Showing papers in "Immunologic Research in 2018"

Pemphigus group: overview, epidemiology, mortality, and comorbidities

Abstract: Pemphigus forms a group of rare autoimmune bullous diseases that affect the skin and mucous membranes. This group has a chronic course leading to high morbidity and mortality. It is characterized by the production of pathogenic autoantibodies directed against different proteins of the desmosome, leading histologically to intraepidermal cleavage, and clinically to vesicles and erosions on the epithelium of the mucous membranes and/or the skin. The diagnosis of the subtype of pemphigus is based on clinical features, the level of histologic cleavage, and the identification of the antigens recognized by circulating autoantibodies by immunoserological analyses. The epidemiological features of pemphigus vary considerably in different regions of the world. Observational studies examining comorbidities and associations among patients with pemphigus are scarce and sometimes inconclusive. The prognosis, mortality, and clinical outcomes in pemphigus have undergone dramatic change throughout the years. This review provides a brief overview about the different subtypes of pemphigus: pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, pemphigus herpetiformis, and IgA pemphigus. In addition, it summarizes the most recent understanding of the epidemiology, mortality data, and comorbidities of this group of organ-specific autoimmune diseases.

Global report on primary immunodeficiencies: 2018 update from the Jeffrey Modell Centers Network on disease classification, regional trends, treatment modalities, and physician reported outcomes.

Abstract: Primary immunodeficiencies (PI) are genetic defects of the immune system that result in chronic, serious, and often life-threatening infections, if not diagnosed and treated. Many patients with PI are undiagnosed, underdiagnosed, or misdiagnosed. In fact, recent studies have shown that PI may be more common than previously estimated and that as many as 1% of the population may be affected with a PI when all types and varieties are considered. In order to raise awareness of PI with the overall goal of reducing associated morbidity and mortality, the Jeffrey Modell Foundation (JMF) established a network of specialized centers that could better identify, diagnose, treat, and follow patients with PI disorders. Over the past decade, the Jeffrey Modell Centers Network (JMCN) has provided the infrastructure to accept referrals, provide diagnosis, and offer treatments. Currently, the network consists of 792 Expert Physicians at 358 institutions, in 277 cities, and 86 countries spanning 6 continents. JMF developed an annual survey for physician experts within the JMCN, using the categories and gene defects identified by the International Union of Immunological Societies Expert Committee for the Classification of PI, to report on the number of patients identified with PI; treatment modalities, including immunoglobulins, transplantation, and gene therapy; and data on gender and age. Center Directors also provided physician-reported outcomes and differentials pre- and post-diagnosis. The current physician-reported data reflect an increase in diagnosed patients, as well as those receiving treatment. Suspected patients are being identified and referred so that they can receive early and appropriate diagnosis and treatment. The significant increase in patients identified with a PI is due, in part, to expanding education and awareness initiatives, newborn screening, and the expansion of molecular diagnosis and sequencing. To our knowledge, this is the most extensive single physician report on patients with PI around the world.

Subepidermal autoimmune bullous diseases: overview, epidemiology, and associations.

Abstract: Subepidermal autoimmune bullous diseases of the skin and mucosae comprise a large group of chronic diseases, including bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and anti-p200 pemphigoid. These diseases are characterized by an antibody response toward structural components of the basement membrane zone, resulting in subepidermal blistering. The epidemiological features of these diseases vary substantially in different regions of the world. Observational studies investigating comorbidities and associations among patients with these diseases are inconsistent and sometimes inconclusive. This review provides a brief overview regarding each one of the subepidermal autoimmune bullous diseases. In addition, it summarizes the most recent understanding of the epidemiological features and associations of this group of organ-specific autoimmune diseases.

Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice

Abstract: Influenza viruses continuously circulate in the human population and escape recognition by virus neutralizing antibodies induced by prior infection or vaccination through accumulation of mutations in the surface proteins hemagglutinin (HA) and neuraminidase (NA). Various strategies to develop a vaccine that provides broad protection against different influenza A viruses are under investigation, including use of recombinant (r) viral vectors and adjuvants. The replication-deficient modified vaccinia virus Ankara (MVA) is a promising vaccine vector that efficiently induces B and T cell responses specific for the antigen of interest. It is assumed that live vaccine vectors do not require an adjuvant to be immunogenic as the vector already mediates recruitment and activation of immune cells. To address this topic, BALB/c mice were vaccinated with either protein- or rMVA-based HA influenza vaccines, formulated with or without the saponin-based Matrix-M™ adjuvant. Co-formulation with Matrix-M significantly increased HA vaccine immunogenicity, resulting in antigen-specific humoral and cellular immune responses comparable to those induced by unadjuvanted rMVA-HA. Of special interest, rMVA-HA immunogenicity was also enhanced by addition of Matrix-M, demonstrated by enhanced HA inhibition antibody titres and cellular immune responses. Matrix-M added to either protein- or rMVA-based HA vaccines mediated recruitment and activation of antigen-presenting cells and lymphocytes to the draining lymph node 24 and 48 h post-vaccination. Taken together, these results suggest that adjuvants can be used not only with protein-based vaccines but also in combination with rMVA to increase vaccine immunogenicity, which may be a step forward to generate new and more effective influenza vaccines.

Role of T cell-derived exosomes in immunoregulation.

Abstract: Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells. They are composed of a lipid bilayer containing transmembrane proteins and enclosing cytosolic proteins and RNA, mediating intercellular communication between different cell types in the body, and thus influencing various physiological and pathological functions of both recipient and parent cells. For their nanolevel structures with a stable nature and various biological functions, studies of exosomes have been the subject of increasing interest in the past few years. It is widely known that different T cell subsets play important roles in cellular and humoral immunity, and their exosomes were also reported to exert similar biological functions. While several groups reported the secretion of exosomes by various T cells, the systematic summary involved in these exosomes are deficient. In this review, we will summarize the structure and functions of exosomes derived from T cells in recent reports, discuss emerging therapeutic opportunities, and consider the associated challenges.

Impaired natural killer cell subset phenotypes in human obesity

Abstract: Obesity is associated with alterations in functionality of immune cells, like macrophages and natural killer (NK) cells, leading to an increased risk for severe infections and several cancer types. This study aimed to examine immune cell populations and functional NK cell parameters focusing on NK cell subset phenotypes in normal-weight and obese humans. Therefore, peripheral blood mononuclear cells (PBMCs) were isolated from normal-weight and obese individuals and analyzed by flow cytometry. Results show no significant changes in the frequency of monocytes, B lymphocytes, or NKT cells but a significantly increased frequency of T lymphocytes in obesity. The frequency of total NK cells was unaltered, whereas the number of low cytotoxic CD56bright NK cell subset was increased, and the number of high cytotoxic CD56dim NK cell subset was decreased in obese subjects. In addition, the frequency of CD56bright NK cells expressing the activating NK cell receptor NKG2D as well as intracellular interferon (IFN)-γ was elevated in the obese study group. In contrast, the frequency of NKG2D- and IFN-γ-positive CD56dim NK cells was lower in obesity compared to normal-weight individuals. Moreover, the expression of the activation marker CD69 was decreased in NK cells, which can be attributed to a reduction of CD69-positive CD56dim NK cells in obese subjects. In conclusion, data reveal an impaired NK cell phenotype and NK cell subset alterations in obese individuals. This NK cell dysfunction might be one link to the higher cancer risk and the elevated susceptibility for viral infections in obesity.

Autoimmune/inflammatory syndrome induced by adjuvants-ASIA-related to biomaterials: analysis of 45 cases and comprehensive review of the literature.

Abstract: Systemic autoimmune or granulomatous disorders related to biomaterials of human use have rarely been described. The aim of this study was to report cases of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) related to biomaterial injections and prostheses, mainly silicone, hyaluronic acid, acrylamides and methacrylate compounds in a Spanish patient cohort. This study is a retrospective analysis of clinical, laboratory, histopathological and follow-up data of 45 cases of patients suffering from late-onset, non-infectious inflammatory/autoimmune disorders related to bioimplants. Late onset was defined as 3 months or more post injection. Data were obtained through a further non-systematic but comprehensive review of the literature. Forty-five cases of late-onset adverse reactions related to biomaterial injections or prostheses were reviewed. All cases had systemic complaints that could be categorised as ASIA. In all but four patients, inflammatory features at the implantation site preceded distant or systemic manifestations. Abnormal blood tests were common. Localised inflammatory nodules and panniculitis in 40/45 (88.88%) evolved into a variety of disorders, viz., primary biliary cirrhosis, Sjogren’s syndrome, sarcoidosis, human adjuvant disease, vasculitis, inflammatory bowel syndrome and inflammatory polyradiculopathy. Five (11.11%) cases presented primarily with systemic autoimmune disorders. Biomaterials and prostheses can provoke late-onset systemic autoimmune disorders fulfilling ASIA criteria, or present primarily local/regional inflammatory reactions that may eventually evolve into systemic autoimmune and/or granulomatous disorders which fall under ASIA.

Autonomic dysfunction and HPV immunization: an overview

Abstract: This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.

Immunomodulatory function of Treg-derived exosomes is impaired in patients with relapsing-remitting multiple sclerosis.

Abstract: Multiple sclerosis (MS) is an autoimmune disease which is characterized by neuroaxonal degeneration in the central nervous system. Impaired function of regulatory T cells (Tregs) is believed to be an underlying pathogenic mechanism in MS. Tregs is able to release exosomes, which contain a considerable amount of protein and RNA. Exosomes are capable of transporting their content to other cells where the released content exerts biological functions. Here, we investigated whether Tregs exosomes of RRMS patients or healthy controls might regulate the proliferation or survival of T lymphocytes. Regulatory T cells derived from MS patients or healthy controls were cultured for 3 days and exosomes were purified from supernatants. Treg-derived exosomes were co-cultured with conventional T cells (Tconv). The percentages of Tconv proliferation and apoptosis were measured. Our findings showed that the percentage of proliferation suppression induced by exosomes in patients compared to healthy controls was 8.04 ± 1.17 and 12.5 ± 1.22, respectively, p value = 0.035. Moreover, the rate of Tconv apoptosis induced by exosome of MS patient was less than healthy controls (0.68 ± 0.12 vs. 1.29 ± 0.13; p value = 0.015). Overall, Treg-derived exosomes from MS patients and healthy controls suppressed the proliferation and induced apoptosis in Tconv. However, the effect of MS-derived exosomes was significantly less than healthy controls. Our results point to an alternative Treg inhibitory mechanism which might be important in immunopathogenesis of MS. Although, the cause of the exosomal defect in MS patients is unclear, manipulation of patients’ Treg-derived exosomes to restore their suppressive activity might be considered as a potential therapeutic approach.

IL-35: a new immunomodulator in autoimmune rheumatic diseases.

Abstract: IL-35 is a relatively new cytokine that emerges as an important immunomodulator. IL-35 belongs to IL-12 cytokine family that includes IL-12, IL-23, IL-27, and IL-35. These cytokines are heterodimers that share subunits and their receptors also share subunits. Whereas IL-12 and IL-23 are clearly proinflammatory cytokines, the role of IL-35 is less clear. In mice, IL-35 appears to be anti-inflammatory and to protect from autoimmune inflammatory diseases. IL-35 induces the expansion of a subset of regulatory T cells (Tregs) and Bregs and mediates their suppressive function and inhibits Th17 cells. It also upregulates osteoprotegerin and suppresses RANKL, thus inhibiting bone resorption. In autoimmune rheumatic diseases, findings are conflicting, although in systemic lupus erythematosus, there is reduced function of IL-35. In psoriatic arthritis, a disease characterized by bone erosion and bone formation in peripheral joints and bone formation in spinal joints, serum levels of IL-35 were found increased in one study. Further data are required to define the exact role of IL-35 in human autoimmune rheumatic diseases.

Phagocytosis and oxycytosis: two arms of human innate immunity.

Abstract: Human innate immunity operates in two compartments: extravascular (the tissues) and intravascular (the bloodstream). Physical conditions (fluid dynamics) in the compartments are different and, as a result, bactericidal mechanisms and involved cells are different as well. In relatively static media (the tissues, lymph nodes), bacteria are killed by phagocytes; in dynamic media (the bloodstream), bacteria are killed by erythrocytes. In the tissues and lymph nodes, resident macrophages and transmigrated from blood leukocytes (neutrophils and monocytes) recognize, engulf, kill, and digest bacteria; the clearance of the bloodstream from bacteria is performed by oxycytosis: erythrocytes catch bacteria by electric charge attraction and kill them by the oxygen released from oxyhemoglobin. Killed by erythrocytes, bacteria are decomposed and digested in the liver and the spleen. Phagocytosis by leukocytes in the tissues and oxycytosis by erythrocytes in the bloodstream are the main bactericidal mechanisms of human innate immunity.

Is there an association between dipeptidyl peptidase-4 inhibitors and autoimmune disease? A population-based study.

Abstract: The association of dipeptidyl peptidase-4 inhibitors (DPP4is) with autoimmune diseases is controversial. While these agents were proposed as a novel therapeutic approach for several inflammatory diseases by blocking T cell proliferation and cytokine production, they were found to trigger inflammatroy bowel disease, inflammatory arthritis and bullous pemphigoid. Our objective is to examine the association between DPP4i and autoimmune diseases. This study was conducted as a cross-sectional study utilizing the database of Clalit Health Services. The prevalence of 15 autoimmune-/immune-mediated diseases was compared between patients on DPP4i treatment and age-, sex-, and ethnicity-matched controls. Univariate analysis was performed using chi-square and the Student t test and multivariate analysis was performed using a logistic regression model. The study included 283 patients treated with DPP4i agents and 5660 age-, sex-, and ethnicity-matched diabetic control subjects. The prevalence of Crohn’s disease (1.1 vs. 0.3%; odds ratios (OR), 3.56; 95% CI, 1.04–12.21, P = 0.031), psoriasis (2.5 vs. 1.2%; OR, 2.12; 95% CI, 0.99–4.66; P = 0.050), and Hashimoto’s thyroiditis (16.6 vs. 12.6%; OR, 1.38; 95% CI, 1.00–1.91; P = 0.049) was significantly higher in patients on DPP4i treatment than in controls. The prevalence of the remaining autoimmune diseases did not differ significantly between DPP4i-treated patients and their matched control subjects. In conclusion, this population-based study demonstrates an association of DPP4i intake with three autoimmune and inflammatory diseases noted to be part of a distinct autoimmune cluster that includes multiple sclerosis, psoriasis, thyroiditis, bullous pemphigoid, and inflammatory bowel disease. Experimental studies are required to define the role of DPP4i in this autoimmune cluster.

IL-2 mediates NK cell proliferation but not hyperactivity

Abstract: Natural killer cells play a major role in innate immunity against tumor and virus-infected cells. NK cells express activating and inhibitory receptors to regulate their function. It has been established that modulation in the NK cell receptor profile results in altered function of NK cell against target cells. Here, we study the effect of IL-2 stimulation on NK cell inhibitory receptors Ly49A, Ly49C, and activating receptor Ly49D in C57BL/6 mice. It was observed that there was significant increase in expression of Ly49A but no change in expression of Ly49C and Ly49D on IL-2 stimulation. We further noticed that although IL-2 stimulation increased the NK cell population and expression of activation marker NK1.1 but IL-2 stimulation does not cause hyper-responsiveness in NK cells, as there was no increase in MIP-1α and IFN-γ production in IL-2 stimulated NK cells as compared to unstimulated controls. These findings provide a framework to understand the effect of IL-2 stimulation on cognate and non-cognate receptor ligand interactions and suggest stratagies for immunotherapies in conjunction with IL-2 combinatorial therapies.

Immune reconstitution therapy (IRT) in multiple sclerosis: the rationale.

Abstract: Immunotherapy of multiple sclerosis (MS) and other neuroimmune diseases is rapidly evolving. For the past 25 years, there has been an accelerating inclusion of new immunomodulating drugs. Based on their molecular construction and their basic mechanism of action, immunotherapeutic agents belong to the following categories: (1) cytotoxic drugs, (2) synthetic immunomodulators, (3) monoclonal antibodies, (4) vaccines (T cell vaccines, antigen vaccines), (5) oral tolerizing agents, (6) modalities that act as indirect immunosuppressants (plasmapheresis, intravenous immunoglobulins [IVIG]), and (7) cellular therapies. MS immunotherapies may also be classified in a different way, into treatments that are given continuously (chronic treatments) and medications that are applied intermittently (IRTs). The principle behind the latter is depletion of the immune system that allows it to rebuild itself. Upon its reconstitution/resetting, the immune system regains the ability to respond to infections and survey the periphery for cancer. An IRT by definition is given at short intermittent courses and not continuously. IRT modalities were shown to induce long-term remission of MS that, in some cases, is close to the definition of a “cure.” There are cohorts of patients having been treated with the IRTs, alemtuzumab, and HSCT, who experience—under these modalities—no evidence of disease activity (NEDA) for over 10 years. Most importantly, IRTs cause radical changes in the lymphocyte repertoire after the reconstitution phase that may explain the long-term beneficial effects of IRT and the possibility of re-induction of self-tolerance to self/myelin antigens. In comparison, a chronic treatment cannot result in cure of the autoimmune reactivity, because it only blocks the immune system, as long as it is given; it cannot therefore radically affect the immunopathogenesis of the disease. The risks of adverse events related to immune suppression (such as opportunistic infections and secondary malignancies) with IRTs are lower and front-loaded, whereas the common side effects of chronic immunomodulation are higher and accumulate with time. In conclusion, IRT provides a novel concept for MS therapy with substantial advantages over chronic immunosuppression. IRT therapies have shown a significantly higher level of efficacy in MS. The “Holy grail” of the treatment of autoimmunity, which is to re-induce the disrupted self-tolerance, seems to be achievable—at least in part—with this approach. Moreover, the benefits of IRT, administered in short pulses, include significantly higher adherence to treatment and lower risks for accumulative side effects that are typically associated with chronic immunosuppression.

Lambda phage nanoparticles displaying HER2-derived E75 peptide induce effective E75-CD8+ T response.

Abstract: We have investigated the in vitro immunogenicity and in vivo prophylactic and therapeutic potential of lambda (λ) phage particles displaying the E75 peptide (derived from HER2 protein) in an implantable TUBO breast tumor model of BALB/c mice. The mice were immunized with the E75-displaying phage (λF7-gpD::E75) every 2-week intervals over a 6-week period, and the generated immune responses were studied. Results showed in vitro induction of immune responses by the λF7 (gpD::E75) construct compared to the control λF7 and buffer groups. In the in vivo prophylactic study, all the control and vaccinated mice groups developed tumors. However, in the therapeutic experiments, we observed a significant difference in tumor size at days 14–36 for mice immunized with λF7 (gpD::E75) compared to control groups (P < 0.05). Moreover, the survival time prolonged in mice immunized with λF7 (gpD::E75). The discrepancy between the results obtained from the in vitro and in vivo studies may have been a result of the induction of Foxp3 CD4+CD25+ which has been previously reported to hamper effective T cell functionality. In conclusion, we observed a significant immune stimulatory response in the in vitro study, while in vivo, the vaccine was not able to exert significant tumor inhibitory effects. We suggest that the presence of Foxp3+ CD4+CD25+ cells may have impaired the anti-tumor response in mice challenged in vivo with the TUBO xenograft tumor.

Induction of CD4 + CD25 + Foxp3 + regulatory T cells by mesenchymal stem cells is associated with RUNX complex factors

Abstract: Among the particular immunomodulation properties of mesenchymal stem cells (MSCs), one relies on their capacity to regulatory T cell (Treg) induction from effector T cells. Stable expression of Foxp3 has a dominant role in suppressive phenotype and stability of induced regulatory T cells (iTregs). How MSCs induce stable Foxp3 expression in iTregs remains unknown. We previously showed MSCs could enhance demethylation of Treg-specific demethylated region (TSDR) in iTregs in cell-cell contact manner (unpublished data). Here, we evaluated the possible effect of MSCs on the mRNA expression of Runx complex genes (Runx1, Runx3, and CBFB) that perch on TSDR in iTregs and play the main role in suppressive properties of Tregs, a regulatory pathway that has not yet been explored by MSCs. Also, we investigated the mRNA expression of MBD2 that promotes TSDR demethylation in Tregs. We first showed that in vitro MSC-iTreg induction was associated with strong mRNA modifications of genes involved in Runx complex. We next injected high doses of MSCs in a murine model of C57BL/6 into Balb/C allogeneic skin transplantation to prolong allograft survival. When splenocytes of grafted mice were analyzed, we realized that the Foxp3 expression was increased at day 5 and 10 post-graft merely in MSC-treated mice. Furthermore, Foxp3 mRNA expression was associated with modified Runx complex mRNA expression comparable to what was shown in in vitro studies. Hence, our data identify a possible mechanism in which MSCs convert conventional T cells to iTreg through strong modifications of mRNA of genes that are involved in Runx complex of Foxp3.

Autoimmune vertigo: an update on vestibular disorders associated with autoimmune mechanisms.

Abstract: The role of the immune system in mediating cochleovestibular pathologies has received increasing attention in recent years. Autoimmune vertigo may be an invalidating condition and may worsen the quality of life of affected patients, especially in the cases of delayed diagnosis. Since the etiopathogenesis is still not clear, also the treatment is not yet completely delineated. According to the clinical presentation, autoimmune vertigo can present as an isolated disorder or in association with systemic autoimmune diseases. The main feature in autoimmune vertigo is the presence of an abnormal immune response, in either absence or presence of systemic autoimmune disease, directed against delicate components of the inner ear. This may determine a functional or anatomical alteration, with an inflammatory reaction often devastating for hearing and balance. Being the exact pathogenesis unknown, the diagnosis of autoimmune vertigo is based either on clinical criteria or on a positive response to steroids. The earlier the diagnosis is made, the sooner the therapy can be installed, giving a chance to the recovery of inner ear damages. Corticosteroids represent the most effective and universally accepted treatment, even if other immunomodulatory drugs are now having a more extensive use. HIGHLIGHTS: Vertigo is relatively frequent in autoimmune diseases; however, it is often misdiagnosed or attributed to central nervous system alterations rather to specific inner ear involvement. Vertigo and other audiovestibular symptoms may be the first manifestation of an autoimmune disease and if correctly addressed could significantly contribute to early diagnosis of the underlying autoimmune disease. Early diagnosis of immune-related vertigo can lead to prompt initiation of targeted therapy with elevate chances of preventing irreversible damages to the inner ear. The presence of alternating phases of well-being and disabling symptoms in patients with vertigo should always been considered, as they could suggest an underlying autoimmune condition.

The link between schizophrenia and hypothyroidism: a population-based study.

Abstract: Schizophrenia is considered to be of the severe psychiatric disorders characterized by chronic debilitating course marked with frequent relapses and high clinical and financial burden. Aberrations of thyroid hormone levels have been documented in several psychiatric conditions including bipolar disease. The aim of this study is to provide insight into whether an association exists between hypothyroidism and schizophrenia. A population-based cross-sectional study was conducted using data retrieved from the largest medical records database in Israel, the Clalit Health Services (CHS). Patients were defined as having hypothyroidism or schizophrenia when there was at least one such documented diagnosis in their medical records. The proportion of schizophrenia was compared between hypothyroid and age- and sex frequency-matched healthy controls. A logistic regression model was used to estimate the association between psychiatric manifestations and hypothyroidism in a multivariate analysis adjusted for age, gender, and smoking status. The study included 40,843 patients with hypothyroidism and 40,918 age- and sex frequency-matched controls. The proportion of schizophrenia in hypothyroid patients was higher than that in controls (2.01% vs. 1.25%, respectively, p < 0.0001). Multivariate logistic regression demonstrated a robust independent association between hypothyroidism and schizophrenia (OR 1.62, p ≤ 0.001). Our study confirms a higher proportion of hypothyroidism among patients with schizophrenia. The awareness of such interrelation should drive physicians treating patients with schizophrenia to consider screening for hypothyroidism. Further studies are required to elucidate the underlying mechanism or the common denominator favoring the co-occurrence of schizophrenia and hypothyroidism.

Increased lipid and protein oxidation and lowered anti-oxidant defenses in systemic lupus erythematosus are associated with severity of illness, autoimmunity, increased adhesion molecules, and Th1 and Th17 immune shift.

Abstract: This study investigated nitro-oxidative stress in patients with systemic lupus erythematosus (SLE) in association with disease activity, immune-inflammatory biomarkers, and adhesion molecules. Two-hundred-four patients with SLE and 256 healthy volunteers were enrolled in this case-control study, which measured nitro-oxidative stress biomarkers, including lipid peroxides (LOOH), advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), sulfhydryl (−SH) groups, products of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) oxidative degradation, and total radical-trapping anti-oxidant parameter (TRAP). Also measured were anti-nuclear antibodies (ANAs), antibodies against double-stranded DNA (dsDNA), plasma levels of diverse cytokines, C-reactive protein, and adhesion molecules. LOOH (p < 0.001) and AOPP (p < 0.001) were significantly higher, while TRAP was significantly lower (p < 0.001) in SLE patients than in controls. AOPP and LOOH were significantly and positively associated with SLE disease activity index (SLEDAI) scores, anti-nuclear antibodies, and antibodies against double-stranded DNA (anti-dsDNA) levels, while TRAP was significantly and inversely correlated with SLEDAI, ANA, and dsDNA antibody levels. There were significant positive associations between AOPP and LOOH and immune-inflammatory markers, indicating T helper (Th)-17 and Th1 bias and Th1 + Th17/Th2 ratio (p = 0.002 and p = 0.001, respectively). AOPP and LOOH (positively) and TRAP (inversely) were associated with adhesion molecule expression. A model predicting SLE was computed showing that, using LOOH, AOPP, NOx, adhesion molecules, and body mass index, 94.2% of the patients were correctly classified with a specificity of 91.5%. Increased nitro-oxidative stress takes part in the (auto)immune pathophysiology of SLE and modulates severity of illness and adhesion molecule expression.

Effects of crocin on inflammatory activities in human fibroblast-like synoviocytes and collagen-induced arthritis in mice

Abstract: Rheumatoid arthritis (RA) is a systemic autoimmune disease, characterized by the irreversible joint destruction resulted from the attack of inflammatory cells to the joints. Recent studies demonstrated that crocin is able to alleviate arthritis and suppress inflammatory responses, implying crocin as a potential promising antiarthritic agent. In this study, we confirmed the effect of crocin on RA and revealed its underlying mechanism by measuring lipopolysaccharides (LPS)-stimulated cytokine production in presence or absence of crocin. The effect of crocin was also tested in vivo using a mouse model of collagen-induced arthritis (CIA). It was found that crocin significantly repressed the LPS-induced expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in human fibroblast-like synoviocytes (FLS). We tested the effect of crocin on nuclear factor-kappa B (NF-κB) signaling and observed that cells pre-treated with 500 μM of crocin exhibited lower levels of LPS-induced p-IκBα, p-IκB kinase (IKK) α/β, and p65 expression than those of untreated cells. In addition, we found when cells were stimulated with IKKβ, crocin pre-treatment showed significantly inhibitory effect on the luciferase activity of IL-1β. In vivo results also showed that crocin treatment dramatically reduced plasma levels of TNF-α, IL-1β, and IL-6 in CIA mice. Crocin is efficient to suppress the productions of TNF-α, IL-6, and IL-1β by blocking NF-κB signal activation through its interaction with IKK, suggesting that crocin could be an efficient treatment for RA.

Serum adenosine deaminase activity is increased in systemic lupus erythematosus patients and correlated with disease activity.

Abstract: Adenosine deaminase (ADA) has been found to be involved in autoimmune disease progression. To assess the potential application of serum ADA activity in diagnosing systemic lupus erythematosus (SLE) and evaluating SLE disease activity, we investigated the serum ADA activity of 120 SLE patients and 120 healthy controls in the present study. The results showed that serum ADA activity in SLE patients was significantly increased (median (IQR) = 14 (11-19) U/L) compared with that in healthy controls (median (IQR) = 8 (7-10) U/L). Based on a receiver operating characteristic curve analysis, the optimal cut-off value for using serum ADA activity to diagnose SLE patients was 10.5 U/L (specificity, 84.2%; sensitivity, 78.3%). The diagnostic performance of serum ADA activity for SLE patients was better than that of other conventional haematology markers. Moreover, serum ADA activity displayed an increasing trend with increasing SLE disease activity. Spearman's correlation analysis showed that serum ADA activity was positively correlated with SLE disease activity. These findings suggest that serum ADA activity could be a diagnostic marker for SLE; moreover, measuring serum ADA activity may be helpful for evaluating and monitoring the disease activity of SLE patients.

Autoimmunity, inflammation, and dysbiosis mutually govern the transition from the preclinical to the clinical stage of rheumatoid arthritis

Abstract: Currently, it is well recognized that in the natural history of rheumatoid arthritis (RA), an at-risk phase, characterized by the development of autoimmunity, precedes the onset of clinical symptoms in a large proportion of patients. For individuals who later develop seropositive RA, this manifests as autoantibodies directed against proteins that have undergone specific post-translational modifications (PTM). These anti-PTM autoantibodies (APMA) are an important biomarker and risk factor for future RA. However, the triggers of autoimmunity remain unknown. This review summarizes data supporting the view that the transition from the at-risk stage to clinical RA is governed by a link between autoimmunity, inflammation, and dysbiosis. In particular, dysbiosis was shown to enhance the generation of PMT-peptides, create an antigenic mimicry with self-antigens, and establish the pro-inflammatory immune profile, all of which lead to the initiation of APMA production. Moreover, we present data supporting a major role of the autoimmunity-inflammation-dysbiosis axis in the development of bone damage and atherosclerosis-associated cardiovascular morbidity in at-risk RA individuals, and we describe potential mechanisms underlying these events. We believe that clarification of the mechanisms triggering the transition from a preclinical to clinical RA stage will pay the way to new prophylactic interventions that will prevent development of classified RA. Graphical abstract.

Sophocarpine attenuates murine lupus nephritis via inhibiting NLRP3 inflammasome and NF-κB activation

Abstract: Inflammation contributes to the pathogenesis of lupus nephritis (LN), which is the most serious complication that increases mortality of systemic lupus erythematosus (SLE). Sophocarpine is a type of quinolizidine alkaloid that possesses anti-inflammatory property. This study investigated the speculation that sophocarpine might play a beneficial effect in LN. Female MRL/lpr mice received sophocarpine treatment for 8 weeks. Renal function and histopathology were evaluated. The level of immune complex deposition was measured by immunofluorescent staining, and the levels of proinflammatory cytokines (IL-1β, IL-6, and TNF-α) and anti-double-stranded DNA (anti-dsDNA) antibodies were measured by ELISA. Western blotting was carried out to evaluate the levels of proteins involved in NLRP3 inflammasome and NF-κB pathway. Sophocarpine treatment reduced urine protein excretion, blood urea nitrogen, and attenuated renal tissue damage. The levels of renal immune complex deposition, serum anti-dsDNA, and serum and renal inflammatory cytokines were significantly reduced by sophocarpine. Sophocarpine treatment reduced the levels of proteins that form NLRP3 inflammasome. Activation of NF-κB in the kidney was inhibited by sophocarpine. Sophocarpine could ameliorate experimental LN in MRL/lpr. These effects might be through suppressing NLRP3 inflammasome and NF-κB pathway.

T cell subsets: an integral component in pathogenesis of rheumatic heart disease.

Abstract: Acute rheumatic fever (ARF) is a consequence of pharyngeal infection of group A streptococcal (GAS) infection. Carditis is the most common manifestation of ARF which occurs in 30-45% of the susceptible individuals. Overlooked ARF cases might further progress towards rheumatic heart disease (RHD) in susceptible individuals, which ultimately leads to permanent heart valve damage. Molecular mimicry between streptococcal antigens and human proteins is the most widely accepted theory to describe the pathogenesis of RHD. In the recent past, various subsets of T cells have been reported to play an imperative role in the pathogenesis of RHD. Alterations in various T cell subsets, viz. Th1, Th2, Th17, and Treg cells, and their signature cytokines influence the immune responses and are associated with pathogenesis of RHD. Association of other T cell subsets (Th3, Th9, Th22, and TFH) is not defined in context of RHD. Several investigations have confirmed the up-regulation of adhesion molecules and thus infiltration of T cells into the heart tissues. T cells secrete both Th type 1 and type 2 cytokines and these auto-reactive T cells play a key role in progression of heart valve damage. In this review, we are going to discuss about the role of T cell subsets and their corresponding cytokines in the pathogenesis of RHD.

Reflex testing of speckled cytoplasmic patterns observed in routine ANA HEp-2 indirect immunofluorescence with a multiplex anti-synthetase dot-blot assay: a multicentric pilot study.

Abstract: Immunofluorescence on HEp2-cells is the standard diagnostic assay for the detection of anti-nuclear antibodies (ANA). Cytoplasmic speckled patterns are a common finding, and are associated with various antibodies, including anti-synthetase antibodies. However, classic ENA testing generally identifies only anti-Jo-1. Moreover, anti-synthetase syndrome is increasingly recognized as a pleomorphic entity, possibly presenting as isolated arthritis or interstitial lung disease. Sera referred for routine ANA testing were selected on the basis of the presence of a fine dense speckled cytoplasmic pattern (254 samples) and compared to control sera with negative cytoplasm (239 samples). All 493 samples were tested with a commercial synthetase profile dot-blot (D TEK - Alphadia-Alifax) including anti-Jo1, anti-PL7, anti-PL12, anti-EJ, anti-OJ, anti-KS, anti-ZO, anti-HA, anti-SRP, and anti-Ribosome P0. Retrospective clinical data was searched for positive patients. Dot-blot identified 18/254 (7.1%) positive sera in the samples with a cytoplasmic fluorescence pattern and 4/239 (1.7%) in the control group (χ2 = 8.4627; p = 0.003625). Blot intensity was more intense in samples with concordant cytoplasmic staining (cytoplasmic negative 27 ± 12.4; cytoplasmic positive 53.9 27 ± 27.7; p = 0.0027). In the positive samples, 8/18 had a highly compatible diagnosis (myositis, interstitial lung disease, arthritis), 7/18 an uncharacterized connective tissue disease, and 3 a diagnosis not associated with the presence of anti-synthetase antibodies. We evaluated the performance of a dot-blot assay for anti-cytoplasmic antibodies in a serologic cohort presenting a cytoplasmic speckled pattern found during routine ANA testing. This algorithm enabled the identification of a significant quota of patients with rare anti-synthetase antibodies and an incomplete or atypical clinical picture. Reflex testing strategies of speckled cytoplasmic patterns with multiplex assays containing cytoplasm-specific antigens, as opposed to standard ENA testing, may yield important data and for this reason should be implemented in routine ANA testing.

Molecular mimicry, genetic homology, and gene sharing proteomic "molecular fingerprints" using an EBV (Epstein-Barr virus)-derived microarray as a potential diagnostic method in autoimmune disease.

Abstract: EBV (Epstein-Barr Virus) and other human DNA viruses are associated with autoimmune syndromes in epidemiologic studies. In this work, immunoglobulin G response to EBV-encoded proteins which share regions with human immune response proteins from the human host including ZEBRA (BZLF-1 encoded protein), BALF-2 recombinase expressed primarily during the viral lytic replication cycle, and EBNA-1 (Epstein-Barr Virus Nuclear Antigen) expressed during the viral latency cycle respectively were characterized using a laser-printed micro-array ( PEPperprint.com ). IgG response to conserved "A/T hooks" in EBV-encoded proteins such as EBNA-1 and the BALF-2 recombinase related to host DNA-binding proteins including RAG-1 recombinase and histones, and EBV-encoded virokines such as the IL-10 homologue BCRF-1 suggest further directions for clinical research. The author suggests that proteomic "molecular fingerprints" of the immune response to viral proteins shared with human immune response genes are potentially useful in early diagnosis and monitoring of autoantibody production and response to therapy in EBV-related autoimmune syndromes.

Expression of human REG family genes in inflammatory bowel disease and their molecular mechanism

Abstract: The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn’s disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all the REG family genes in IBD is still unclear. Here, we analyzed expression of all the REG family genes (REGIα, REGIβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in LS-174T and HT-29 human colonic epithelial cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (− 220~− 211, − 179~− 156, and − 146~− 130) in REG Iα and the region (− 274~− 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNA for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD.

T cell receptor-β J usage, in combination with particular HLA class II alleles, correlates with better cancer survival rates

Abstract: T cell receptor (TCR) β V and J usage correlates with either the HLA class I or HLA class II major histocompatibility subtypes, and in both infectious diseases and autoimmune settings, the use of particular TCR-β V and J's, in persons with specific HLA alleles, represents either better outcomes or certain clinical features. However, the relationship of TCR V and J usage, HLA alleles, and clinical parameters in the cancer setting has been less well studied. Here, we have evaluated the relationship of what is likely dominant TCR-β V and J usage among tissue-resident lymphocytes for lung, head and neck, kidney, stomach, ovarian, and endometrial cancers, with patient HLA class II alleles. The most striking indication is that TCR-β J subgroup usage, in combination with particular patient HLA class II alleles, correlated with either better or worse outcomes for lung cancer. One combination, TCR-β J2 segment usage and the HLA-DRB1*1501 allele, correlated with a better survival rate for both lung and head and neck cancers. These results fill a gap in knowledge regarding the relevance of HLA typing to cancer and indicate that HLA typing, along with an indication of dominant TCR-β J usage among tissue-resident lymphocytes, can be useful for prognosis.

RGC-32 regulates reactive astrocytosis and extracellular matrix deposition in experimental autoimmune encephalomyelitis.

Abstract: Extracellular matrix (ECM) deposition in active demyelinating multiple sclerosis (MS) lesions may impede axonal regeneration and can modify immune reactions. Response gene to complement (RGC)-32 plays an important role in the mediation of TGF-β downstream effects, but its role in gliosis has not been investigated. To gain more insight into the role played by RGC-32 in gliosis, we investigated its involvement in TGF-β-induced ECM expression and the upregulation of the reactive astrocyte markers α-smooth muscle actin (α-SMA) and nestin. In cultured neonatal rat astrocytes, collagens I, IV, and V, fibronectin, α-SMA, and nestin were significantly induced by TGF-β stimulation, and RGC-32 silencing resulted in a significant reduction in their expression. Using astrocytes isolated from RGC-32 knock-out (KO) mice, we found that the expression of TGF-β-induced collagens I, IV, and V, fibronectin, and α-SMA was significantly reduced in RGC-32 KO mice when compared with wild-type (WT) mice. SIS3 inhibition of Smad3 phosphorylation was also associated with a significant reduction in RGC-32 nuclear translocation and TGF-β-induced collagen I expression. In addition, during experimental autoimmune encephalomyelitis (EAE), RGC-32 KO mouse astrocytes displayed an elongated, bipolar phenotype, resembling immature astrocytes and glial progenitors whereas those from WT mice had a reactive, hypertrophied phenotype. Taken together, our data demonstrate that RGC-32 plays an important role in mediating TGF-β-induced reactive astrogliosis in EAE. Therefore, RGC-32 may represent a new target for therapeutic intervention in MS.

Antibodies to small ubiquitin-like modifier activating enzyme are associated with a diagnosis of dermatomyositis: results from an unselected cohort

Abstract: The aim of this study was to examine the frequency and significance of antibodies targeting the small ubiquitin-like modifier 1 activating enzyme (SAE) in patients under serologic evaluation for idiopathic inflammatory myopathies. Patient sera (n = 17) recognizing bands at approximately 40 (SAE1) and 90 (SAE2) kDa were identified in 6445 consecutive samples for myositis autoantibody evaluation by immunoprecipitation (IP) of S35-labeled K562 cell lysate. All 17 positive samples, 176 disease, and 67 healthy controls were evaluated for SAE1 antibodies using a line immunoblot assay (LIA). Clinical data of SAE antibody-positive patients were obtained by retrospective chart review. Positivity with both methods was associated with a diagnosis dermatomyositis with characteristic skin manifestations of varying severity and muscle involvement. Majority of the patients were female (73.7%), mean age of 55.0 (range 12.0–82.0) years at the time of testing. Using the IP as reference, the SAE1 LIA had a sensitivity of 100% (95% CI 82.4–100%), specificity of 99.6% (95% CI 97.7–100%), positive predictive value of 95.0% (95% CI 75.1–99.9%), and negative predictive value of 100% (95% CI 98.5–100%). This study confirms the association of SAE antibodies in patients with dermatomyositis. A combination of IP and the LIA specific for SAE1 may be useful in antibody detection.