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PubMed2000

Association of HELLP syndrome with autoimmune antibodies and glucose intolerance.

OBJECTIVE: HELLP syndrome is a severe form of preeclampsia, characterized by hemolysis (H), elevated liver enzymes (EL), and low platelets (LP), whose pathogenesis is unclear. Autoimmunity is thought to play an important role. After the observation of development of type 1 diabetes in a patient with HELLP syndrome, we assumed a possible disease association based on autoimmune reactions. RESEARCH DESIGN AND METHODS: We examined 70 women with HELLP syndrome for the presence of autoimmune markers and glucose intolerance. Free thyroxine, triiodothyronine, thyroid-stimulating hormone, anti-thyroglobulin antibodies, thyroperoxidase antibodies, thyrotropin receptor antibodies, antinuclear antibodies (ANAs) and anti-DNA, islet cell antibodies, GADA, an oral glucose tolerance test, and HbA1c were determined postpartum. Patients with positive autoimmune markers or glucose intolerance were prospectively followed and repeated testing was performed. There were 60 women with a normal course of pregnancy matched for age, BMI, and number of pregnancies, which served as a control group. RESULTS: From the HELLP patients, 22 (31%) compared with only 6 (10%) control subjects had autoimmune antibodies (P < 0.01). There were 16 HELLP patients (23%) who exhibited only 1 kind of autoantibody (5 ANA, 9 thyroid antibodies, and 2 GADA), whereas in 6 HELLP patients (8.5%) 2 different antibodies were found. In all but 4 patients of the study group, these antibodies disappeared during 3 +/- 1.5 years of follow-up. Glucose intolerance was detected in 22 (31%) of the HELLP patients, 17 of them had impaired glucose tolerance (IGT), and 5 had diabetes, whereas only 4 subjects (6.5%) with IGT at postpartum were found in the control group (P < 0.01). During the follow-up, 2 HELLP patients were still diabetic and another 2 HELLP patients (1 GADA positive) had IGT versus 1 control subject. CONCLUSIONS: Our data give evidence that HELLP syndrome is associated with various autoimmune antibodies and glucose intolerance. Because glucose intolerance and/or autoimmune markers persisted during long-term follow-up in 6 patients with HELLP syndrome versus 1 in the control group, it may become advisable to reexamine patients with HELLP syndrome for detection of diabetes and autoimmune disorders.

Adult↗

PubMed2002

Millennium Award. Proteomics for the development of DNA tolerizing vaccines to treat autoimmune disease.

Autoimmune disease affects 3% of the world population, yet current therapies that globally suppress immune function are inadequate. Tremendous need exists for specific and curative therapies, and we describe a strategy for development of antigen-specific therapies that inactivate pathogenic lymphocytes causing tissue injury. Major barriers to development of antigen-specific therapies for T-cell-mediated autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and autoimmune diabetes, include (i) lack of knowledge of the specificity of autoimmune responses, for which proteomic technologies represent powerful tools to identify the self-protein targets of the autoimmune response, and (ii) lack of methods to induce specific immune tolerance, for which DNA tolerizing vaccines represent a promising strategy. We termed our approach Reverse Genomics: use of the proteomics-determined specificity of the autoantibody response to develop and select DNA tolerizing vaccines. Studies performed using animal models for multiple sclerosis and autoimmune diabetes support our Reverse Genomics approach. Through integration of proteomics with specific tolerizing therapies, we are developing a comprehensive approach to treat human autoimmune disease.

Animals↗

PubMed1998

The role of infection in the pathogenesis of autoimmune disease.

Autoimmune disease has long been considered a shadow following infectious diseases. Epidemiological evidence shows that rheumatic fever follows streptococcal infection and Trypanosoma cruzi infection is the instigator of Chagas' disease. There is, however, very little information of the mechanism by which such a train of events is initiated. Autoimmunity, in a form of autoantibodies, is common after many infections and may well result from the mimicking of host proteins by antigens of the infectious agent. There are, however, few if any examples in humans where molecular mimicry gives rise to autoimmune disease. The progression from benign autoimmunity to pathogenic autoimmune disease depends upon the balance of cytokines produced during the inflammatory process accompanying infection. In many autoimmune diseases, the cytokine profile favors the proinflammatory cytokines, IFN-gamma and IL-1, which support the production of disease. A searching study of cytokine profiles during infection may offer a promising approach to avoiding the harmful consequences of post-infection autoimmune responses.

Animals↗

PubMed1994

Central immune system, the self and autoimmunity.

We model how auto-reactive B cells are kept under control by an idiotypic network. Autoimmunity occurs when the control is broken by an infection or not achieved through an abnormal ontogenetic evolution. We describe the idiotypic network, viz., the central immune system, by idiotype-anti-idiotype pairs which are coupled to a set of highly connected clones, which interact with each clone of the network. Some clones of the central immune system recognize self-antigen. We find a huge variety of fixed points which can be classified as tolerant, autoimmune, and neutral states according to the concentration of the auto-reactive antibody. Most significant are auto-reactive clones which are a member of an idiotype-anti-idiotype pair. In a healthy individual, an autoimmune disease is induced by an antigen infection which triggers a transition from a tolerant to an autoimmune state. Autoimmunity is induced more readily by an antigen coupling to the anti-idiotype than by one interacting with the auto-reactive clone itself. We indicate a possible therapy which simply reverses the processes that have lead to the autoimmune disease. In the early development of the central immune system its highly connected, core part serves to draw the more specific clones of idiotype-anti-idiotype pairs into the network. In order to avoid autoimmunity in ontogenetic evolution the anti-idiotype of an auto-reactive clone must be formed in advance by a sufficiently long period of time. Thus, a well ordered succession of the appearance of the more specific clones is required.

Animals↗

PubMed1989

The significance of T suppressor cells in the development of autoimmunity.

Despite intensive research, autoimmune-disease pathogenesis is still an enigma, but in the past decade Ts-cell defects have assumed a central role in this pathogenesis. Ts-cell dysfunctions have been reported in numerous autoimmune diseases (e.g. SLE, autoimmune thyroid disease, myasthenia gravis) and in animal models of autoimmune diseases. Therefore, it is currently believed that Ts cells are responsible for maintaining self-tolerance and that perturbations in suppressor functions may initiate development of autoimmune diseases. Ts-cell abnormalities can result from LCTA production, intrinsic biochemical alterations, genetic susceptibility, or environmental factors. Since Ts-cells dysfunctions are believed to initiate autoimmunity, it may be possible to treat autoimmune diseases by correcting the suppressor defects, and indeed, preliminary trials in this direction are promising.

Animals↗

PubMedDate not supplied

Limited heterogeneity of autoantigens and T cells in autoimmune diseases?

For many induced and spontaneous autoimmune diseases, a predominant role for T cells in the organ-specific destruction process has been shown. In one of the induced models of autoimmunity, experimental allergic encephalomyelitis (EAE), a very small heterogeneity of T-cell receptor (TcR) molecules is expressed by the pathogenic T cells in both rats and mice. Contrary to induced autoimmune diseases, little is known about the autoantigens recognized by these autoimmune T cells and the heterogeneity of their TcR in spontaneous autoimmune diseases. The aim of this work was to establish a system which allows characterization of relevant autoantigens in spontaneous insulin-dependent diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice. A completely different approach was taken to characterize the gene products of the minor lymphocyte stimulatory (Mls) loci. These gene products are responsible for the clonal elimination or the clonal stimulation of T cells expressing particular TcR V beta genes and therefore could be implicated in induction of autoimmune diseases by oligoclonal T-cell populations. The finding that Mls antigens are encoded by retroviral sequences leads to the hypothesis that viruses could be the inducing agents of autoimmune diseases.

Animals↗

PubMed2005

CNS demyelination in autoimmune diseases.

Autoimmune diseases represent a diverse group of disorders that have generally of unknown etiology and poorly understood pathogenesis. They may be organ-specific or systemic, giving rise to overlapping syndromes; more than one autoimmune disease may occur in the same patient. Numerous case reports have documented that multiple sclerosis (MS) may be present concurrently with other autoimmune diseases, most commonly rheumatoid arthritis, autoimmune thyroid disease, type I diabetes mellitus and pernicious anemia. Case reports of disseminated encephalomyelitis (DEM) coincidental with other autoimmune diseases are rare. Many of systemic autoimmune diseases cause central nervous system (CNS) demyelination and are frequently then diagnosed as MS, whereas they often are instances of DEM, the result of vascular, granulomatous or postinfectious manifestations. We have reviewed 15 patients with autoimmune diseases and CNS demyelination in order to determine the nature of the demyelinating process.

Adolescent↗

PubMed2004

Inverse correlation between the incidences of autoimmune disease and infection predicted by a model of T cell mediated tolerance.

The contribution of pathogenic infections to the etiology of autoimmune diseases remains one of the outstanding problems in immunology. According to the classical concept of antigen mimicry, a direct correlation between the incidence of autoimmunity and infections would be expected. This view is supported by a few examples of autoimmune disorders, which are documented as being caused by infection with particular pathogens. In contrast, there are several experimental animal models where infection appears to prevent the onset of autoimmunity. Moreover, some epidemiological studies suggest an inverse correlation between the incidence of autoimmunity and infections in human populations. Here we propose a solution to this puzzle based on a theoretical model of tolerance driven by regulatory T cells. The concepts here developed delineate the conditions predicting an inverse correlation between the incidence of autoimmunity and exposition to common infections, and those in which antigen mimicry and inflammation of target organs have a role in the etiology of specific autoimmune disorders.

Animals↗

PubMed2004

IgM monomers accelerate disease manifestations in autoimmune-prone Fas-deficient mice.

The monomeric form of IgM, also known as low molecular weight IgM, is found in increased concentrations in patients chronically infected with a variety of viral and bacterial pathogens or suffering from various autoimmune diseases. Whether monomeric IgM contributes to the disease process, however, is not known. To address this question, transgenic mice were created that secreted elevated levels of IgM monomers. In normal mice (C57BL/6), the presence of IgM monomers did not alter the composition of the immune system significantly: lymphocyte subsets and serum antibody levels were normal, with the exception of increased levels of IgM due to the presence of the monomers. Immune responses also appeared to be normal. Transgenic mice did develop antinuclear antibodies (ANA) earlier than non-transgenic littermates, but did not develop further indications of autoimmune disease. When the transgene was expressed in the autoimmune-prone strain of mice, B6.MRL-Tnfrsf6(lpr) (B6/lpr), these mice developed autoimmune manifestations more rapidly than non-transgenic littermates, including hypergammaglobulinemia, splenomegaly, and ANA production. Transgenic mice also displayed earlier evidence of immune complex deposition in the kidneys. From these results, we conclude that monomeric IgM does not induce autoimmune disease, but its presence can accelerate the onset of autoimmune manifestations in otherwise autoimmune prone animals.

Amino Acid Sequence↗

PubMed2001

Dendritic cells in autoimmune diseases.

Subclinical autoimmune responses can be frequently detected in healthy individuals. Sustained activation of autoreactive lymphocytes is, however, required for the development of autoimmune diseases associated with ongoing tissue destruction either in single organs or generalized with multiple manifestations. Clinical and experimental evidence suggests that prolonged presentation of self antigens by dendritic cells is crucial for the development of destructive autoimmune disease. We discuss here a simplified threshold model where the key parameters for the magnitude of the autoimmune response are the amount of previously ignored self peptides presented by dendritic cells and the duration of the antigen presentation in secondary lymphoid organs. Multiple factors influence the threshold for the conversion of an autoimmune response to overt autoimmune disease. Frequent or persistent viral infections of the target organ may favor autoimmune disease by increasing the amounts of released self antigens, generating cytokine-mediated bystander activation of self-reactive lymphocytes and/or sustaining a chronic response via neoformation of lymphoid structures in the target organ.

Animals↗

PubMed2006

[Autoimmune liver diseases and their overlap syndromes].

Autoimmune diseases of the liver are chronic inflammatory diseases leading to an etiologically undefined immune-mediated attack aimed at the hepatocyte, small microscopic bile ducts, and the entire biliary system detectable by cholangiography, respectively. From the standpoint of clinical disease three entities can be distinguished: autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). These are not only different regarding their clinical profile but also differ in diagnostic strategy, therapeutic regimen and probability of remission, as well as their association with other immune-mediated diseases and cancer. PBC and PSC are cholestatic diseases. PBC is most often diagnosed in women. The diagnosis is readily reached by the detection of specific antimitochondrial autoantibodies directed against pyruvate dehydrogenase (PDH-E2), is associated with an array of rheumatological extrahepatic syndromes and responds unsatisfactorily to immunosuppressive drugs. Ursodeoxycholic acid leads to biochemical and possibly histological benefits. In contrast, PSC affects younger men who suffer from inflammatory bowel disease in 75% of cases. PSC is not characterized by specific serum autoantibodies. The diagnosis is reached by histology and typical findings upon cholangiography. In 10-20% PSC is associated with cholangiocarcinoma and also with colon cancer. PSC also does not respond well to immunosuppression. Therapeutic interventions include mechanical endoscopic manipulation of the bile ducts, treatment of cholangitis and ursodeoxycholic acid. AIH is a classical autoimmune disease with a female predisposition, circulating autoantibodies, elevated immunoglobulins, the association of other extrahepatic autoimmune diseases, and a dramatic response to immunosuppression with normalization of the patient's prognosis upon remission and prevention of cirrhosis. However, the diagnosis is only reached by the exclusion of other liver diseases also characterized by biochemical, histological and clinical features of chronic hepatitis. In this light, the precise diagnosis is essential. In spite of the clear distinctions of the three diseases overlapping syndromes do exist. These can be characterized as the coexistence of serological parameters of PBC and AIH, of cholestasis and hepatitis, of autoantibodies and viral markers, or the consecutive manifestation of PBC and AIH, or AIH and PSC. However, the overlap of genuine autoimmune diseases is rare. This is relevant regarding therapy and must lead to the precise clinical and diagnostic discrimination of serological autoimmunity (autoantibodies) and genuine autoimmune disease (i.e. AIH) for the initiation of efficatious therapeutic measures. AIH, PBC and PSC are well established indications for liver transplantation with good results. Transplantation is required when cirrhosis is progressive despite therapy and is likely to lead to liver failure.

Adult↗

PubMed2006

FK506 controls CD40L-induced systemic autoimmunity in mice.

Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.

Animals↗

PubMed1999

Autoimmunity and extranodal lymphocytic infiltrates in lymphoproliferative disorders.

OBJECTIVE: To examine the relationship between autoimmunity and extranodal lymphocytic infiltrates in different lymphoproliferative disorders with immunoglobulin alterations. SUBJECTS AND DESIGN: A clinical review combined with a retrospective cohort study of 380 patients, 28 with monoclonal gammopathy of undetermined significance, three with common variable immunodeficiency, 147 with chronic lymphocytic leukaemia, 57 with Waldenström's macroglobulinaemia and 145 with non-Hodgkin's malignant lymphoma. SETTING: A university hospital and The State Serum Institute in Copenhagen. INTERVENTION: Clinical examination of each patient with special attention to chronic inflammatory and autoimmune manifestations. Biopsies were taken from non-infectious infiltrates, some of which were additionally tested with PCR analysis for gene rearrangements. Serological screening with a test battery for various autoantibodies was used in combination with techniques for the detection of M-components and monoclonal B-cell proliferation. MAIN OUTCOME MEASURES: Clinical and/or serological autoimmune manifestations, M-component and other immunoglobulin alterations, and inflammatory tissue changes were studied in patients with chronic inflammatory, polyclonal or oligoclonal pseudolymphomas and in monoclonal, malignant extranodal lymphomas. RESULTS: In 380 consecutive patients, 49 (12.9%) had extranodal manifestations, of whom 47 also had autoimmune manifestations. Nearly half of the 47 patients had more than one autoimmune manifestation. There was a strong correlation between clinical signs and corresponding autoantibodies such as anti-SSA and -SSB antibodies in Sjögren's syndrome (10 cases), antithyroid peroxidase antibodies in thyroiditis and Graves' disease (10 cases), and parietal cell antibodies in gastric ulcers with maltoma (12 cases). Clinical and serological signs of autoimmunity correlated strongly with female sex (34, 72% women; and 13, 28% men) and with immunoglobulin alterations. CONCLUSIONS: To our knowledge this is the first systematic review of B-lymphoproliferative and autoimmune disorders indicating that pseudolymphoma and malignant lymphomas, including maltomas, may develop in the context of a permanent autoantigenic drive.

Aged↗

PubMed1997

The nature of autoimmune disease.

The primary function of the immune system is protection and defense against infection. However, the maintenance of normal immune function is a very intricate process, and the failure of these processes to establish and maintain tolerance to self results in autoimmunity. The damage that results from autoimmune disease can be extensive and can be directed at any tissue in the body. One of the major issues in autoimmunity is whether this is a natural or an unnatural phenomenon. Although there have been numerous and exciting theories proposed to explain the autoimmune response, the basic underlying risk factors remain unclear. Both genetic and environmental factors have been incriminated, but the highly variable expression of autoimmune disease and the multiple genetic and environmental determinants make conclusions difficult. Primary biliary cirrhosis is considered a model autoimmune disease because it reflects a highly directed and highly specific response to an identified target, the biliary epithelium. In this review we attempt to place these issues in perspective both from the generic perspective of autoimmunity and from the specific perspective of primary biliary cirrhosis.

Autoimmune Diseases↗

PubMed2002

Allergic disease and autoimmune effectors pathways.

Allergy and autoimmunity result from dysregulation of the immune system. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest possible common pathogenetic effector pathways. This review illustrates the concomitant presentation of these conditions and the potential relationship or common mechanism in some cases, by looking at the key elements that regulate the immune response in both allergic and autoimmunite conditions: mast cells, antibodies, T cells, cytokines, and genetic determinants. The parallel appearance of allergic and autoimmune conditions in the some patients may reveal that such aberrations of the immune system have a common pathophysiologic mechanism. Mast cells, which play a key role in allergic reactions, and the wealth of inflammatory mediators they express, make it likely that they have profound effects on many autoimmune processes. Activation of protein kinases by inflammatory cytokines and environmental stresses may contribute to both allergic and autoimmune diseases. The presence of autoantibodies in some allergic conditions suggests an autoimmune basis for these conditions. Because of the central role T cells play in immune reactivity, the T-cell receptor (TCR) loci have long been considered important candidates for common disease susceptibility within the immune system such as asthma, atopy, and autoimmunity. Immunomodulation is the key to a successful treatment of allergic and autoimmune conditions.

Autoimmune Diseases↗

PubMed2005

Cytotoxic T lymphocytes and autoimmunity.

PURPOSE OF REVIEW: The possibility of the recognition by cytotoxic T lymphocytes of tissue autoantigens has been largely ignored in explaining organ-specific autoimmune diseases. Recent advances in the understanding of human leukocyte antigen class I-binding peptides motifs have led to the detection and the characterization of those autoreactive CD8(+) cytotoxic T lymphocytes involved in organ-specific autoimmune diseases. The purpose of this review is to discuss recent studies that shed light on the implication of cytotoxic T lymphocytes in several autoimmune disorders as well as the mechanisms underlying their stimulation. RECENT FINDINGS: Significant progress has been made in the characterization of autoantigens targeted by cytotoxic T lymphocytes in several class I-restricted autoimmune diseases, including Behçet's disease and ankylosing spondylitis, and their implication in systemic autoimmune disease such as systemic lupus erythematosus. Moreover, the signals involved in the activation of autoreactive cytotoxic T lymphocytes have been better characterized, particularly the molecular requirements of the antigen presentation at the surface of the dendritic cell system, mainly because of a better understanding of the Toll-like receptor-induced signals or the discovery of a defect in regulatory T cells. SUMMARY: New findings in the pathophysiology of cytotoxic T lymphocytes in autoimmunity and especially a better comprehension of their activation may give a new impetus for the development of targeted immunologic therapies in various autoimmune disorders.

Animals↗

PubMedDate not supplied

Autoimmune toxicities associated with the administration of antitumor vaccines and low-dose interleukin-2.

The purpose of this investigation was to evaluate the occurrence of autoimmune toxicities associated with the administration of low-dose IL-2 in conjunction with vaccines for melanoma. Ninety-three patients with stage IIB, III, or IV melanoma were enrolled in three clinical trials and received anti-melanoma vaccines on days 1, 8, 15, 29, 36, and 43. The vaccines comprised peptide-pulsed dendritic cells, autologous tumor cells with GM-CSF in Montanide ISA-51, or synthetic peptides with GM-CSF in Montanide ISA-51. In conjunction with the vaccines, all patients were administered 3 x 10(6) IU/m2/d IL-2 subcutaneously for 42 days, either days 8 to 49 or 29 to 70. Clinical and laboratory data from these studies were reviewed in aggregate to evaluate the occurrence of autoimmune toxicities. Of 91 evaluable patients, vitiligo was documented in 6 patients (7%). In addition, one patient experienced transient severe insulin-dependent diabetes that resolved after discontinuing IL-2, and another experienced an exacerbation of his pre-existing diabetes; these occurrences are consistent with an autoimmune insulitis. Four occurrences (4%) of transient minor ocular toxicity were documented, but no autoimmune ocular toxicities or changes in visual acuity were found. Of 55 evaluable patients, 14 experienced thyroid abnormalities (25%). These were attributed to an autoimmune thyroiditis, which was supported by findings of antithyroid antibodies in three of the seven patients evaluated. Overall, autoimmune toxicities affecting several organ systems were observed in patients receiving melanoma vaccines in conjunction with low-dose IL-2. None of these toxicities caused major long-term effects, though one was acutely life-threatening and others contributed to treatment-related morbidity. Peptide- or cell-based vaccines administered in combination with low-dose IL-2 appear to be capable of breaking tolerance to self-antigens; despite the associated toxicities, these combinations may still be useful to administer as an immunotherapy for cancer. However, careful monitoring for autoimmune toxicities should be incorporated in future clinical studies incorporating low-dose IL-2.

Adult↗

PubMed2006

Systemic autoimmune disorders in celiac disease.

PURPOSE OF REVIEW: Celiac disease is an immune-mediated disorder clinically characterized by a multitude of symptoms and complications. The comorbidity between celiac disease and other autoimmune disorders has been clearly established. RECENT FINDINGS: Two main theories have been postulated to explain this comorbidity: (1) linkage disequilibrium between the genes responsible for celiac disease and those responsible for the coexpressed autoimmune diseases or (2) untreated celiac disease leading to the onset of other autoimmune diseases. This article reviews the current literature supporting either theory and places the current knowledge in the field within the context of the most recent data on the pathogenesis of celiac disease. SUMMARY: The current literature did not clearly establish which of the two theories explain the comorbidity between celiac disease and other autoimmune disorders. There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.

Animals↗