Showing papers in "Autoimmunity in 2006"
TL;DR: It is hypothesize that the humoral immune response to EBNA-1 in susceptible individuals leads to the generation of cross-reactive antibodies, which target additional, non-cross reactive autoepitopes, spread to additional autoantigens, and become pathogenic, leading eventually to clinical lupus.
Abstract: Systemic lupus erythematosus (SLE or lupus) is a complex disease with a multifactoral etiology, with genetic, hormonal, and environmental influences. Molecular mimicry as a result of viral infectio...
237 citations
TL;DR: Evidence for the hypotheses of molecular mimicry and epitope spreading are reviewed and the potential pathogenic mechanisms by which the immune response against the group A streptococcus attacks the rheumatic valve leading to chronic rhematic heart disease are unraveled.
Abstract: Molecular mimicry is a hallmark of the pathogenesis of rheumatic fever where the streptococcal group A carbohydrate epitope, N-acetyl glucosamine, and the α-helical coiled-coil streptococcal M protein structurally mimic cardiac myosin in the human disease, rheumatic carditis, and in animal models immunized with streptococcal M protein and cardiac myosin. Recent studies have unraveled the potential pathogenic mechanisms by which the immune response against the group A streptococcus attacks the rheumatic valve leading to chronic rheumatic heart disease. Both B- and T-cell responses are involved in the process, and evidence for the hypotheses of molecular mimicry and epitope spreading are reviewed.
184 citations
TL;DR: The reduced specific antibody response to tetanus in obese children and adolescent might be due to mechanical factors such as lower relative vaccination dose, or reduced absorption from the injection site due to increased adipose tissue, or related to reduce immune response due to the chronic low grade inflammation expressed by the higher levels of IL-6.
Abstract: Under-nutrition impairs immune responses, but far less is known about the impact of over-nutrition, such as obesity, on the response to vaccines. We measured the effect of childhood overweight status on inflammatory mediators, circulating immunoglobulins and tetanus antibodies in fifteen overweight children (BMI > 85 age-adjusted percentile) and 15 age-matched normal weight controls. Fitness was measured by a progressive ramp type exercise test. Lean body mass (LBM) and fat mass were determined by DXA. Tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), interleukin-1 beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1ra) were used to assess the inflammatory status; and circulating immunoglobulins (IgM, IgA, IgG and IgG subclasses) and specific IgG titer to tetanus were used to assess humoral immunity. Overweight children had higher LBM and percent fat mass, and lower peak VO2 normalized to body weight. IL-6 was significantly higher in the obese children (2.6 +/- 0.3 vs. 1.3 +/- 0.3 pg/ml, in overweight and normal weight children, respectively; p < 0.05). No significant differences were found in TNF-a, IL-1beta and IL-1ra between the groups. No significant differences were found in immunoglobulin levels (IgM, IgA, IgG and IgG subclasses) between the groups. Anti-tetanus IgG antibodies were significantly lower in the overweight children compared to normal weight controls (2.4 +/- 0.6 vs. 4.2 +/- 0.5 IU/ml, in overweight and normal weight children, respectively; p < 0.05). The reduced specific antibody response to tetanus in obese children and adolescent might be due to mechanical factors such as lower relative vaccination dose, or reduced absorption from the injection site due to increased adipose tissue, or related to reduce immune response due to the chronic low grade inflammation expressed by the higher levels of IL-6.
181 citations
TL;DR: The results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.
Abstract: Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a n...
179 citations
TL;DR: Screening of anti-ARS may be useful to predict late-onset myopathy in ILD-preceding patients and to predict the clinical course of ILD in PM/DM patients.
Abstract: In the treatment of polymyositis and dermatomyositis (PM/DM), the complication of interstitial lung disease (ILD) is an important prognostic factor. It has been reported that autoantibodies against...
177 citations
TL;DR: The finding that leukocyte-derived microparticles induce the production of matrix metalloproteinases and cytokines by synovial fibroblasts point to novel signaling pathways of cellular cross-talk that may operate along the spectrum of soluble cytokines and mediators of direct cell–cell contact.
Abstract: Microparticles are a heterogeneous population of membrane-coated vesicles which can be released from virtually all cell types during activation or apoptosis. Release occurs from the cell surface in an exogenous budding process involving local rearrangement of the cytoskeleton. Given their origin, these particles can be identified by staining for cell surface markers and annexin V. As shown in in vitro studies, microparticles may represent a novel subcellular element for intercellular communication in inflammation. Thus, microparticles can transfer chemokine receptors and arachidonic acid between cells, activate complement, promote leukocyte rolling and stimulate the release of pro-inflammatory mediators. Under certain conditions, however, microparticles may also exert anti-inflammatory properties by inducing immune cell apoptosis and the production of anti-inflammatory mediators. Microparticles may play an important role in the pathogenesis of rheumatologic diseases as evidenced by their elevation in diseases such as systemic sclerosis (SSc), systemic vasculitis and antiphospholipid antibody syndrome and correlation with clinical events. A role in inflammatory arthritis is suggested by the finding that leukocyte-derived microparticles induce the production of matrix metalloproteinases and cytokines by synovial fibroblasts. Together, these findings point to novel signaling pathways of cellular cross-talk that may operate along the spectrum of soluble cytokines and mediators of direct cell-cell contact.
164 citations
TL;DR: Interestingly, the AS patients with associated anti-Ro/SS-A antibodies seem to be predisposed to the development of a more severe ILD, expressed as HRCT total score ≥ 7.
Abstract: We studied the clinical features and autoantibody profile in 21 patients with antisynthetase syndrome (AS) comparing to 48 patients with classical polymyositis and dermatomyositis without AS. At presentation, the AS group showed more frequently the presence of interstitial lung disease (ILD), arthritis/arthralgia, mechanic's hand and anti-Ro/SSA antibodies. Patients without AS had more frequent proximal weakness and cutaneous erythematosus rash. Interestingly, the AS patients with associated anti-Ro/SS-A antibodies seem to be predisposed to the development of a more severe ILD, expressed as HRCT total score > or = 7. During a follow up of about 3 years (range 6-110 months), the presence of anti-Jo-1 antibody alone or in association with anti-Ro/SSA did not influence survival or a more severe prognosis of ILD.
161 citations
TL;DR: Monoclonal antibodies from Sydenham's chorea demonstrated the mimicry between lysoganglioside and the group A streptococcal carbohydrate epitope.
Abstract: Recent evidence suggests that the pathogenesis of Sydenham's chorea following group A streptococcal infection is due to antibodies which develop due to the infection and infiltrate the brain and basal ganglia. Antibodies present in acute chorea react with the surface of neuronal cells and signal the induction of calcium calmodulin dependent protein kinase II with elevation of tyrosine hydroxylase and subsequent dopamine release which may lead to the movement disorder. The antibodies present in disease recognize lysoganglioside and the group A streptococcal epitope, N-acetyl-glucosamine. Monoclonal antibodies (mAbs) from Sydenham's chorea demonstrated the mimicry between lysoganglioside and the group A streptococcal carbohydrate epitope. A group of antibodies present in pediatric autoimmune neuropsychiatric disorders (PANDAS) were similar but not identical to the antibodies observed in chorea.
141 citations
TL;DR: The inflammatory myopathies are a group of acquired diseases, characterized by an inflammatory infiltrate of the skeletal muscle, where CD8-positive cytotoxic T cells invade muscle fibres expressing MHC class I antigens, thus leading to fibre necrosis.
Abstract: The inflammatory myopathies are a group of acquired diseases, characterized by an inflammatory infiltrate of the skeletal muscle. On the basis of clinical, immuno-pathological and demographic features, three major diseases can be identified: dermatomyositis (DM); polymyositis (PM); and inclusion body myositis (IBM). New diagnostic criteria have recently been introduced, which are crucial for discriminating between the three different subsets of inflammatory myopathies and for excluding other disorders. DM is a complement-mediated microangiopathy affecting skin and muscle. PM and IBM are T cell-mediated disorders, where CD8-positive cytotoxic T cells invade muscle fibres expressing MHC class I antigens, thus leading to fibre necrosis. In IBM, vacuolar formation with amyloid deposits are also present. This article summarizes the main clinical, laboratory, electrophysiological, immunological and histologic features as well as the therapeutic options of the inflammatory myopathies.
121 citations
TL;DR: The authors will review the evidence in support of an autoimmune basis for CCC pathogenesis in humans and experimental animals, with a special emphasis on molecular mimicry as a fundamental mechanism of autoimmunity.
Abstract: Up to 18 million of individuals are infected by the protozoan parasite Trypanosoma cruzi in Latin America, one third of whom will develop chronic Chagas disease cardiomyopathy (CCC) up to 30 years after infection. Cardiomyocyte destruction is associated with a T cell-rich inflammatory infiltrate and fibrosis. The presence of such lesions in the relative scarcity of parasites in the heart, suggested that CCC might be due, in part, to a postinfectious autoimmune process. Over the last two decades, a significant amount of reports of autoimmune and molecular mimicry phenomena have been described in CCC. The authors will review the evidence in support of an autoimmune basis for CCC pathogenesis in humans and experimental animals, with a special emphasis on molecular mimicry as a fundamental mechanism of autoimmunity.
118 citations
TL;DR: It is proposed that a combination of two mechanisms, molecular mimicry and bystander activation, induced by virus infection, can lead to CNS demyelinating diseases, including MS.
Abstract: Polymicrobial infections have been associated with plausible immune mediated diseases, including multiple sclerosis (MS). Virus infection can prime autoimmune T cells specific for central nervous system (CNS) antigens, if virus has molecular mimicry with CNS proteins. On the other hand, infection of irrelevant viruses will induce two types of cytokine responses. Infection with a virus such as lymphocytic choriomeningitis virus (LCMV), can induce interferon (IFN)-alpha/beta production and suppress autoimmunity, while infection with a virus, such as murine cytomegalovirus (MCMV), can activate natural killer (NK), NKT and dendritic cells, resulting in interleukin (IL)-12 and IFN-gamma production. These cytokines can cause bystander activation of autoreactive T cells. We established an animal model, where mice infected with vaccinia virus encoding myelin protein can mount autoimmune responses. However, the mice develop clinical disease only after irrelevant immune activation either with complete Freund's adjuvant or MCMV infection. In this review, we propose that a combination of two mechanisms, molecular mimicry and bystander activation, induced by virus infection, can lead to CNS demyelinating diseases, including MS. Viral proteins having molecular mimicry with self-proteins in the CNS can prime genetically susceptible individuals. Once this priming has occurred, an immunologic challenge could result in disease through bystander activation by cytokines.
TL;DR: Although a great improvement has been achieved in the last decades in controlling IM, this study indicates that the mortality rate in this group of patients remains high, and a careful search for cardiac involvement should be done in every patient with IM.
Abstract: Objective: To investigate the causes of death, survival and clinical factors associated with mortality, in a group of Spanish patients with inflammatory myopathies (IM) followed in the same University Hospital during a 25 year period.Methods: A cross sectional study was performed, including 107 patients diagnosed with IM according to the Bohan and Peter criteria. Demographical and clinical information were extracted from the charts. Bivariate odds ratio with 95% confidence interval (CI) was used to measure the strength of association between variables. Kaplan-Meyer analysis was used to estimate survival. Univariate and multivariate Cox regression analysis were used to study clinical associations with mortality.Results: Twenty-eight patients (26%) died. Deaths were considered to be disease related in 21 cases. Main causes of death were cancer extension, cardiac involvement and lung involvement. Survival for the whole group was 92, 80 and 71% after 1, 5 and 10 years, respectively. By the log rank test, surv...
TL;DR: Searching for MSA and MAA in patients with autoimmmune myositis is recommended because of its diagnostic and clinical value; anti-ARS non-Jo-1 antibodies seem to preferentially target patients with pulmonary fibrosis without overt myopathy.
Abstract: Objective: To evaluate the clinical usefulness of serum autoantibody profiling in patients with autoimmune myositis.Methods: We retrospectively studied 74 consecutive patients: 68 had definite or probable myositis according to Bohan–Peter criteria, six suffered from antisynthetase syndrome with subclinical myopathy. Myositis specific antibodies (MSA) (anti-ARS, -SRP, -Mi-2) were determined by RNA immunoprecipitation or immunoblot, myositis associated antibodies (MAA) (anti-RoRNP, -U1RNP, -PM/Scl, -Ku) by immunoblot.Results: Forty-three patients (58%) were positive for MSA: anti-Jo-1 in 15/27 polymyositis (PM) (55%), 4/33 dermatomyositis (DM) (12%), 1/8 overlap (12%) and 2/6 antisynthetase syndrome (33%); anti-ARS non-Jo-1 in 1/27 PM (4%), 2/33 DM (6%) and 4/6 antisynthetase syndrome (67%); anti-Mi-2 in 1/27 PM (4%) and 11/33 DM (33%); anti-SRP in 3/27 PM (11%) and 1/33 DM (3%). One patient was anti-Jo-1/Mi-2 positive, one anti-Jo-1/SRP positive. Moreover, 27 patients (36%) were positive for MAA: anti-Ro/S...
TL;DR: The endothelial layer represents a continuous physical barrier that controls coagulation and allows selective passage of soluble molecules and circulating cells across the vessel wall into the tissue.
Abstract: The endothelial layer represents a continuous physical barrier that controls coagulation and allows selective passage of soluble molecules and circulating cells across the vessel wall into the tissue. The functional activity of the endothelial cells may be influenced by their interaction with components of the complement system. In this review we shall discuss the complex interplay that can be established between the endothelium and complement proteins or activation products. Endothelial cells may also secrete several complement components which contribute to the circulating pool. This process can be regulated by cytokines and other pro-inflammatory stimuli. In addition, complement activation products stimulate endothelial cells to acquire a pro-inflammatory and pro-coagulant status. Expression of regulatory molecules on the cell surface provides protection against an undesired attack by complement activation products. Unrestricted complement activation under pathological conditions may lead to structural and functional changes of the endothelium resulting in vascular disease.
TL;DR: This review characterizes and summarizes the clinical, pathologic, and immunohistologic features of PAMS and outlines the possible role of cytotoxic T lymphocytes in the pathogenesis of this syndrome.
Abstract: Paraneoplastic autoimmune multiorgan syndrome (PAMS), first described as paraneoplastic pemphigus in 1990, is an autoimmune blistering disease associated with neoplasia. Patients with this rare disorder have severe blistering and painful erosions of the oral cavity and various other cutaneous findings ranging from classic pemphigus vulgaris-like erosions to targetoid lesions resembling erythema multiforme and papular to more confluent lichenoid eruptions. This syndrome involves multiple organ systems, and its high rate of mortality often stems from constrictive bronchiolitis obliterans. The histologic findings are as diverse as the clinical presentation, often making diagnosis difficult initially. Immunodermatologic and serologic laboratory findings typically establish the diagnosis. These results can be confirmed with immunoprecipitation profiling of specific molecular weight protein markers. The proposed pathogenesis of PAMS continues to evolve, and recent reports implicate the involvement of cell-mediated, cytotoxic immunity, in addition to humoral autoantibodies. This review characterizes and summarizes the clinical, pathologic, and immunohistologic features of PAMS and outlines the possible role of cytotoxic T lymphocytes in the pathogenesis of this syndrome.
TL;DR: Data on sensor systems for carbohydrate epitopes and implications for autoimmunity is reviewed, which indicates that autoimmune diseases are being associated with defined changes of glycosylation.
Abstract: The immune system is a complex functional network of diverse cells and soluble molecules orchestrating innate and adaptive immunity. Biological information, to run these intricate interactions, is not only stored in protein sequences but also in the structure of the glycan part of the glycoconjugates. The spatially accessible carbohydrate structures that contribute to the cell's glycome are decoded by versatile recognition systems in order to maintain the immune homeostasis of an organism. Microbial carbohydrate structures are recognized by pathogen associated molecular pattern (PAMP) receptors of innate immunity including C-type lectins such as MBL, the tandem-repeat-type macrophage mannose receptor, DC-SIGN or dectin-1 of dendritic cells, certain TLRS or the TCR of NKT cells. Natural autoantibodies, a long known effector branch of this network-based operation, are effective to home in on non-self and self-glycosylation also. The recirculating pool of mammalian immune cells is recruited to inflammatory sites by a reaction pathway involving the self-carbohydrate-binding selectins as initial recognition step. Galectins, further key sensors reading the high-density sugar code, exert regulatory functions on activated T cells, among other activities. Autoimmune diseases are being associated with defined changes of glycosylation. This correlation deserves to be thoroughly studied on the levels of structural mimicry and dysregulation as well as effector molecules to devise innovative anti-inflammatory strategies. This review briefly summarizes data on sensor systems for carbohydrate epitopes and implications for autoimmunity.
TL;DR: The role of the complement system in SLE is reviewed and hypotheses advanced to explain the complex relationships between complement and lupus are advanced.
Abstract: Complement is involved in the pathogenesis of systemic lupus erythematosus (SLE) in multiple ways and may act as both friend and foe. Inherited homozygous deficiency of one of the earliest components of the classical pathway is strongly associated with susceptibility to the development of SLE. However, complement is also implicated in the effector inflammatory phase of the autoimmune response that characterizes the disease. A further paradox in the links between complement and SLE is the observation that autoantibodies to some complement proteins, especially to C1q, develop as part of the autoantibody response. In this chapter, the role of the complement system in SLE is reviewed and hypotheses advanced to explain the complex relationships between complement and lupus.
TL;DR: A fundamental role for PKC theta in T cell activation and in the development of T cell-mediated inflammatory diseases is indicated by these results.
Abstract: In the present study we have characterized T cell-driven immune function in mice that are genetically deficient in PKC theta. In response to simple immunologic stimulation invoked by in vivo T cell receptor (TCR) cross-linking, these mice showed significantly depressed plasma cytokine levels for IL-2, IL-4, IFNgamma, and TNFalpha compared to wild-type (WT) mice. In parallel, spleen mRNA levels for these cytokines were reduced, and NF-kappaB activation was also reduced in PKC theta knockouts (KO). Injection of allogeneic cells into the footpad of PKC theta deficient mice provoked a significantly diminished local T cell response compared to WT mice similarly challenged. Unlike comparable cells from wild type mice, CD45RBhi T cells harvested from PKC theta deficient mice failed to induce colitis in the SCID-CD45RB cell transfer model of IBD. In another T cell-dependent model of inflammatory disease, PKC theta deficient animals developed far less severe neurologic signs and reduced spinal cord inflammatory cell infiltrate compared to WT controls in the MOG-induced EAE model. A fundamental role for PKC theta in T cell activation and in the development of T cell-mediated inflammatory diseases is indicated by these results.
TL;DR: The crucial role of TGF-β signaling in Treg cell biology is focused on and the current studies regarding T GF-β in the generation and function of CD4+CD25+Treg cells both in vivo and in vitro are summarized.
Abstract: The transforming growth factor-beta (TGF-beta) protein family is highly evolutionarily conserved and they have been implicated in many biological processes. Also, TGF-beta can exert pivotal functions in the immune system. It is widely accepted that regulatory T cells (Treg cells) play an important role in the maintenance of the immune homeostasis, but the underlying molecular mechanisms through which they can gain and/or perform suppressive functions in an active way remains to be defined. Though the engagement of TGF-beta in the Treg cells has been discounted for a period of time, an emerging body of data has established a close link between Treg cells and TGF-beta, as TGF-beta has been demonstrated to induce the expression of Foxp3, which acts as a master regulator for the development and function of Treg cells. We will, herein, focus on the crucial role of TGF-beta signaling in Treg cell biology and summarize the current studies regarding TGF-beta in the generation and function of CD4+CD25+Treg cells both in vivo and in vitro.
TL;DR: Clinical features of cutaneous lupus and recent genetic data that elucidate potential candidate genes for both cutaneouslupus erythematosus (CLE) and SLE are reviewed and promising experimental therapies based on these advances are reviewed.
Abstract: Cutaneous features of the protean disease lupus erythematous (LE) constitute 4 of 11 diagnostic criteria for systemic lupus erythematosus (SLE) and are exhibited by approximately 3/4 of patients during the course of their disease. Because the pathogenesis of LE is multifactorial and polygenic, many of the details of the pathogenesis remain unclear. We review here the clinical features of cutaneous lupus and recent genetic data that elucidate potential candidate genes for both cutaneous lupus erythematosus (CLE) and SLE. We discuss advances in elucidating the autoimmune pathogenesis of CLE and SLE. Furthermore, promising experimental therapies based on these advances are reviewed in the context of B cell directed therapies, T cell directed therapies, disruption of B and T cell interactions, cytokine directed therapies and finally, end-effector targeted therapies.
TL;DR: Thyroid enlargement was associated with high levels of TPOAb and TgAb and no association was found with sex, age, iodine deficiency level or serum TSH level, and autoimmunity played a dominant role in practically all patients classified as spontaneously hypothyroid.
Abstract: Objectives: Thyroid autoimmunity is a major cause for hypothyroidism. We describe thyroid auto-antibodies in patients with various nosological subtypes of hypothyroidism identified in a population study.Design: Population-based follow-up study identifying all new cases of hypothyroidism in an open cohort.Methods: We established a monitoring system, and identified all new cases with primary overt hypothyroidism (n = 685) in a 4 year period in a well-defined population cohort (2,027,208 person-years of observation). Patients were sub-classified into: spontaneous hypothyroidism, presumably of autoimmune origin (n = 578); non-spontaneous hypothyroidism (associated with medication, delivery, neck-irradiation or subacute thyroiditis, n = 97); and congenital hypothyroidism (n = 10). A total of 186 adult patients (61% of those invited) underwent thyroid ultrasonography and measurements of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb).Results: In spontaneously hypothyroid patients: >99% we...
TL;DR: Although the exact role of cytokines in chronic idiopathic inflammatory myopathies remains to be delineated their potential role as targets for new therapies in this disorder will be discussed in this review.
Abstract: Recent findings suggest cytokines as important key molecules in the pathogenic mechanisms of idiopathic inflammatory myopathies, myositis. In this review, we focus on cytokines with a potential role in disease mechanisms in myositis and present some general information on individual cytokines and an updated summary from the literature concerning cytokines in these disorders. The idiopathic inflammatory myopathies is a heterogeneous group of disorders clinically characterized by symmetric proximal muscle weakness and by certain defined histolopathological findings, including inflammatory infiltrates in muscle tissue. Other prominent findings in the target tissue of these patients are defined molecular changes of blood vessels and muscle fibers, including reformation to high endothelial venule (HEV)-like blood vessels and intensive MHC class I expression in muscle fibers. The predominant clinical symptoms of muscle weakness and decreased muscle endurance are shared by all subsets of inflammatory myopathies and indicate that some pathogenic mechanisms related to muscle function may be shared by the different disease groups. Studies on cytokine gene, RNA and protein expression in muscle tissue from patients with various forms of the disease also indicate similar profiles, despite different phenotypes of the inflammatory cells present in muscle tissue from the different subsets of myositis. There is a pronounced expression of various cytokines in muscle tissue, among which the proinflammatory cytokines TNF-alpha and IL-1 are most widely explored in the inflammatory myopathies, which has made them into potential therapeutic targets. The use of targeted cytokine therapy has been successful in several other chronic inflammatory diseases and although the exact role of cytokines in chronic idiopathic inflammatory myopathies remains to be delineated their potential role as targets for new therapies in this disorder will be discussed in this review.
TL;DR: Several animal models provide evidence that this series of events forms the basis for the pathophysiology found in many lung diseases, such as asthma and acute respiratory distress syndrome.
Abstract: Complement proteins play an integral role in both innate and adaptive immune responses of the host. Complement activation leads to the formation of bioactive molecules including the anaphylatoxins, C3a and C5a, and the lytic membrane attack complex (C5b-9). These molecules trigger a series of events that culminate in the recruitment of phagocytic cells, release of cytokines/chemokines and reactive oxygen species, enhanced expression of adhesion molecules and apoptosis at the site of inflammation. Several animal models provide evidence that this series of events forms the basis for the pathophysiology found in many lung diseases, such as asthma and acute respiratory distress syndrome. Clinical data further confirm these findings. This review briefly discusses recent data from such studies.
TL;DR: Experimental data indicate that the EGFR is instrumental in transducing apoptotic/acantholytic signals in keratinocytes cultures in response to PV-IgG treatment, and suggests that activation of EGFR, followed by its internalization, is pivotal for intracellular apoptotic signal transduction via ERK/c-Jun pathways, leading to acantholysis.
Abstract: Pemphigus is an autoimmune cutaneous disease characterized by circulating autoantibodies that cause blistering and erosions on skin and mucous membranes. Circulating autoantibodies bind to epidermal cell membrane and cause cell-cell detachment (acantholysis), leading to epidermal tissue damage and cell death. The principal target of pemphigus vulgaris autoantibodies (PV-IgG) is desmosomal cadherin desmoglein 3 (Dsg3), a constituent of desmosomes, mediating cell-cell adhesion. Several hypotheses for the mechanisms of acantholysis induction by PV-IgG exist, but the actual mechanism is not clear as yet. We have previously reported on apoptosis induction in PV-IgG-mediated epidermal tissue and cell damage as a possible mechanism of acantholysis and cell death (Wang et al. 2004, Apoptosis, 9:131-143). In this study we investigated the involvement of the EGFR and intracellular signal transduction pathways in the PV-IgG-induced apoptosis. We show here that PV-IgG induced activation/autophosphorylation of EGFR in cultured keratinocytes in vitro. The specific tyrosine kinase inhibitor AG1478 abrogated EGFR autophosphorylation, cell death, FasL appearance and acantholysis, all induced by PV-IgG, in parallel, confirming the involvement of EGFR in this Fas apoptotic cascade. Activation of EGFR was followed by phosphorylation of its downstream substrates, MAP kinase ERK and transcription factor c-Jun, and internalization of EGFR. Pharmacological inactivation of the EGFR and ERK kinase activities, by use of specific inhibitors AG1478 and PD98059 respectively, blocked PV-IgG-induced phosphorylation of EGFR, ERK and c-Jun and cellular apoptosis, measured by flow cytometry and caspase 3 activity. Prolonged activation of EGFR by PV-IgG led to dramatic internalization of this receptor, possibly reducing the ability of the cell to perform survival signals. This suggests that activation of EGFR, followed by its internalization, is pivotal for intracellular apoptotic signal transduction via ERK/c-Jun pathways, leading to acantholysis. Our experimental data indicate that the EGFR is instrumental in transducing apoptotic/acantholytic signals in keratinocytes cultures in response to PV-IgG treatment. The acantholytic effect caused by PV-IgG binding to cell surface receptors begins with and depends on cell surface receptor (EGFR) activation of intracellular signaling pathways (ERK pathway) and apoptosis induction (FasR pathway), which later lead to major cell-cell separation (acantholysis) and cell death.
TL;DR: These findings strongly suggest that complement activation and membrane assembly of C5b-9 can play a role in injury but can also provide neuroprotection depending on the pathophysiological context.
Abstract: The activation of complement system is important factor in inflammatory, neurodegenerative and cerebrovascular diseases. CNS cells are able to synthesize complement components, and myelin and oligodendrocytes (OLG) are known to activate the classical pathway of complement in vitro in the absence of antibodies. Although activation of the complement system is known to promote tissue injury, recent evidence has also indicated that this process can have neuroprotective effects. In particular, terminal C5b-9 complexes enhance OLG survival both in vitro and in vivo. Complement activation may also reduce the accumulation of amyloid and degenerating neurons by promoting their clearance and suggest that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease. Complement system activation plays also an important role in brain damage after ischemic injury or head trauma. These findings strongly suggest that complement activation and membrane assembly of C5b-9 can play a role in injury but can also provide neuroprotection depending on the pathophysiological context.
TL;DR: Clinical symptoms, treatment and outcome in both groups were good, and improvement was achieved in the 14 (100%) Jo-1 positive patients, and in 25 (92.5%) controls.
Abstract: The idiopathic inflammatory myopathies are a heterogeneous group of diseases that can involve various systems. Antibodies directed against aminoacyl-tRNA synthetases, such as anti-Jo-1 antibodies, are strongly associated with a syndrome which consists of myositis, interstitial lung disease (ILD), arthritis and Raynaud's phenomenon. Forty-one patients with various forms of idiopathic inflammatory myopathies were assessed: 14 patients with anti-Jo-1 antibodies and 27 patients without anti-Jo-1 antibodies as a control group. We retrospectively analysed clinical symptoms, treatment and outcome in both groups. Patients with anti-Jo-1 antibodies more often had ILD (64.2 vs. 11.1%), arthritis (64.2 vs. 18.1%) and Raynaud's phenomenon (38 vs. 0%). Patients without the anti-Jo-1 antibody presented worse muscle strength and more frequently myalgia (37 vs. 21%), cutaneous rash (18.5 vs. 7%), heliotrope rash (29% vs. 7%) and periungueal changes (22 vs. 0%) than the anti-Jo-1-positive patients. Outcome was good in both groups. Improvement was achieved in the 14 (100%) Jo-1 positive patients, and in 25 (92.5%) controls. Two (7.5%) patients from control group achieved remission.
TL;DR: Available evidence suggests that membrane complement regulatory proteins may act to suppress autoimmunity via both complement-dependent and -independent mechanisms.
Abstract: The complement system is known to be involved in autoimmunity at several levels. Activated complement contributes to the inflammatory tissue injury characteristic of many autoimmune disease settings. On the other hand, early components of the classical pathway, including C1q, C4 and C2, are thought to be important for disposing apoptotic cellular autoantigens and/or the induction of B cell tolerance in the bone marrow, and their deficiency is a strong risk factor for systemic autoimmunity. Recent studies using transgenic mice have revealed membrane complement regulatory proteins as important modulators in the pathogenesis and manifestation of autoimmune injury. Available evidence suggests that these regulatory proteins may act to suppress autoimmunity via both complement-dependent and -independent mechanisms.
TL;DR: IA in pemphigus demonstrates that a rapid and dramatic decline in desmoglein (Dsg)-reactive autoantibodies is accompanied by clinical remission of mucocutaneous blisters and erosions, and is generally safe and well tolerated.
Abstract: The principle of extracorporal immunoadsorption (IA) is based on affinity adsorption of pathogenic (auto-)antibodies and circulating immune complexes (CIC) which reversibly bind to an immobilized ligand of the adsorber. In pemphigus, a blistering autoimmune disease affecting skin and mucous membranes, autoantibodies, mainly of the IgG subclass are directed against desmosomal adhesion molecules and other non-desmosomal antigens on the surface of epidermal keratinocytes, such as acetylcholine receptors. The pathogenicity of these autoantibodies has been shown in various in vitro and in vivo systems. Recently, IA was applied in severe pemphigus demonstrating that a rapid and dramatic decline in desmoglein (Dsg)-reactive autoantibodies is accompanied by clinical remission of mucocutaneous blisters and erosions. As an adjuvant treatment, IA was combined with systemic immunosuppressive medication and current protocols initially apply treatment cycles of 3–4 IAs on consecutive days followed by immunoapheresis on...
TL;DR: Intraveneous immunoglobulin can rapidly control active PV unresponsive to conventional therapy by causing a selective and very rapid decline in the autoantibodies that mediate the disease.
Abstract: Background: Intraveneous immunoglobulin (IVIg) is increasingly used to treat pemphigus vulgaris (PV). The mechanism by which it does so is not known. The following study was conducted to confirm the effectiveness of IVIg for the acute control of active PV and to elucidate the mechanism by which it does.Methods: Twelve patients with active and severe PV unresponsive to conventional therapy with high doses of systemic steroids together with or without a cytotoxic drug were treated with a single dose of IVIg (400 mg/kg/day for 5 days). All patients were concurrently given cyclophosphamide or azathioprine of not already on one of these two drugs. The primary end-points were healing of skin lesions, changes in serum levels of intercelular (IC) autoantibodies and in steroid doses one to 3 weeks after initiation of IVIg.Results: Within 1 week of initiating IVIg the activity of PV was controlled in most cases. Within 3 weeks the average baseline dose of systemic steroid was reduced by 40%. Serum levels of IC anti...
TL;DR: The available treatment options and novel therapies for pemphigus are reviewed and there are still very few randomized, controlled studies to evaluate the true effectiveness of the available therapies.
Abstract: Pemphigus is a group of rare autoimmune mucocutaneous bullous diseases with potential significant morbidity and mortality. The two main subtypes are pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Systemic corticosteroid use and other advances in management have dramatically decreased the mortality rate for pemphigus. At present, the primary cause of morbidity and mortality is complications from treatment. Thus, the goal of pemphigus management is to induce and maintain remission with the lowest possible doses of medication and with the fewest side effects. Although our scientific knowledge of pemphigus is advancing and our treatment options are expanding, there are still very few randomized, controlled studies to evaluate the true effectiveness of the available therapies. Here we review the available treatment options and novel therapies for pemphigus and the supporting data.