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Moderate-to-severe systemic lupus erythematosus (SLE) is characterized by extensive autoantibody deposition and persistent autoinflammation. As the existing animal models are limited in accurately reproducing the pathological characteristics of human SLE, we introduced a novel animal model simulating multi-organ autoinflammation through intra-organ injections. The model closely mimicked key features of SLE, including IgG deposition, inflammation, and tissue damage. The model could be used to assess the roles of IgG, immune cells, cytokines, and Fc gamma receptor (FcγR) in the pathogenesis of autoinflammation. The results obtained from this model could be confirmed by lupus MRL/ lpr mice. The review suggested that the diagnostic criteria should be reconsidered to incorporate IgG deposition in tissues and highlighted the limitations of current T-cell and B-cell-focused treatments. To summarize, the IgG deposition model can be used to investigate the pathogenesis and treatment of multi-organ tissue damage associated with SLE. • Introduction of a novel animal model: a new animal model mimicing the pathogenesis of lupus autoantibodies IgG-induced organ-tissue damage. • Comprehensive Exploration and Validation of New Model: The roles of lupus autoantibody IgG, immune cells, cytokines and FcγR in organ tissue inflammation were investigated by using this new model. Confirmation of the results from the new model using lupus-prone MRL/lpr mice. • Implications for SLE Research and Treatment: Importance and convenience of the IgG deposition model in investigating the pathogenesis of SLE and its potential for developing targeted therapies. • This paper significantly contributes to the understanding of SLE pathogenesis by introducing a novel animal model that accurately replicates key aspects of the disease, providing a platform for more effective therapeutic exploration and diagnostic considerations. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a significant global public health issue with a high incidence, disability, and mortality rate. A robust inflammatory cascade with complex and wide-ranging mechanisms occurs following ischemic brain injury. Inflammasomes are multiprotein complexes in the cytoplasm that modulate the inflammatory response by releasing pro-inflammatory cytokines and inducing cellular pyroptosis. Among these inflammasomes, the Absent in Melanoma 2 (AIM2) inflammasome shows the ability to detect a wide range of pathogen DNAs, thereby triggering an inflammatory response. Recent studies have indicated that the aberrant expression of AIM2 inflammasome in various cells is closely associated with the pathological processes of ischemic brain injury. This paper summarizes the expression and regulatory role of AIM2 in CNS and peripheral immune cells and discusses current therapeutic approaches targeting AIM2 inflammasome. These findings aim to serve as a reference for future research in this field. • The AIM2 inflammasomes are regarded as the key participants in the inflammatory response following ischemic stroke. • The pathological progression of ischemic brain injury involves aberrant expression of AIM2 inflammasomes in various cells. • Specific inhibitors directed towards AIM2 inflammasomes have the potential to serve as therapeutic agents for the management of neurological damage following an ischemic stroke [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE. • Epigenetic modifications are widely involved in the pathogenesis of SLE. • Epigenetic modifications promote and maintain continuous immune activation and chronic inflammation. • Epigenetic modifications promote and maintain continuous immune activation and chronic inflammation. [ABSTRACT FROM AUTHOR]

Autoinflammatory diseases are rare group of conditions manifested by recurrent fevers, systemic inflammation, and dysfunctions of the innate immune system. These conditions are characterized by overproduction or lack of inhibition of various cytokines, and the advent of biologic drugs that block specific cytokines involved in these conditions has revolutionized their treatment. In this review, I will discuss the most common autoinflammatory conditions of adulthood including familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), mevalonate kinase deficiency/hyperimmunoglobulinemia D Syndrome (MKD/HIDS), TNF receptor-associated autoinflammatory syndrome (TRAPS), and systemic juvenile idiopathic arthritis/adult-onset Still's disease (SJIA/AOSD). I will discuss how IL-1, IL-6, IL-18, and TNF play pathogenic roles in these conditions and will review the evidence behind cytokine blockade for these diseases. Throughout the paper, I will reflect on gaps in knowledge of autoinflammatory diseases and will highlight the latest advances and newest drugs in development. [ABSTRACT FROM AUTHOR]

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder marked by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). At the present time, treatment is primarily focused on anticoagulation. However, there is increasing awareness of the mechanisms involved in APS pathogenesis, which has led to the trial of novel therapies targeting those mechanisms. Following a brief review of the etiopathogenesis of and current management strategies in APS, this paper focuses on the evidence for these potential, targeted APS treatments, e.g., hydroxychloroquine, statins, rituximab, belimumab, eculizumab, defibrotide, sirolimus, and peptide therapy. [ABSTRACT FROM AUTHOR]

Finding a non-invasive biomarker to monitor allograft status after transplantation could contribute to better control of the post-transplant status of transplant recipients and, if possible, could be used instead of invasive biopsy for proving rejection. On the other hand, reducing the dosage of immunosuppression or stopping lifelong use of them because of their severe side effects is an important goal in order to dispose of their severe side effects. The ability of exosomes as a biomarker of rejection and as a therapeutic strategy was investigated in the human kidney, heart, and lung transplantation or in transplantation models with interesting results. Moreover, the ability of exosome was assessed as antigen-presenting vesicles (APVs), in which exosomes can either participate in immune stimulation (semi-direct recognition) or immune suppression thereby, influence on the transplantation outcome. In this paper, authors try to provide comprehensive information about triple role of exosomes in the transplantation medicine. • Exosomal content are different between transplant recipients with rejection and those without rejection. • Exosomal content remarkably discriminate patients with rejection and those without rejection. • Exosomes could be novel biomarkers of rejection in transplantation. • Exosomes can both directly and indirectly activate T cells and therefore can participate in graft rejection/tolerance. • Exosomes as a therapeutic strategy promote the allograft survival time in the transplantation. [ABSTRACT FROM AUTHOR]

Abstract The incorporation of next generation sequencing into routine immunological practice has enabled the identification of novel inborn errors of disease, helped define new categories of immune deficiency and extended the clinical spectrum associated with many long-recognised diseases. The family of EBV (Epstein Barr Virus)-sensitive primary immune deficiencies is one such group and in this paper we describe three families: two with X-linked lymphoproliferative disease type-1 (XLP-1) and one with deficiency of Interleukin-2 Inducible T-cell Kinase (ITK). Both diseases have a wide range of clinical manifestations and are united by an exquisite predisposition to EBV, dysgammaglobulinemia, hemophagocytic lymphohistiocytosis, and lymphoma. We detail our approach to diagnosis, treatment, and risk stratification in these diseases where both clinicians and patients must grapple with constant uncertainty. [ABSTRACT FROM AUTHOR]

Abstract Epigenetics is known to be an important mechanism in the pathogenesis of autoimmune diseases. Epigenetic variations can act as integrators of environmental and genetic exposures and propagate activated states in immune cells. Studying epigenetic alterations by means of genome-wide approaches promises to unravel novel molecular mechanisms related to disease etiology, disease progression, clinical manifestations and treatment responses. This paper reviews what we have learned in the last five years from epigenome-wide studies for three systemic autoimmune diseases, namely systemic lupus erythematosus, primary Sjögren's syndrome, and rheumatoid arthritis. We examine the degree of epigenetic sharing between different diseases and the possible mediating role of epigenetic associations in genetic and environmental risks. Finally, we also shed light into the use of epigenetic markers towards a better precision medicine regarding disease prediction, prevention and personalized treatment in systemic autoimmunity. [ABSTRACT FROM AUTHOR]

This paper summarizes and reviews the mechanisms of action and data concerning efficacy of recommended treatments as well as other treatments that have been tested, independently of the outcomes, in the management of chronic spontaneous urticaria. Due to the central role of mast cells, basophils and histamine in the pathophysiology of this disease, H 1 -antihistamines remain the first-line treatment. However, current knowledge about this complex disease, also recognizes an important role for T lymphocytes, B lymphocytes, and autoantibodies. Implications of these others mediators thus provide further targets for treatment. Indeed, agents previously used to treat other autoimmune and inflammatory diseases, have demonstrated efficacy in chronic spontaneous urticaria and are therefore potential therapeutic alternatives for antihistamine unresponsive patients. [ABSTRACT FROM AUTHOR]

Behcet syndrome is a systemic vasculitis which can involve many different organ systems. As such, treatment decisions need to be based on organ system involved. In addition, specific patient characteristics potentially predict milder or more severe course, and all these factors need to be taken into consideration when making treatment decisions. In this paper, we review the current approaches to treating Behcet syndrome patients. [ABSTRACT FROM AUTHOR]

We have encountered a patient with HIV who developed rapid worsening altered mental status positive for both acute West Nile encephalitis and amphiphysin antibodies. Upon literature review, we read Dr. Moutsopoulos's paper from your journal with great interest (Karagianni et al., 2019 [ 1 ]). While an autoimmune encephalitis following West Nile encephalitis is not novel, there are several interesting features in a patient we have encountered. Firstly, amphiphysin antibodies coexisting with West Nile encephalitis has not been described before. Second, the fact that the clinical course is monophasic, not biphasic, may lead to the suggestion that autoimmune encephalitis triggered by, or coexisting with, West Nile encephalitis may be grossly underrecognized. Third, our patient was HIV positive, but not grossly immunocompromised, which may have played a factor in the autoimmune status. [ABSTRACT FROM AUTHOR]

During the last decades the efficacy of biologic agents, mainly of anti-TNFs, in controlling the activity of serious manifestations of Behcet's Disease (BD) has been established. On the other hand, the clinical heterogeneity of BD has precluded the validation of a widely-accepted composite index for disease assessment and for target disease-state definitions, such as low disease activity and remission, and the testing of their implementation in clinical practice. Therefore, in contrast to other systemic rheumatic diseases, a treat-to-target strategy has not yet been developed in BD. There are several challenges towards this approach, including standardization of outcome measures for assessing the disease activity in each-affected organ and construction of a composite disease activity index. The challenges for the development of a treat-to-target strategy and possible solutions are discussed in this position paper, which stemmed from a round table discussion that took place in the 19th International Conference on BD. • Expression and severity of the clinical features of BD varies. Therefore measuring overall disease activityis challenging • Efforts are ongoing to determine the best instruments to assess disease activity in BD • Given the emerging therapies in BD, definition of therapeutic targets and development of treat-to-target strategy is needed. [ABSTRACT FROM AUTHOR]

The newly discovered subset of memory T cells, tissue resident memory T (TRM) cells, reside in peripheral tissues for a long time, contributing to a rapid immune response and constituting the first line of defense when pathogens invade cells. Tissue resident memory T cells have unique transcriptome characteristics, and their presence in peripheral tissues is regulated by many factors. TRM cells residing in different tissues often express different surface markers. In addition to CD8+ and CD4+ T cells, which are the best-characterized T cells, Treg cells and various innate T cells can reside in nonlymphoid tissues. Many recent studies have shown that tissue resident memory T cells play indispensable roles in tumor immunity and allergic diseases. This paper reviews the differentiation, regulation, variety and function of TRM cells and the roles they play in skin diseases, including cutaneous melanoma and psoriasis. • Tissue-resident memory T cells exhibit distinct tissue-specific and niche-specific functions in immune detection network. • Multiple factors control the development and resident of Tissue-resident memory T cell. • Tissue-resident memory T cells participate in skin inflammation and contribute tomaintaining the recurrence of skin diseases. [ABSTRACT FROM AUTHOR]

Allergy are a global public health problem with serious consequences for human health. Many studies have confirmed that probiotics can play an active role in the treatment of allergies, and early intervention of probiotics can significantly reduce the incidence in infants and young children. As an adjuvant of allergen-specific immunotherapy (AIT), probiotics also show advantages in improving the therapeutic effect and reducing side effects. This paper reviewed the research progress of probiotics in the prevention and alleviation of allergies, focused on the use of probiotics as adjuvants for AIT, and pointed out the possibility of probiotics' extracellular proteins, extracellular vesicles, metabolites, and Toll-like Receptors (TLR) agonist analog as AIT adjuvant alone. • Probiotics can help prevent and alleviate allergies. • Probiotics may be used as adjuvants in AIT. • The extracellular vesicles and ISS-ODN of probiotics may be used as adjuvants in AIT. [ABSTRACT FROM AUTHOR]

Proanthocyanidins have been shown to inhibit the signaling pathways related to oxidative stress and inflammation, also improved cell membrane integrity. The effect of peanut skin proanthocyanidins (PSPc) on CD remains unknown. In this paper, the effect and mechanism of PSPc on glial protein-induced Caco-2 cytotoxicity were studied. The results showed that PSPc may inhibit oxidative stress in DPG-induced CD model in vitro by regulating SIRT1/NRF2 pathway. By regulating SIRT1 and IκB signaling pathways, inhibit the phosphorylation of NF-κB and the deacetylation of NF-κB, inhibit inflammatory response, reduce release of inflammatory cytokines (IL-1β, IL-6, TNF-α), the cell survival rate was and the expression of TGM2 were improved, avoiding the damage of cell monolayer model. This experiment proved the prominent effect of PSPc on CD intervention. Studying the mechanism of PSPc in the treatment of CD injury will contribute to explore new therapies for CD which will be of great significance to supplement or replace gluten-free diets. • 1) The study found that PSPc reduces damage by inhibiting signaling pathways of inflammation and oxidative stress in the CD model. • This study found that PSPc can inhibit apoptosis and cell membrane damage in the CD model. • This study offers the possibility of a food-derived active ingredient for the treatment of CD. [ABSTRACT FROM AUTHOR]

This paper is a review, personal memoir, a tribute to Henry Kunkel, and a critique regarding laboratory tests used for the evaluation, diagnosis, and understanding Autoimmune Rheumatic Diseases, in particular systemic lupus erythematosus (SLE). [ABSTRACT FROM AUTHOR]

Laminins are ubiquitous constituents of the basement membranes with major architectural and functional role as supported by the fact that absence or mutations of laminins lead to either lethal or severely impairing phenotypes. Besides genetic defects, laminins are involved in a wide range of human diseases including cancer, infections, and inflammatory diseases, as well as autoimmune disorders. A growing body of evidence implicates several laminin chains as autoantigens in blistering skin diseases, collagenoses, vasculitis, or post-infectious autoimmunity. The current paper reviews the existing knowledge on autoimmunity against laminins referring to both experimental and clinical data, and on therapeutic implications of anti-laminin antibodies. Further investigation of relevant laminin epitopes in pathogenic autoimmunity would facilitate the development of appropriate diagnostic tools for thorough characterization of patients' antibody specificities and should decisively contribute to designing more specific therapeutic interventions. [ABSTRACT FROM AUTHOR]

DNA methylation is now widely recognized as being critical to maintain the function of immune cells. Recent studies suggest that aberrant DNA methylation levels not only can result in immune cells autoreactivity in vitro, but also are related to autoimmunity in vivo. Environmental factors and genetic polymorphisms cause abnormal methylation, which affects the expression of certain immune-related genes, being becoming hot spot of explaining the mechanism of autoimmune diseases. This paper reviews the importance of abnormal methylation during the development of common autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, aiming at a better understanding of the pathogenesis of autoimmune diseases and providing new ideas for the treatment of these diseases. [ABSTRACT FROM AUTHOR]

Radiographs of hands and feet are traditionally the images that are used to assess structural damage progression in drug trials in patients with rheumatoid arthritis, aiming at proving the disease modifying capacity of a drug. Although treatment has largely improved over the past decade and consequently radiographic progression is limited in control arms in clinical trials, recent trials are still able to show inhibition of structural progression by new drugs. The requirements for the successful use of radiographic progression as an outcome in rheumatoid arthritis trials will be discussed in this paper. [ABSTRACT FROM AUTHOR]

Biomarkers have become, and will continue to become, increasingly important to clinical immunology research. Yet, biomarkers often present new problems and raise new statistical and study design issues to scientists working in clinical immunology. In this paper I discuss statistical considerations related to the important biomarker problems of: 1) The design and analysis of clinical studies which seek to determine whether changes from baseline in a biomarker are associated with changes in a metabolic outcome; 2) The conditions that are required for a biomarker to be considered a “surrogate”; 3) Considerations that arise when analyzing whether or not a predictive biomarker could act as a surrogate endpoint; 4) Biomarker timing relative to the clinical endpoint; 5) The problem of analyzing studies that measure many biomarkers from few subjects; and, 6) The use of statistical models when analyzing biomarker data arising from count data. [ABSTRACT FROM AUTHOR]

The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity. [ABSTRACT FROM AUTHOR]

Abstract: Oral lichen planus (OLP) is a chronic inflammatory disorder of oral mucosa, which represents cell-mediated autoimmune diseases. Pathological study demonstrated that abundant T lymphocytes infiltrated the oral mucosa, in which the activated T cells that trigger apoptosis of oral epithelial cells is an important mechanism for OLP. However, to date the molecular mechanisms underlying the T lymphocytes infiltration and accumulation in OLP remain unclear. In this paper, we found that the levels of plasma OPN were elevated and were associated with the up-regulated expressions of CD44 in OLP patients. In vitro, the addition of exogenous OPN can suppress the apoptosis of activated CD8+ T cells via CD44, and this T cell resistance to apoptosis may be attributed to the reduction of endogenous mature granzyme B. Our results suggested that the abnormally elevated levels of OPN may contribute to the abnormal infiltration and accumulation of the activated T cells by up-regulating CD44 in OLP. [Copyright &y& Elsevier]

Abstract: To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren''s syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR. In addition, transgenic IL-14a mice were analyzed from 6 weeks of age to death for both histological and immunological features of Sjögren''s disease. Patients with both primary and secondary Sjögren''s syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop hypergammaglobulinemia, autoantibodies, infiltration of the parotid glands with lymphocytes, mild immune-complex mediated renal disease and large B cell lymphoma. In this paper we expand these observations to demonstrate that these mice develop all the clinical and immunological features of primary Sjögren''s disease in the same relative time frame as patients with primary Sjögren''s disease: stage 1—early hypergammaglobulinemia and autoantibody production, stage 2—decreased salivary gland function with early lymphocytic infiltration of the submandibular glands only, but antibody deposition in the submandibular and parotid glands, stage 3—lymphocytic infiltration of the submandibular, parotid and lacrimal glands with B and T lymphocytes and plasma cells along with interstitial lung disease and mild renal disease, and stage 4—large B cell lymphoma. Thus IL-14a is important in the pathophysiology of Sjögren''s disease. The IL-14a transgenic mouse is a novel animal model that can be utilized to understand the pathophysiology of Sjögren''s disease. [Copyright &y& Elsevier]

Abstract: The immune system has evolved elaborate mechanisms to respond to diverse antigens while minimizing the risk for autoimmune reactivity. During lymphopenia, however, some mechanisms that normally serve to maintain host tolerance are temporarily suspended. Peripheral T cells proliferate in response to self-antigens in lymphopenic hosts, but proliferation toward these same antigens is prevented when T cell numbers are normal. This process, termed homeostatic peripheral expansion, augments peripheral T cell number and limits repertoire skewing during recovery from lymphopenia and also predisposes lymphopenic hosts to autoimmune disease. This paper reviews murine and human settings in which autoimmunity occurs in the context of lymphopenia. We propose a two-hit model, in which lymphopenia plus another insult is sufficient to induce autoimmune disease. Among the secondary insults that appear sufficient to induce autoimmunity during lymphopenia are overproduction of IL-21 as occurs in the NOD.SCID mouse, depletion of Tregs as demonstrated in murine colitis and gastritis models, and tissue inflammation as seen in HIV infected patients who develop immune reconstitution inflammatory syndrome (IRIS). Delineating critical cofactors which result in autoimmune disease during lymphopenia can provide insight into the pathophysiology of naturally occurring autoimmune diseases as well as generating testable hypothesis for inducing tumor-specific autoimmunity in lymphopenic hosts with cancer. [Copyright &y& Elsevier]

Abstract: Although autoantibodies against the α1-adrenergic receptor which had been found in hypertensive patients had agonist-like activity as phenylephrine, the effects of these antibodies on cardiac remodeling have not been known. In this paper, the models with agonist-like activity of antibodies to α1-adrenergic receptor were made by immunized Wistar rats using synthesized peptides of α1A-adrenergic receptor and raised for 1 year, and the excited antibodies against the α1-adrenergic receptor which could elevate the free Ca2+ in isolated adult rat cardiomyocytes had been existed throughout the experiments after immunization. In immunized rats, despite that systolic blood pressure (SBP) had no difference with normal control, the hypertrophy of heart and cardiomyocytes was observed, the collagen deposition in heart interstitium increased, and c-jun expression and matrix metalloproteinase (MMP)-2 mRNA expression and activity in heart had increased. The results suggested that antibodies against the α1-adrenergic receptor could induce cardiac remodeling and maybe play a particular role in hypertension. [Copyright &y& Elsevier]

Evidence supports the association between infectious agents, antiphospholipid syndrome (APS), and the presence of antiphospholipid antibodies and anti-β2-glycoprotein-I (β2GPI) antibodies. Several mechanisms have been proposed to explain the role of bacteria/viruses in induction of an autoimmune condition, such as molecular mimicry between structures of a pathogen and self antigen and bystander activation or bacterial/viral superantigens. Protein databases reveal high homologies between the β2GPI-related synthetic peptides and infectious agents. Studies employing experimental APS models proved molecular mimicry between β2GPI-related synthetic peptides, which serve as target epitopes for anti-β2GPI Abs, and structures within bacteria, viruses (e.g., CMV), and tetanus toxoid. Any explanation of how microbial infections might induce APS must take into account the genetic predisposition. In this paper, we discuss the association of antiphospholipid antibodies, infectious states, and molecular mimicry as a proposed mechanism for development of APS. [Copyright &y& Elsevier]

The preliminary classification criteria for definite antiphospholipid syndrome (APS) include the presence of anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA) as laboratory criteria. However, antiphospholipid antibodies (aPL) are a heterogeneous group of antibodies comprising also antibodies against phospholipid-binding proteins or their complexes with phospholipids. Prothrombin is one of the antigen recognized by aPL. In the last decade, there has been increasing interest in antibodies against prothrombin alone and those against phosphatidylserine–prothrombin complex. The latter, phosphatidylserine-dependent antiprothrombin antibodies (aPT), have been closely associated with APS and LA. In this paper, we review the properties of antiprothrombin antibodies. [Copyright &y& Elsevier]

The use of multimodality molecular imaging has recently facilitated the study of molecular and cellular events in living subjects in a noninvasive and repetitive manner to improve the diagnostic capability of traditional assays. The noninvasive imaging modalities utilized for both small animal and human imaging include positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), ultrasound, and computed tomography (CT). Techniques specific to small-animal imaging include bioluminescent imaging (BIm) and fluorescent imaging (FIm). Molecular imaging permits the study of events within cells, the examination of cell trafficking patterns that relate to inflammatory diseases and metastases, and the ability to rapidly screen new drug treatments for distribution and effectiveness. In this paper, we will review the current field of molecular imaging assays (especially those utilizing PET and BIm modalities) and examine how they might impact animal models and human disease in the field of clinical immunology. [Copyright &y& Elsevier]

In the mammalian immune system, V(D)J rearrangement of immunoglobulin (Ig) and T-cell receptor (TCR) genes is regulated in a lineage- and stage-specific fashion. Because each of the seven loci capable of rearrangement utilizes the same recombination machinery, it is thought that V(D)J recombination of each antigen receptor locus is regulated through the differential accessibility of each locus to the V(D)J recombination machinery. Accumulating evidence indicates that chromatin remodeling mediated by DNA methylation and demethylation plays important roles in regulating V(D)J recombination and germline transcription through the Ig and TCR loci. DNA demethylation within the antigen receptor loci appears to be regulated by cis-elements also required for coordinated V(D)J recombination and germline transcription. In this paper, we critically examine the relationship between demethylation and V(D)J recombination as well as the mechanism to regulate DNA demethylation within the antigen receptor loci. [Copyright &y& Elsevier]

The role of DNA methylation in immune function is discussed extensively in other papers in this issue. Many of these discussions assume that DNA methylation, a major mediator of epigenetic information, is fairly immutable and uniform in adult cells and tissues. There is, however, growing evidence that DNA methylation changes subtly with age. Normal aging cells and tissues show a progressive loss of 5-methylcytosine content, primarily within DNA repeated sequences, but also in potential gene regulatory areas. In parallel, selected genes show progressive age-related increases in promoter methylation, which, once a critical methylation density is reached, have the potential to permanently silence gene expression. These changes are highly mosaic within a given tissue and introduce a high degree of epigenetic variability in aging cells. Such epigenetic phenomena could impact immune response through masking/unmasking potential tissue antigens as well as by modulating the differentiation and response of immune effector cells. The contribution of epigenetic changes to the altered immune function observed in aging humans deserves careful investigation. [Copyright &y& Elsevier]

DNA methylation plays an essential role in maintaining T-cell function. A growing body of literature indicates that failure to maintain DNA methylation levels and patterns in mature T cells can result in T-cell autoreactivity in vitro and autoimmunity in vivo. Defective maintenance of DNA methylation may be caused by drugs such as procainamide or hydralazine, or failure to activate the genes encoding maintenance DNA methyltransferases during mitosis, resulting in the development of a lupus-like disease or perhaps other autoimmune disorders. This paper reviews the evidence supporting a role for abnormal T-cell DNA methylation in causing autoimmunity in an animal model of drug-induced lupus, and discusses some of the mechanisms involved. T cells from patients with active lupus have evidence for most if not all of the same methylation abnormalities, suggesting that abnormal DNA methylation plays a role in idiopathic human lupus as well. [Copyright &y& Elsevier]

This paper evaluates the expression and functional significance of PPAR-γ on human B cells. Recent interest in PPAR-γ has focused on its adipogenic effects on non-bone marrow-derived cells. PPAR-γ agonists also have been proposed as anti-inflammatory agents owing to inhibition of NF-κB activation. We report herein the first study evaluating PPAR-γ expression and functional significance in human B lineage cells. Interestingly, normal human B cells and a variety of B lymphoma cells (e.g., Daudi, Ramos, and Raji) express PPAR-γ protein as determined by immunocytochemistry. The expression of 80-kDa PPAR-γ on human B lymphocytes and B lymphomas was confirmed by Western blot analysis. 15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2), a natural PPAR-γ agonist, has a dose-dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [3H]thymidine and MTT assays. Only PPAR-γ agonists (thiazolidinediones) and not PPAR-α agonists mimicked the effect of 15d-PGJ2 on B lineage cells, indicating that the mechanism by which 15d-PGJ2 negatively affects B lineage cells involves, in part, PPAR-γ. The mechanism whereby PPAR-γ agonists induce cytotoxicity is via apoptosis as shown by Annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay. This is the first study evaluating PPAR-γ expression and its significance on human B lymphocytes. PPAR-γ agonists may serve as a counterbalance to the stimulating effects of other prostaglandins, namely PGE2, which promotes B cell immunoglobulin class switching. Finally, the use of prostaglandins such as 15d-PGJ2 and synthetic PPAR-γ agonists to induce apoptosis in B lineage cells may lead to the development of novel therapies for potentially fatal B lymphomas. [Copyright &y& Elsevier]

Children with idiopathic nephrotic syndrome (INS) usually have podocyte injury, and recent studies suggest a B cell dysfunction in INS. Therefore, this study attempts to screen and identify the podocyte autoantibodies in patients. Two-dimensional electrophoresis and mass spectrometry were used to screen and identify the pathogenic podocyte autoantibodies in children with INS. The positive rate, expression pattern, and clinical correlation of these podocyte autoantibodies in children with INS were determined by clinical study. At least 66% of INS children have podocyte autoantibodies. Seven podocyte autoantibodies closely related to INS were screened and identified for the first time in this study. These podocyte autoantibodies are positively correlated with proteinuria, and its titer will decrease rapidly after effective treatment. In this study, a group of new disease subgroup-"autoimmune podocytes" were identified by podocyte autoantibodies. This paper used 2D electrophoresis combined with mass spectrometry to screen and identify podocyte autoantibodies specific to primary nephrotic syndrome. The protein microarray was used for clinical validation. Finally, seven podocytes autoantibodies specific to the serum of primary nephrotic syndrome were identified. These antibodies were positively correlated with urinary protein levels and efficacy. [Display omitted] [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is characterized by systemic synovitis leading to joint destruction in which imbalances in pro-inflammatory and anti-inflammatory cytokines promote the induction of autoimmunity. Some pro-inflammatory cytokines can trigger the signaling pathways which responsible for immune-mediated inflammation in RA, and the activated signaling pathways produce pro-inflammatory cytokines, resulting in aggravation of RA. Hence, understanding of the signaling pathways and their inhibitors might be advantageous in the development of therapeutic targets and new drugs for RA. In the current review, we summarize the signaling pathways involved in the pathogenesis of RA as well as the potential role of specific inhibitors in its management. We hope this paper may serve a reference for future studies on signaling pathways implicated in the pathogenesis of RA and benefit the treatment of RA. • Pathogenesis of rheumatoid arthritis. • Signaling pathways involved in the pathogenesis of RA as well as the potential role of specific inhibitors in its management. • The specific inhibitors for the potential treatment of RA. [ABSTRACT FROM AUTHOR]

Abstract Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy. • Autoimmune aspects of CFS, POTS, CRPS and SIIS are discussed. • The common denominators of anti-GPCR AAb and SFN are identified for these syndromes. • A new concept of autoimmune neurosensory dysautonomia is suggested. • Sjogren's syndrome can illustrate the suggested concept. [ABSTRACT FROM AUTHOR]

Mercury (Hg) is widely recognized as a neurotoxic metal, besides it can also act as a proinflammatory agent and immunostimulant, depending on individual exposure and susceptibility. Mercury exposure may arise from internal body pathways, such as via dental amalgams, preservatives in drugs and vaccines, and seafood consumption, or even from external pathways, i.e., occupational exposure, environmental pollution, and handling of metallic items and cosmetics containing Hg. In susceptible individuals, chronic low Hg exposure may trigger local and systemic inflammation, even exacerbating the already existing autoimmune response in patients with autoimmunity. Mercury exposure can trigger dysfunction of the autoimmune responses and aggravate immunotoxic effects associated with elevated serum autoantibodies titers. The purpose of the present review is to provide a critical overview of the many issues associated with Hg exposure and autoimmunity. In addition, the paper focuses on individual susceptibility and other health effects of Hg. • Mercury (Hg) is a proinflammatory agent and immunostimulant. • Exposure to Hg can trigger immunotoxic effects, inflammation, and autoimmune dysfunction. • In susceptible individuals, Hg may play a role in autoimmune diseases, including MS. • Characterization of epigenetic markers is needed to highlight individual predispositions to Hg-induced toxic outcomes. [ABSTRACT FROM AUTHOR]

New, innovative, costly diagnostic methods for patients with primary immunodeficiencies (PID) demand upfront insight into their potential cost savings and added value for individual patients. As such, high quality, comparable economic evaluations are of utmost importance to enable informed decisions. The objective of this review was therefore to create an extensive overview of current costing studies and potential cost savings of early diagnosis in primary immunodeficiency disease. A literature search in PubMed was conducted and studies involving any form of costing study in the field of PIDs were included. Of the included studies, study characteristics, cost parameters and benefits of early diagnosis were extracted and outlined in separate tables. Twenty two studies met the inclusion criteria and were included in the review. The papers were categorized according to their subject: neonatal screening for severe combined immunodeficiency (SCID), Ig replacement therapies and studies reporting on costs of general or specific PIDs. Within and between these groups variability in reported costing characteristics was observed. In studies that reported cost savings pre- and post-diagnosis, cost savings ranged from 6500 to 108,463 USD of total costs per patient. This literature review shows that, regardless of what aspect of PIDs has been studied, in nearly all cases early diagnosis reduces health care consumption and leads to better health outcomes for patients with PIDs. We found considerable variability in costing characteristics of economic evaluations of PID patients, which hampers the comparability of outcomes. More effort is needed to create uniformity and define cost parameters in economic evaluations in the field of PIDs, facilitating further prospective research to extensively assess the benefits of early diagnosis. • Economic evaluation studies involving primary immunodeficiencies focus on cost-effectiveness of Ig replacement therapy or newborn screening for severe combined immunodeficiency. • Few general cost analyses of primary immunodeficiencies are available in literature • There is considerable variability in the inclusion of costing characteristics in economic evaluations of PID patients and this variability hampers the comparability of outcomes. • There are differences in cost savings depending on the main subject of the study but all studies agreed that early diagnosis and treatment is beneficial in terms of costs. [ABSTRACT FROM AUTHOR]