AIT guidelines published under official auspicies were included. A large heterogeneity among the various recommendations on contraindications was registered. Common contraindications to most of the guidelines were: lack of adherence, pregnancy before the start of AIT, the use of beta‐blockers, certain age groups, uncontrolled asthma, autoimmune diseases and malignancies. Conclusion: As new data arise, revisions might soon be needed allowing AIT in the cases of patients treated with ACE inhibitors and beta‐blockers, in elderly patients and in patients with concomitant autoimmune diseases and neoplasias in remission. The decision to prescribe AIT is always tailor‐made, balancing risk vs benefit. Creating globally accepted guidelines would help Allergologists in their decision making. [ABSTRACT FROM AUTHOR]

Aim The cognitive and psychiatric aspects of adult movement disorders are well established, but specific behavioural profiles for paediatric movement disorders have not been delineated. Knowledge of non-motor phenotypes may guide treatment and determine which symptoms are suggestive of a specific movement disorder and which indicate medication effects. Method The goal of this review is to outline the known cognitive and psychiatric symptoms associated with paediatric movement disorders. We used a systematic approach, via PubMed, and reviewed over 400 abstracts of studies of selected disorders, of which 88 papers reporting paediatric non-motor symptoms are summarized. Results Obsessive-compulsive disorder was manifest in children with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and Sydenham chorea. Children with opsoclonus-myoclonus syndrome had, for the most part, cognitive and behavioural problems, and attention-deficit-hyperactivity disorder was reported as a major comorbidity in Tourette syndrome, stereotypies, and restless legs syndrome. Symptoms of depression and anxiety were more frequent in individuals with idiopathic dystonia. Affective disorders were suggestive of Wilson disease. Cognitive decline was common in children with juvenile Huntington disease. A limitation of this review was the lack of systematic assessment in paediatric movement disorders for evaluation and uniform definitions. Interpretation Although the literature in non-motor phenomena is still emerging, recognition of salient cognitive and psychiatric phenomena may facilitate management of paediatric movement disorders. [ABSTRACT FROM AUTHOR]

Pemphigus vulgaris (PV) is considered to be an autoimmune disease affecting skin and mucous membranes. Traditionally, PV autoantibodies are thought to recognize antigens located in the intercellular substance (ICS) of keratinocytes; antigens represented mainly by the desmosomal cadherin desmoglein 3 (Dsg3). Accordingly, titres of anti-ICS and anti-Dsg3 immunoglobulin G (IgG) are considered to be major laboratory criteria when making a diagnosis of PV. In this paper, we demonstrated for the first time that PV IgG bind antigen(s) expressed on the surface of peripheral blood mononuclear cells (PBMC), as revealed by immunofluorescence studies. This novel autoantigen is immunoprecipitated by PV IgG as a 130 000 molecular weight protein. However, Western blot analysis of the immunocomplexes failed to show reactivity with anti-Dsg3 monoclonal and polyclonal antibodies. Taken together, our data provide strong evidence that PV autoimmunity targets a 130 000 antigen other than Dsg3 on PBMC. This shifting from epidermis to blood cells may open new perspectives for a better understanding of pemphigus autoimmunity and more rational approaches to its treatment. [ABSTRACT FROM AUTHOR]

Celiac disease is an intestinal malabsorption characterized by an intolerance to cereal proteins accompanied by immunological responses to dietary gliadins and an autoantigen located in the endomysium. The latter has been identified as the enzyme tissue transglutaminase which belongs to a family of enzymes that catalyze protein cross-linking reactions and is constitutively expressed in many tissues as well as being activated during apoptosis. In a recent paper, we described the selection and characterization of anti-transglutaminase Igs from phage antibody libraries created from intestinal lymphocytes from celiac disease patients. In this work, using transglutaminase gene fragments, we identify a region of tissue transglutaminase recognized by these antibodies as being conformational and located in the core domain of the enzyme. This is identical to the region recognized by anti-transglutaminase Igs found in the serum of celiac disease patients. [ABSTRACT FROM AUTHOR]

In this paper we describe the first in vitro response to the liver alloantigen F. The anti-F response serves as a valuable model for autoimmune phenomena since priming appropriate strains of mice (responders) with allogeneic but not syngeneic type F leads to autoantibody production. The in vitro system is based on the proliferation of T cells, from mice primed in vivo with F, when coincubated with splenic adherent cells (SAC) prepulsed with F in vivo. The system displays two important correlates of the in vivo antibody response to F:1.T cells from mice primed with syngeneic F do not proliferate when incubated with SAC prepulsed with syngeneic F and 2. Mice that do not make antibody responses to allo F in vivo (DBA/2) do not show in vitro proliferative responses. These findings indicate that the proliferative assay is a good in vitro model for the F response. [ABSTRACT FROM AUTHOR]

We have previously reported an experimental autoimmune model induced by the local infection of Listeria monocytogenes. The unilateral inoculation of virulent Listeria into a testis of a normal mouse induced a delayed-type hypersensitivity response against testicular antigen and caused autoimmune orchitis in the contralateral testis. The orchitis was transferred to naive mice by T cells from the intratesticularly infected mice. In this paper, we demonstrated that avirulent Listeria, which lacks the expression of listeriolysin O, failed to induce any anti-testicular responses or contralateral orchitis even when it was inoculated at a high dose into the testis. Furthermore, the intraperitoneal inoculation of virulent Listeria with testicular antigen induced the antitesticular responses and orchitis although intraperitoneal inoculation of testicular antigen with avitulent Listeria failed to induce them. The difference between virulent and avirulent Listeria in the induction of anti-testicular responses was supposed to be dependent on the difference in macrophage activation by the two bacterial strains because, first, the anti-testicular responses were elicited in normal mice when macrophages from virulent Listeria-infected mice were intraperitoneally transferred with testicular antigen although no viable bacteria were detected from the macrophages, and secondly, in contrast, the intraperitoneal co-inoculation of macrophages from avirulent Listeria-infected mice and testicular antigen failed to elicit any antitesticular responses. Finally, we found that the virulent Listeria-induced macrophages expressed a higher level of CD80 (BT-1) and CD86 (B7-2) molecules than did the avirulent Listeria-induced macrophages and naive peritoneal macrophages. These results thus suggest that virulent Listeria activates macrophages to induce autoreactive T cells while avirulent Listeria does not. The up-regulation of B7 molecules by virulent Listeria infection is a candidate of the mechanism for the activation of autoreactive T cells. [ABSTRACT FROM AUTHOR]

Autoimmune and autoinflammatory diseases (AIIDs) involve a deficit in an individual's immune system function, whereby the immune reaction is directed against self‐antigens. Many AIIDs have a strong genetic component, but they can also be triggered by environmental factors. AIIDs often have a highly negative impact on the individual's physical and mental wellbeing. Understanding the genetic underpinning of AIIDs is thus crucial both for diagnosis and for identifying individuals at high risk of an AIID and mental illness as a result thereof. The aim of the present study was to perform systematic statistical and genetic analyses to assess the role of human leukocyte antigen (HLA) alleles in 30 AIIDs and to study the links between AIIDs and psychiatric disorders. We leveraged the Danish iPSYCH Consortium sample comprising 65 534 individuals diagnosed with psychiatric disorders or selected as part of a random population sample, for whom we also had genetic data and diagnoses of AIIDs. We employed regression analysis to examine comorbidities between AIIDs and psychiatric disorders and associations between AIIDs and HLA alleles across seven HLA genes. Our comorbidity analyses showed that overall AIID and five specific AIIDs were associated with having a psychiatric diagnosis. Our genetic analyses found 81 significant associations between HLA alleles and AIIDs. Lastly, we show connections across AIIDs, psychiatric disorders and infection susceptibility through network analysis of significant HLA associations in these disease classes. Combined, our results include both novel associations as well as replications of previously reported associations in a large sample, and highlight the genetic and epidemiological links between AIIDs and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Aims: A causal link between non‐ischaemic heart failure (HF) and humoral autoimmunity against G‐protein‐coupled receptors (GPCR) remains unclear except for Chagas' cardiomyopathy. Uncertainty arises from ambiguous reports on incidences of GPCR autoantibodies, spurious correlations of autoantibody levels with disease activity, and lack of standardization and validation of measuring procedures for putatively cardio‐pathogenic GPCR autoantibodies. Here, we use validated and certified immune assays presenting native receptors as binding targets. We compared candidate GPCR autoantibody species between HF patients and healthy controls and tested associations of serum autoantibody levels with serological, haemodynamic, metabolic, and functional parameters in HF. Methods: Ninety‐five non‐ischaemic HF patients undergoing transcatheter endomyocardial biopsy and 60 healthy controls were included. GPCR autoantibodies were determined in serum by IgG binding to native receptors or a cyclic peptide (for β1AR autoantibodies). In patients, cardiac function, volumes, and myocardial structural properties were assessed by cardiac magnetic resonance imaging; right heart catheterization served for determination of cardiac haemodynamics; endomyocardial biopsies were used for histological assessment of cardiomyopathy and determination of cardiac mitochondrial oxidative function by high‐resolution respirometry. Results: Autoantibodies against β1 adrenergic (β1AR), M5‐muscarinic (M5AR), and angiotensin II type 2 receptors (AT2R) were increased in HF (all P < 0.001). Autoantibodies against α1‐adrenergic (α1AR) and angiotensin II type 1 receptors (AT1R) were decreased in HF (all P < 0.001). Correlation of alterations of GPCR autoantibodies with markers of cardiac or systemic inflammation or cardiac damage, haemodynamics, myocardial histology, or left ventricular inflammation (judged by T2 mapping) were weak, even when corrected for total IgG. β1AR autoantibodies were related inversely to markers of left ventricular fibrosis indicated by T1 mapping (r = −0.362, P < 0.05) and global longitudinal strain (r = −0.323, P < 0.05). AT2R autoantibodies were associated with improved myocardial mitochondrial coupling as measured by high‐resolution respirometry in myocardial biopsies (r = −0.352, P < 0.05). In insulin‐resistant HF patients, AT2R autoantibodies were decreased (r = −.240, P < 0.05), and AT1R autoantibodies were increased (r = 0.212, P < 0.05). Conclusions: GPCR autoantibodies are markedly altered in HF. However, they are correlated poorly or even inversely to haemodynamic, metabolic, and functional markers of disease severity, myocardial histology, and myocardial mitochondrial efficiency. These observations do not hint towards a specific cardio‐pathogenic role of GPCR autoantibodies and suggest that further investigations are required before specific therapies directed at GPCR autoantibodies can be clinically tested in non‐ischaemic HF. [ABSTRACT FROM AUTHOR]

Two major chaperones, calreticulin (CRT) and binding immunoglobulin protein (GRP78/BiP) dependent on their location, have immunoregulatory or anti‐inflammatory functions respectively. CRT induces pro‐inflammatory cytokines, dendritic cell (DC) maturation and activates cytotoxic T cells against tumours. By contrast, GRP78/BiP induces anti‐inflammatory cytokines, inhibits DC maturation and heightens T‐regulatory cell responses. These latter functions rebalance immune homeostasis in inflammatory diseases, such as rheumatoid arthritis. Both chaperones are therapeutically relevant agents acting primarily on monocytes/DCs. Endogenous exposure of CRT on cancer cell surfaces acts as an 'eat‐me' signal and facilitates improved elimination of stressed and dying tumour cells by DCs. Therefore, therapeutics that promote endogenous CRT translocation to the cell surface can improve the removal of cancer cells. However, infused recombinant CRT dampens this cancer cell eradication by binding directly to the DCs. Low levels of endogenous BiP appear as a surface biomarker of endoplasmic reticulum (ER) stress in some types of tumour cells, a reflection of cells undergoing proliferation, in which resulting hypoxia and nutrient deprivation perturb ER homeostasis triggering the unfolded protein response, leading to increased expression of GRP78/BiP and altered cellular location. Conversely, infusion of an analogue of GRP78/BiP (IRL201805) can lead to long‐term immune resetting and restoration of immune homeostasis. The therapeutic potential of both chaperones relies on them being relocated from their intracellular ER environment. Ongoing clinical trials are employing therapeutic interventions to either enhance endogenous cell surface CRT or infuse IRL201805, thereby triggering several disease‐relevant immune responses leading to a beneficial clinical outcome. [ABSTRACT FROM AUTHOR]

The article presents information about abstracts of various papers that will be discussed at the Platform Session of the 6th European Congress on Epileptology that will be held on June 2, 2004. One of the papers that will be discussed is "Analysis of Autoantibodies (AAB) Against Human Brain AMPA Receptor in a Patient With Partial Epilepsy," by I.Y. Kovaleva. The changing of the level of AAB to AMPA receptors can be recommended as a tool for monitoring treatment and for the prediction of treatment outcome. Other papers that will be discussed are "Extrapyramidal Motor Symptoms in Focal Seizures," by E. Trinka and "Expression and Functional Significance of MDR1 Expression in a Chronic Model of Limbic Seizures," by N. Marchi.

Autoreactive T cells with the phenotype and function of different memory subsets are present in patients who developed type 1 diabetes (TID). According to the progressive differentiation model, memory subsets generate from naïve precursors in a linear and unidirectional path depending on the strength and quality of stimulatory signals. By observing human naïve T cells in contact with GAD65 loaded autologous dendritic cells, we observed that approximately 10% of cells divided with the plane of cell division parallel to the one of the immune synapse, causing phenotypic asymmetries in the proximal and distal daughter T cells. After the first T cell division, proximal and distal daughter T cells showed different phenotype, metabolic signature and commitment to differentiate towards long‐lived memory T cells or T cells with effector function. Subjects with or without T1D showed a similar frequency of asymmetric T cell division (ATCD) for autoantigens and recall antigens specific T cells, however the frequency of ATCD is significantly increased in autoreactive T cells in patients with T1D when IL‐7 was added to the culture. An increased upregulation of GLUT1 in response to IL‐7 in patients with T1D was related to the rate of ATCD. Our results showed that ATCD is associated with an early divergence in the differentiation fate of naïve T cells specific for GAD65 during first antigen encounter. [ABSTRACT FROM AUTHOR]

Introduction: The frequencies and functions of T stem cell memory (TSCM) subsets vary in autoimmune diseases. We evaluated the frequencies of CD4+ and CD8+ TSCM subsets as well as their PD‐1 expression levels in patients with T1D. Methods: Blood samples were collected from new case (NC) (n = 15), and long‐term (LT) (n = 15) groups and healthy controls (n = 15). Five subsets of T cells including TCM(CD4+/CD8+ CCR7+ CD45RO+ CD95+), TCMhi (CD4+/CD8+ CCR7+ CD45ROhi CD95+), TEM(CD4+/CD8+ CCR7− CD45RO+ CD95+), TSCM(CD4+/CD8+ CCR7+ CD45RO− CD95+), and T naive (CD4+/CD8+ CCR7+ CD45RO− CD95−) were detected by flow‐cytometry. Results: The frequency of CD4+ TSCM was higher in NC patients than LT patients and controls (p <.0001 and p =.0086, respectively). A higher percentage of the CD8+ T naive cells was shown in NC patients as compared with LT and healthy individuals (p =.0003 and p =.0002, respectively). An increased level of PD‐1 expression was observed on the CD4+TCM and TCMhi cells in LT patients as compared with healthy controls (p =.0037 and p =.0145, respectively). Also, the higher PD‐1 expression was observed on the CD8+ TCM and TCMhi in NC and LT patients as compared with controls (p =.0068 and p <.0001; p =.0012 and p =.0012, respectively). Conclusion: Considering TSCMs' capacities to generate all memory and effector T cells, our results may suggest a potential association between the increased frequencies of TSCMs and T1D progression. [ABSTRACT FROM AUTHOR]

Neutrophil granulocytes form the first line of host defense against invading pathogens and tissue injury. They are rapidly recruited from the blood to the affected sites, where they deploy an impressive arsenal of effectors to eliminate invading microbes and damaged cells. This capacity is endowed in part by readily mobilizable proteins acquired during granulopoiesis and stored in multiple types of cytosolic granules with each granule type containing a unique cargo. Once released, granule proteins contribute to killing bacteria within the phagosome or the extracellular milieu, but are also capable of inflicting collateral tissue damage. Neutrophil‐driven inflammation underlies many common diseases. Research over the last decade has documented neutrophil heterogeneity and functional versatility far beyond their antimicrobial function. Emerging evidence indicates that neutrophils utilize granule proteins to interact with innate and adaptive immune cells and orchestrate the inflammatory response. Granule proteins have been identified as important modulators of neutrophil trafficking, reverse transendothelial migration, phagocytosis, neutrophil life span, neutrophil extracellular trap formation, efferocytosis, cytokine activity, and autoimmunity. Hence, defining their roles within the inflammatory locus is critical for minimizing damage to the neighboring tissue and return to homeostasis. Here, we provide an overview of recent advances in the regulation of degranulation, granule protein functions, and signaling in modulating neutrophil‐mediated immunity. We also discuss how targeting granule proteins and/or signaling could be harnessed for therapeutic benefits. [ABSTRACT FROM AUTHOR]

The pathogenic immune response in celiac disease (CeD) is orchestrated by phenotypically distinct CD4+ T cells that recognize gluten epitopes in the context of disease‐associated HLA‐DQ allotypes. Cells with the same distinct phenotype, but with elusive specificities, are increased across multiple autoimmune conditions. Here, whether sorting of T cells based on their distinct phenotype (Tphe cells) yields gluten‐reactive cells in CeD is tested. The method′s efficiency is benchmarked by parallel isolation of gluten‐reactive T cells (Ttet cells), using HLA‐DQ:gluten peptide tetramers. From gut biopsies of 12 untreated HLA‐DQ2.5+ CeD patients, Ttet+/Tphe+, Ttet−/Tphe+, and Ttet−/Tphe− cells are sorted for single‐cell T‐cell receptor (TCR)‐sequencing (n = 8) and T‐cell clone (TCC)‐generation (n = 5). The generated TCCs are TCR sequenced and tested for their reactivity against deamidated gluten. Gluten‐reactivity is observed in 91.2% of Ttet+/Tphe+ TCCs, 65.3% of Ttet−/Tphe+ TCCs and 0% of Ttet−/Tphe− TCCs. TCR sequencing reveals clonal expansion and sequence sharing across patients, features reflecting antigen‐driven responses. The feasibility to isolate antigen‐specific CD4+ T cells by the sole use of phenotypic markers in CeD outlines a potential avenue for characterizing disease‐driving CD4+ T cells in autoimmune conditions. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies with nuclear antigen (nAg) specificity. Using (SWRxNZB)F1 (SNF1) mice, we showed higher levels of Immunoglobulin A (IgA) production in the intestine and the nAg reactivity of faecal IgA under lupus susceptibility. Here, we determined whether the faecal IgA abundance and nAg reactivity are higher in, different among, various lupus‐prone preclinical models (MRL/lpr, NZBxNZW‐F1, SNF1, NZM2410 and NZM2328). We also determined whether the faecal IgA nAg reactivity at preseropositive ages correlates with the eventual serum autoantibody levels in males and females of these mouse models. We show that age‐dependent increase in the abundance and nAg reactivity of faecal IgA can vary among different lupus‐prone mouse models. Importantly, faecal IgA in these mice show significant levels of nAg reactivity, starting as early as at juvenile age. Furthermore, the pre‐seropositive stage nAg reactivity of faecal IgA in most lupus‐prone strains correlates well with that of eventual, seropositive stage systemic autoantibody levels. Gender differences in serum autoantibody levels were preceded by similar differences in the faecal IgA abundance and nAg reactivity. These observations suggest that faecal IgA features, nAg reactivity particularly, could serve as a biomarker for early prediction of the eventual systemic autoimmunity in lupus‐prone subjects. [ABSTRACT FROM AUTHOR]

Phenotypic manifestations of antibody-mediated disorders are highly diverse, may evolve insidiously over years, and especially in elderly populations may not be accompanied by evidence of an inflammatory CNS response.9 Homer-3 antibody mediated disease should be added to the growing list of potentially treatable auto-immune MSA mimics. Keywords: multiple system atrophy; progressive supranuclear palsy; corticobasal syndrome; autoimmunity; immunotherapy; parkinsonian disorders EN multiple system atrophy progressive supranuclear palsy corticobasal syndrome autoimmunity immunotherapy parkinsonian disorders 178 182 5 02/07/22 20220201 NES 220201 Liu M, Ren H, Fan S, et al. Homer-3 Antibody Disease: A Potentially Treatable MSA-C Mimic In anti Homer-3 disease, corticosteroids, intravenous immunoglobulin(IVIG), plasma exchange and mycophenolate mofetil have been tried, resulting in partial improvement or stabilization in some patients. [Extracted from the article]

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immunoinflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods:We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aβ-mediated neurotoxicities in AD. Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. Results: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membranepenetrating attack by antimicrobial peptides (AMPs) such as Aβ. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self-perpetuating autoimmune cycle. AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. Discussion: Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that hypothyroidism and thyroid autoimmunity (TAI) are possibly associated with ovarian dysfunction. This meta-analysis aimed to investigate whether hypothyroidism and/or TAI affect the ovarian reserve and evaluated using the anti-Mullerian hormone (AMH). Methods: PubMed, EMBASE, Web of Science, and Cochrane Controlled Trials Register databases from inception to October 2020 were searched to identify relevant studies. Studies comparing the AMH levels between the control and the affected groups were included in the data synthesis. The primary endpoint in the meta-analysis was AMH levels compared with the controls. Main findings: Nine trials were included in the analysis. The AMH levels were significantly lower in the adults with euthyroid TAI (mean difference -0.12, [95% CI: -0.18 to -0.06]). The AMH levels tended to be lower in subclinical hypothyroidism and overt hypothyroidism than in the control group, although the differences were not significant. The AMH levels were significantly higher in the euthyroid TAI group in the adolescents (mean difference 2.51, [95% CI 1.82 to 3.21]). Conclusion: TAI and hypothyroidism may affect the ovarian reserve. The opposite effects on AMH levels depending on age suggest that TAI may be implicated in the depletion of follicles in adults following extensive activation of primordial follicles in adolescence. [ABSTRACT FROM AUTHOR]

The identification of CD4+ CD25+ Foxp3+ regulatory T (Treg) cells as natural regulators of immunity in the periphery and tissues has stimulated tremendous interest in developing therapeutic strategies for autoimmune diseases. In this review, the site of origin, antigen specificity, homing markers and cytokine profiles of Treg cells were evaluated in autoimmune colitis and type 1 diabetes, two examples in which Treg cells were effective as therapy. These studies were compared with studies of Treg cells in experimental autoimmune encephalomyelitis and multiple sclerosis, where successful therapy has not yet been achieved. Antigen-specific Treg cells appear to have more potent activity than polyclonal Treg cells and therefore hold more promise as therapeutic agents. However, Treg cells specific for the pathogenic T effector cells themselves have largely been overlooked and deserve consideration in future studies. [ABSTRACT FROM AUTHOR]

Oral lichen planus (OLP) is a T cell–mediated immunoinflammatory disease. Glycolysis plays an essential role in T‐cell immune responses. Blocking glycolytic pathway in activated T cells represents a therapeutic strategy for restraint of immunologic process in autoimmune disorders. 2‐Deoxy‐D‐glucose (2‐DG) has been widely used to probe into glycolysis in immune cells. This study was aimed to explore the role of glycolysis inhibition by 2‐DG on regulating immune responses of OLP‐derived T cells. We observed that lactic dehydrogenase A (LDHA) expression was elevated in OLP lesions and local T cells. 2‐DG inhibited the expression of LDHA, p‐mTOR, Hif1α and PLD2 in T cells; meanwhile, it decreased proliferation and increased apoptosis of T cells. T cells treated by 2‐DG showed lower LDHA expression and elevated apoptosis, resulting in a reduced apoptotic population of keratinocytes that were co‐cultured with them, which was related to the decreased levels of IFN‐γ in co‐culture system. Rapamycin enhanced the effects of 2‐DG on immune responses between T cells and keratinocytes. Thus, these findings indicated that OLP‐derived T cells might be highly dependent upon high glycolysis for proliferation, and 2‐DG treatment combined with rapamycin might be an option to alleviate T‐cell responses, contributing to reducing apoptosis of keratinocytes. [ABSTRACT FROM AUTHOR]

Across the natural and social world, some fairly advanced and apparently robust systems destroy themselves without discernible reason, function, or purpose. Whereas such and similar cases have been discussed within specific branches of scholarships, the attempts to propose and test a general theory of self‐destruction in complex systems remain, to our knowledge, a thing of the future. To move in this direction, we suggest that the conflicts between explicit stratification, thorough functional differentiation and tacit segmentation within complex systems, are likely to provoke their unintended self‐annihilation. Furthermore, we hypothesize that whenever such systems collapse, it is the circular co‐dependency of noisy signaling, redundancy, and semantic inflation that sets self‐destructive mechanisms in motion. We illustrate our preliminary findings with examples from social, natural, and artificial life; reexamine autoimmunity as a popular model of systemic self‐destruction; and indicate potential avenues of empirical research aimed at supporting, qualifying or disproving the underlying hypothesis. [ABSTRACT FROM AUTHOR]

Regulatory T cells play a key role in immune tolerance to self‐antigens, thereby preventing autoimmune diseases. However, no drugs targeting Treg cells have been approved for clinical trials yet. Here, a chimeric peptide is generated by conjugation of the cytoplasmic domain of CTLA‐4 (ctCTLA‐4) with dNP2 for intracellular delivery, dNP2‐ctCTLA‐4, and evaluated Foxp3 expression during Th0, Th1, Treg, and Th17 differentiation dependent on TGF‐β. The lysine motif of ctCTLA‐4, not tyrosine motif, is required for Foxp3 expression for Treg induction and amelioration of experimental autoimmune encephalomyelitis (EAE). Transcriptome analysis reveals that dNP2‐ctCTLA‐4‐treated T cells express Treg transcriptomic patterns with properties of suppressive functions. In addition, the molecular interaction between the lysine motif of ctCTLA‐4 and PKC‐η is critical for Foxp3 expression. Although both CTLA‐4‐Ig and dNP2‐ctCTLA‐4 treatment in vivo ameliorated EAE progression, only dNP2‐ctCTLA‐4 requires Treg cells for inhibition of disease progression and prevention of relapse. Furthermore, the CTLA‐4 signaling peptide is able to induce human Tregs in vitro and in vivo as well as from peripheral blood mononuclear cells (PBMCs) of multiple sclerosis patients. These results collectively suggest that the chimeric CTLA‐4 signaling peptide can be used for successful induction of regulatory T cells in vivo to control autoimmune diseases, such as multiple sclerosis. [ABSTRACT FROM AUTHOR]

Diabetes classification is not as defined as it used to be. A patient with one type of diabetes can have diagnostic criteria of another type, which may affect the course of the disease. Clinicians need to consider that when dealing with patients who do not fit the exact description of their diagnosed type of diabetes. [ABSTRACT FROM AUTHOR]

The article focuses on neuritin has unmasked as a checkpoint for the pathogenesis of allergy and autoimmunity. Topics include the follicular regulatory T cells (Tfr) in the germinal centre suppress the development of B-cell-driven autoimmunity and IgE-mediated allergic sensitisation via their secretion of the neuropeptide neuritin, and the unmasks a lack of neuritin as a previously unrecognised critical contributor to the development of allergic and autoimmune disease.

Cold antibodies were separated from the sera of six patients suffering from the cold-haemagglutinin syndrome and from one patient with acquired haemolytic anaemia secondayr to lymphosarcoma by dissociation of the specific antigen-antibody complexes. The eluted antibodies were studied (a) by immuno-electrophoresis along with the parent sera against horse anti-human serum and (b) by double diffusion in agar gel along with electrophoretically separated ‘γ1 globulin’† against anti-19S ‘γ-globulin’ rabbit sera. The protein forming the cold antibody was localized in the β2-M position on immuno-electrophoresis in each instance. It was found by double diffusion in agar gel to be immunologically identical with the protein forming the abnormal ‘γl-globulin’ electrophoretic peak in the parent serum. The results of these experiments indicate that the cold antibodies derived from patients with the cold-antibody type of acquired haemolytic anaemia are macro-molecular globulins. [ABSTRACT FROM AUTHOR]

Summary: In the 20‐or‐so years that immunologists have spent describing the mechanisms and functions of regulatory T‐cells, a very great deal has been learnt: a T‐cell subset once described for the generic ability to harness autoimmunity in vivo or diminish T‐cell proliferation in vitro is now appreciated to act on a plethora of cellular pathways using a diverse array of mechanisms. Recent studies have shed new light on basic and applied aspects of Treg function, including T‐cell receptor usage, specialist functions of tissue‐resident Tregs, and the therapeutic consequences of tuning Treg function up or down for applications in autoimmunity or cancer, respectively. [ABSTRACT FROM AUTHOR]

The most commonly used vaccine worldwide, bacillus Calmette-Guerin (BCG), appears to have the ability to restore blood sugar control in humans with early-onset but long-duration type 1 diabetes when a repeat vaccination strategy is used. This is a process that may be driven by a metabolic switch from overactive oxidative phosphorylation to accelerated aerobic glycolysis and a reset of the immune system. BCG is a live, attenuated strain of Mycobacteria bovis, a cousin of M. tuberculosis. Humans and Mycobacteria, which are found in the environment and in warm-blooded hosts, share a long coevolutionary history. In recent times, humans have had fewer exposures to these and other microorganisms that historically helped shape the immune response. By 're-introducing' an attenuated form of Mycobacteria via BCG vaccination, humans might benefit from an immunological perspective, a concept supported by a growing body of data in autoimmunity and robust data on the nonspecific immune effects of BCG related to protection from diverse infections and early mortality. New findings of immune and metabolic defects in type 1 diabetes that can be corrected with repeat BCG vaccination suggest that this therapeutic strategy may be applicable in other diseases with inadequate aerobic glycolysis, including Parkinson's disease, dementia, depression and other disorders affecting the nervous system. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pemphigus is caused by autoantibodies against desmoglein (Dsg) 1, Dsg3, and/or non‐Dsg antigens. Pemphigus vulgaris (PV) is the most common manifestation of pemphigus, with painful erosions on mucous membranes. In most cases, blistering also occurs on the skin, leading to areas of extensive denudation. Despite improvements in pemphigus treatment, time to achieve remission is long, severe adverse events are frequent and 20% of patients do not respond adequately. Current clinical developments focus exclusively on modulating B cell function or autoantibody half‐life. However, topical modulation of PV autoantibody‐induced blistering is an attractive target because it could promptly relieve symptoms. Experimental Approach To address this issue, we performed an unbiased screening in a complex biological system using 141 low MW inhibitors from a chemical library. Specifically, we evaluated PV IgG‐induced Dsg3 internalization in HaCaT keratinocytes. Validation of the 20 identified compounds was performed using keratinocyte fragmentation assays, as well as a human skin organ culture (HSOC) model. key Results: Overall, this approach led to the identification of four molecules involved in PV IgG‐induced skin pathology: MEK1, TrkA, PI3Kα, and VEGFR2. Conclusion and Implications: This unbiased screening revealed novel mechanisms by which PV autoantibodies induce blistering in keratinocytes and identified new treatment targets for this severe and potentially life‐threatening skin disease. [ABSTRACT FROM AUTHOR]

IL‐38 is a newly identified cytokine that belongs to the IL‐1 family. In our previous study, we found elevated plasma levels of IL‐38 in patients with systemic lupus erythematosus (SLE). However, the clear relationship of IL‐38 expression in plasma, peripheral blood mononuclear cells (PBMCs) and clinical and laboratory features needs elucidation. Additionally, we evaluated the possible role of IL‐38 in regulating production of inflammatory cytokines in PBMCs in vitro. A pristane‐induced murine lupus model was used to further demonstrate the effects of IL‐38 on cytokines in vivo and discuss the significance of IL‐38 in lupus development. The results showed that mRNA expression of IL‐38 in PBMCs of patients with SLE was elevated compared with volunteers, and expression of IL‐38 in both plasma and PBMCs was strongly related to clinical features, such as haematuria and proteinuria, and correlated with a SLEDAI score. Plasma levels of TNF‐α, IL‐1β, IL‐6 and IL‐23 were elevated in patients with SLE and were related to plasma levels of IL‐38. In vitro, PBMCs of patients with SLE stimulated with IL‐38 showed a decreased expression of the four inflammatory cytokines compared with PBMCs of patients without treatment. Interestingly, IL‐38 administration in lupus mice significantly reduced the development of lupus, such as reduced proteinuria, improved histological examinations of the kidneys and down‐regulated inflammatory cytokines. In conclusion, IL‐38 may suppress synthesis of pro‐inflammatory cytokines and therefore regulate lupus pathogenesis. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by deficits in social communication and stereotypical behaviours. ASD's aetiology remains mostly unclear, because of a complex interaction between genetic and environmental factors. Recently, a strong consensus has developed around ASD's immune‐mediated pathophysiology, which is the subject of this review. For many years, neuroimmunological studies tried to understand ASD as a prototypical antibody‐ or cell‐mediated disease. Other findings indicated the importance of autoimmune mechanisms such as familial and individual autoimmunity, adaptive immune abnormalities and the influence of infections during gestation. However, recent studies have challenged the idea that autism may be a classical autoimmune disease. Modern neurodevelopmental immunology shows the double‐edged nature of many immune effectors, which can be either beneficial or detrimental depending on tissue homeostasis, stressors, neurodevelopmental stage, inherited and de novo gene mutations and other variables. Nowadays, mother–child interactions in the prenatal environment appear to be crucial for the occurrence of ASD. Studies of animal maternal–foetal immune interaction are being fruitfully carried out using different combinations of type and timing of infection, of maternal immune response and foetal vulnerability and of resilience factors to hostile events. The derailed neuroimmune crosstalk through the placenta initiates and maintains a chronic foetal neuroglial activation, eventually causing the alteration of neurogenesis, migration, synapse formation and pruning. The importance of pregnancy can also allow early immune interventions, which can significantly reduce the increasing risk of ASD and its heavy social burden. [ABSTRACT FROM AUTHOR]

I have briefly reviewed the factors that motivated me to change my views about the existence and importance of suppressor/regulatory T cells and to devote the majority of my laboratory efforts to this newly revitalized area of immunologic research. I am optimistic that manipulation of regulatory T-cell function will shortly be applicable to the clinic. [ABSTRACT FROM AUTHOR]

Background: Recommendations on contraindications to allergen immunotherapy (AIT) have been independently developed by National and International Societies/Academies. AIT contraindications are mainly based on case reports, case-series, or experts' opinion, while evidence-based information is limited. The aim of the present review was to describe existing guidelines on contraindications to AIT and to highlight differences between them. Main body: An extended review of the literature regarding contraindications to AIT for respiratory allergy and venom hypersensitivity was performed. Furthermore, Societies and Academies registered in the World Allergy Organization and EAACI databases, were asked for additional information. Only AIT guidelines published under official auspicies were included. A large heterogeneity among the various recommendations on contraindications was registered. Common contraindications to most of the guidelines were: lack of adherence, pregnancy before the start of AIT, the use of beta-blockers, certain age groups, uncontrolled asthma, autoimmune diseases and malignancies. Conclusion: As new data arise, revisions might soon be needed allowing AIT in the cases of patients treated with ACE inhibitors and beta-blockers, in elderly patients and in patients with concomitant autoimmune diseases and neoplasias in remission. The decision to prescribe AIT is always tailor-made, balancing risk vs benefit. Creating globally accepted guidelines would help Allergologists in their decision making. [ABSTRACT FROM AUTHOR]

The pathophysiology of atopic dermatitis (AD) is highly complex and understanding of disease endotypes may improve disease management. Immunoglobulins E (IgE) against human skin epitopes (IgE autoantibodies) are thought to play a role in disease progression and prolongation. These antibodies have been described in patients with severe and chronic AD, suggesting a progression from allergic inflammation to severe autoimmune processes against the skin. This review provides a summary of the current knowledge and gaps on IgE autoreactivity and self‐reactive T cells in children and adults with AD based on a systematic search. Currently, the clinical relevance and the pathomechanism of IgE autoantibodies in AD needs to be further investigated. Additionally, it is unknown whether the presence of IgE autoantibodies in patients with AD is an epiphenomenon or a disease endotype. However, increased knowledge on the clinical relevance and the pathophysiologic role of IgE autoantibodies and self‐reactive T cells in AD can have consequences for diagnosis and treatment. Responses to the current available treatments can be used for better understanding of the pathways and may shed new lights on the treatment options for patients with AD and autoreactivity against skin epitopes. To conclude, IgE autoantibodies and self‐reactive T cells can contribute to the pathophysiology of AD based on the body of evidence in literature. However, many questions remain open. Future studies on autoreactivity in AD should especially focus on the clinical relevance, the contribution to the disease progression and chronicity on cellular level, the onset and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Neuromyelitis optica spectrum disorders (NMOSD) is a heterogeneous group of neuroinflammatory conditions associated with demyelination primarily in spinal cord and optic nerve, and to a lesser extent in brain. Most NMOSD patients are seropositive for IgG autoantibodies against aquaporin‐4 (AQP4‐IgG), the principal water channel in astrocytes. There has been interest in establishing experimental animal models of seropositive NMOSD (herein referred to as NMO) in order to elucidate NMO pathogenesis mechanisms and to evaluate drug candidates. An important outcome of early NMO animal models was evidence for a pathogenic role of AQP4‐IgG. However, available animal models of NMO, based largely on passive transfer to rodents of AQP4‐IgG or transfer of AQP4‐sensitized T cells, often together with pro‐inflammatory maneuvers, only partially recapitulate the clinical and pathological features of human NMO, and are inherently biased toward humoral or cellular immune mechanisms. This review summarizes current progress and shortcomings in experimental animal models of seropositive NMOSD, and opines on the import of advancing animal models. [ABSTRACT FROM AUTHOR]

HLA gene expression has an important role in the autoimmune disease predisposition. We investigated the mRNA expression profile of the risk alleles HLA‐DRB1*15 and HLA‐DRB1*13 in a cohort of subjects both multiple sclerosis (MS) patients and healthy controls. Moreover, we explored the expression of the allele HLA‐DRB1*11 that is very frequent in our cohort from southern Italy. We found that the expression of MS‐associated alleles in heterozygous MS patients was always higher than the nonassociated alleles. The differential risk allele expression occurred also in nonaffected subjects, though with a lower increment compared to MS patients. [ABSTRACT FROM AUTHOR]

The chronic inflammatory response plays an important role in adverse cardiac remodelling and the development of heart failure (HF). There is also evidence that in the pathogenesis of several cardiovascular diseases, chronic inflammation is accompanied by antibody and complement deposits in the heart, suggestive of a true autoimmune response. However, the role of antibody‐mediated immune responses in HF progression is less clear. We assessed whether immune cell infiltration and immunoglobulin levels are associated with HF type and disease stage, taking sex differences into account. We found IgG deposits and increased infiltration of immune cells in the affected myocardium of patients with end‐stage HF with reduced ejection fraction (HFrEF, n = 20). Circulating levels of IgG1 and IgG3 were elevated in these patients. Furthermore, the percentage of transitional/regulatory B cells was decreased (from 6.9% to 2.4%) compared with healthy controls (n = 5). Similarly, increased levels of circulating IgG1 and IgG3 were observed in men with left ventricular diastolic dysfunction (LVDD, n = 5), possibly an early stage of HF with preserved EF (HFpEF). In conclusion, IgG deposits and infiltrates of immune cells are present in end‐stage HFrEF. In addition, both LVDD patients and end‐stage HFrEF patients show elevated levels of circulating IgG1 and IgG3, suggesting an antibody‐mediated immune response upon cardiac remodelling, which in the early phase of remodelling appear to differ between men and women. These immunoglobulin subclasses might be used as marker for pre‐stage HF and its progression. Future identification of auto‐antigens might open possibilities for new therapeutic interventions. [ABSTRACT FROM AUTHOR]

Click here to view the Letter to the Editor by Dr. S. Dahan & Y. Shoenfeld [ABSTRACT FROM AUTHOR]

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. Approximately 30% of patients do not respond to therapy with ursodeoxycholic acid (UDCA). Previous studies have implicated increased senescence of cholangiocytes in patients who do not respond to UDCA. This may increase the release of cytokines which drive pathogenic T cell polarization. As FXR agonists are beneficial in treating UDCA non‐responsive patients, the current study was designed to model the interactions between cholangiocytes and CD4+ T cells to investigate potential immunomodulatory mechanisms of bile acid receptor agonists. Human cholangiocytes were co‐cultured with CD4+ T cells to model the biliary stress response. Senescent cholangiocytes were able to polarize T cells toward a Th17 phenotype and suppressed expression of FoxP3 (P = 0.0043). Whilst FXR and TGR5 receptor agonists were unable directly to alter cholangiocyte cytokine expression, FGF19 was capable of significantly reducing IL‐6 release (P = 0.044). Bile acid receptor expression was assessed in PBC patients with well‐characterized responsiveness to UDCA therapy. A reduction in FXR staining was observed in both cholangiocytes and hepatocytes in PBC patients without adequate response to UDCA. Increased IL‐6 expression by senescent cholangiocytes represents a potential mechanism by which biliary damage in PBC could contribute to excessive inflammation. [ABSTRACT FROM AUTHOR]

Summary: Immune cell‐mediated destruction of salivary glands is a hallmark feature of Sjögren syndrome. Similar to the female predominance in humans, female non‐obese diabetic (NOD) mice develop spontaneous salivary gland autoimmunity. However, in both humans and mice it is unclear what factors contribute to the initial immune infiltration of the salivary glands. Here, we used an adoptive transfer model of Sjögren syndrome to determine if female mice harbor a sex‐specific defect in salivary‐gland‐protective regulatory T (Treg) cells. Transfer of cervical lymph node (LN) cells from female NOD mice into sex‐matched NOD‐severe combined immunodeficient (SCID) recipients resulted in sialadenitis, regardless of the presence or absence of Treg cells. In contrast, transfer of cervical LN cells from male NOD mice into sex‐matched NOD‐SCID recipients only resulted in sialadenitis when Treg cells were depleted before transfer, suggesting that male NOD mice have functional salivary‐gland‐protective Treg cells. Notably, the host environment affected the ability of Treg cells to prevent sialadenitis with testosterone promoting salivary gland protection. Treg cells from male mice did not protect against sialadenitis in female recipients. Testosterone treatment of female recipients of bulk cervical LN cells decreased sialadenitis, and Treg cells from female mice were capable of protecting against development of sialadenitis in male recipients. Hence, our data demonstrate that female NOD mice develop sialadenitis through a defect in salivary‐gland‐protective Treg cells that can be reversed in the presence of testosterone. [ABSTRACT FROM AUTHOR]

Summary: High‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear. [ABSTRACT FROM AUTHOR]

Summary: High salt consumption has since long been associated with elevated blood pressure and cardiovascular disease. Recently, mouse studies suggested that a high dietary salt intake exacerbates the clinical manifestations of autoimmunity. Using naïve cells ex vivo after pre‐exposure of mice to high salt intake, we showed that increased salt exposure affects the viability and effector functions of immune cells. CD4+ T‐cells evidenced a pro‐inflammatory phenotype characterized by increased secretion of IFNγ and IL‐17A, when exposed to high salt concentrations in vitro. Interestingly, this phenotype was associated with osmotic pressure, as replacing salt for d‐mannitol resulted in similar observations. However, high salt intake did not alter the development of T‐cell‐dependent autoimmunity. Instead, recruitment of peritoneal macrophages was increased in mice pre‐exposed to high salt concentrations. These cells had an increased production of both TNFα and IL‐10, suggesting that salt stimulates expansion and differentiation of different subsets of macrophages. Moreover, mice pre‐exposed to high salt intake developed exacerbated symptoms of colitis, when induced by dextran sulphate sodium. The aggravated colitis in salt‐exposed animals was associated with a higher frequency of CD4+ T‐cells and CD11b+ CD64+ macrophages producing TNFα. These phenotypes correlated with elevated titres of faecal IgA and higher lymphocytic cellularity in the colon, mesenteric lymph nodes and spleen. In conclusion, we report here that high salt intake affects both lymphoid and myeloid cells ex vivo. However, the effects of high salt intake in vivo seem less pronounced in terms of CD4+ T‐cell responses, whereas macrophage‐dependent pathologies are significantly influenced. [ABSTRACT FROM AUTHOR]

Summary: Recent studies report that loss and dysfunction of mitochondria and peroxisomes contribute to the myelin and axonal damage in multiple sclerosis (MS). In this study, we investigated the efficacy of a combination of lovastatin and AMP‐activated protein kinase (AMPK) activator (AICAR) on the loss and dysfunction of mitochondria and peroxisomes and myelin and axonal damage in spinal cords, relative to the clinical disease symptoms, using a mouse model of experimental autoimmune encephalomyelitis (EAE, a model for MS). We observed that lovastatin and AICAR treatments individually provided partial protection of mitochondria/peroxisomes and myelin/axons, and therefore partial attenuation of clinical disease in EAE mice. However, treatment of EAE mice with the lovastatin and AICAR combination provided greater protection of mitochondria/peroxisomes and myelin/axons, and greater improvement in clinical disease compared with individual drug treatments. In spinal cords of EAE mice, lovastatin‐mediated inhibition of RhoA and AICAR‐mediated activation of AMPK cooperatively enhanced the expression of the transcription factors and regulators (e.g. PPARα/β, SIRT‐1, NRF‐1, and TFAM) required for biogenesis and the functions of mitochondria (e.g. OXPHOS, MnSOD) and peroxisomes (e.g. PMP70 and catalase). In summary, these studies document that oral medication with a combination of lovastatin and AICAR, which are individually known to have immunomodulatory effects, provides potent protection and repair of inflammation‐induced loss and dysfunction of mitochondria and peroxisomes as well as myelin and axonal abnormalities in EAE. As statins are known to provide protection in progressive MS (Phase II study), these studies support that supplementation statin treatment with an AMPK activator may provide greater efficacy against MS. [ABSTRACT FROM AUTHOR]