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There is a paradoxical relationship between immunodeficiency diseases and autoimmunity. While not all individuals with immunodeficiency develop autoimmunity, nor are all individuals with autoimmunity immunodeficient, defects within certain components of the immune system carry a high risk for the development of autoimmune disease. Inherited deficiencies of the complement system have a high incidence of systemic lupus erythematosus (SLE), glomerulonephritis, and vasculitis. Carrier mothers of children with chronic granulomatous disease, an X-linked defect of phagocytosis, often develop discoid lupus. Several antibody deficiencies are associated with autoimmune disease. Autoimmune cytopenias are commonly observed in individuals with selective IgA deficiency and common variable immune deficiency. Polyarticular arthritis can be seen in children with X-linked agammaglobulinemia. Combined cellular and antibody deficiencies, such as Wiskott-Aldrich syndrome, carry an increased risk for juvenile rheumatoid arthritis and autoimmune hemolytic anemia. Several hypothetical mechanisms have been proposed to explain the associations between autoimmunity and immunodeficiency. Immunologic defects may result in a failure to exclude microbial antigens, resulting in chronic immunologic activation and autoimmune symptoms. There may be shared genetic factors, such as common HLA alleles, which predispose an individual to both autoimmunity and immunodeficiency. Defects within one component of the immune system may alter the way a pathogen induces an immune response and lead to an inflammatory response directed at self-antigens. An understanding of the immunologic defects that contribute to the development of autoimmunity will provide an insight into the pathogenesis of the autoimmune process.
Before autoimmune diseases in humans can be treated with gene therapy, the safety and efficacy of the used vectors must be tested in valid experimental models. Monkeys, such as the rhesus macaque or the common marmoset, provide such models. This publication reviews the state of the art in monkey models for rheumatoid arthritis and multiple sclerosis and the (few) gene therapy experiments that have been performed in these models.
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Systemic autoimmune diseases are generally treated with immunosuppressive agents. In some instances immunomodulatory agents have shown promise in the treatment of certain types of autoimmune disorders. The in vitro and/or in vivo effects of some of these agents (glutaurine, ketoconazole, gutimine and its derivative) are demonstrated. Glutaurine exerts moderate immunostimulating activity, but fails to influence the clinical course of systemic lupus erythematosus. Although ketoconazole suppresses immune responses in vitro, it does not influence cellular reactivity of patients in vivo. The immunostimulatory activity of gutimine and its derivative (T 001) have been demonstrated in vitro, and need to be tested also in vivo.
AIM: To study the potential risk factors leading to peptic ulcer disease among autoimmune disease patients on corticosteroid treatment. METHODS: One hundred and thirty-eight corticosteroid-treated autoimmune disease patients were enrolled; their demographic data were recorded and laboratory data were measured. Endoscopy was performed to assess the occurrence of peptic ulcer disease. Helicobacter pylori infection was diagnosed on the basis of rapid urease test and histological examination. RESULTS: Twenty-eight (20%) of 138 autoimmune disease patients had peptic ulcer disease, including 17 with gastric ulcer, eight with duodenal ulcer and three with gastric ulcer plus duodenal ulcer. Eighty five (62%) had used non-steroidal anti-inflammatory drugs and 46 (33%) had H. pylori infection. The majority of peptic ulcer disease subjects showed the following characteristics: age >or= 60 years; male; smokers; non-steroidal anti-inflammatory drug users, particularly the non-specific cyclo-oxygenase inhibitors; presence of hyperpepsinogenaemia I; low H. pylori colonization (P < 0.05). Multivariate analysis revealed that an age >or= 60 years [odds ratio (OR), 6.80; P = 0.001], smoking (OR, 7.94; P = 0.004) and the use of non-specific cyclo-oxygenase inhibitors (OR, 4.71; P = 0.030) were the predominant risk factors for the development of peptic ulcer disease among these patients, whereas H. pylori infection showed a protective role (OR, 0.20; P = 0.022). CONCLUSIONS: Old age, smoking and the use of non-specific cyclo-oxygenase inhibitors are risk factors for peptic ulcer disease in autoimmune disease patients on corticosteroid treatment. H. pylori infection appears to protect against peptic ulcer disease in these patients.
Systemic autoimmune disorders may affect several organs, including the heart. We analyzed two-dimensional and pulsed Doppler echocardiograms of patients (n = 37) with systemic lupus erythematosus (SLE, n = 24) or rheumatoid arthritis (RA, n = 13) to determine whether atrial ejection force (AEF) could represent a suitable parameter for detecting left ventricular filling abnormalities in SLE and RA. In both patient subgroups, AEF was significantly higher than in healthy controls (n = 40) matched for gender and age (14.0 +/- 5.4 vs. 11.0 +/- 3.5 kdyn, p < 0.01). Because conventional echocardiographic parameters of left ventricular function failed to detect such a difference, AEF might serve as an additional sensitive parameter for detecting left ventricular diastolic filling abnormalities early in the course of a systemic autoimmune disease.
Most autoimmune diseases are responsive to corticosteroids administered in dosages sufficient to shut off the inflammatory process. The protocol outlined suppresses the most severe manifestations while minimizing toxic drug effects.
DNA vaccines represent one of the most significant developments in vaccine technology in recent years. Although, in general, studies have primarily focused on the induction of protective immune responses against infectious pathogens, the technology may prove useful for other immune-related diseases, including autoimmunity. Autoimmune disease results from a breakdown in tolerance to self antigens; however, the same fundamental immunological reactions that control immune responses to foreign antigens are also likely to operate during the course of autoimmune disease. These include the reciprocal regulation of Th cell subsets. Th1 cells appear to be involved in many organ-specific autoimmune diseases while suppression of disease is associated with cells of the Th2 phenotype. It has been possible, therefore, to suppress many of the pathological consequences of autoimmunity by manipulating the Th1/Th2 cell balance. The induction of Th2 responses by DNA immunization might therefore be expected to have a profound effect on the course of autoimmune disease. Indeed, we have demonstrated that DNA immunization can protect animals against the autoimmune central nervous system inflammatory disease, experimental autoimmune encephalomyelitis (EAE). As many other autoantigens have now been identified, the application of this technology to other autoimmune diseases warrants investigation.
Systemic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, continue to cause significant morbidity in affected persons. In the past few years, significant progress was made in understanding their pathogenesis and the underlying molecular mechanisms. As a result, a number of new exciting therapeutic options have become available, and novel therapeutic targets have emerged, including B-cell depletion therapies, B cell-activating factor of tumor necrosis factor family (BAFF) antagonists, and FcgammaRIIB receptor antagonists. Also promising is the current interest centered on the development of inhibition of signal transduction pathways, such as pharmacological inhibitors that act at various levels of signal transduction pathways.
Systemic autoimmune diseases are characterized by extensive alterations in immune system function, with cytokines and autoantibodies contributing to impaired immunoregulation and tissue damage. Characterization of the expression and function of cytokines is important for elucidation of pathogenic mechanisms and for identification of therapeutic targets and strategies. We reviewed the utility of assays that reflect individual variability in cytokine gene sequence, expression of messenger ribonucleic acid (mRNA) or protein, as well as measurement of expression of target genes regulated by cytokines. Real-time reverse transcriptase polymerase chain reaction and intracellular staining for cytokine expression are two sensitive and quantitative approaches for analysis of cytokine mRNA and protein, respectively. Detailed methods are provided for these assays.
Most autoimmune diseases (ADs) are still associated with high morbidity and mortality despite the use of a wide range of drugs that can delay their progression, control their symptoms, but never bring about a complete cure. This failure has aroused interest in new forms of monoclonal antibody-based experimental immunotherapy (IT), aiming at targeting cellular antigens or cytokines involved in the pathogenesis of ADs. The first part of this review offers a general overview of the molecular mechanisms that mediate the immune response and the molecule regarded as potential IT targets. A critical evaluation will then be made of some forms of IT, with particular emphasis on TNF-alpha and CD20-blocking reagents. Lastly an account will be given of active IT whereby an endogenous response against antigens regarded as the target of passive IT can be induced by anti-idiotype or peptides.
In autoimmune diseases, autoantibodies may be the actual pathogenetic agents of the disease, the secondary consequences of tissue damage, or the harmless footprints of an etiologic agent. Establishing a pathogenetic role for autoantibodies requires that they meet stringent criteria. It appears that the location of the presumptive target antigen most critically influences the pathogenetic potential of autoantibodies. Autoantibodies directed against cell surface targets, such as hormone receptors, are clearly pathogenetic; those directed against extracellular targets, such as circulating molecules or extracellular matrix, may or may not cause any damage. Those apparently directed against intracellular targets are usually not pathogenetic unless it can be clearly demonstrated (a) that the antigen is released from within the cell so that it can bind onto a cell surface receptor or other extracellular location, such as proteinase 3; (b) that the antigen moves to an aberrant site on the cell surface, such as, perhaps, the small ribonucleoprotein antigen Ro; or (c) that a cross-reactive molecule, the actual target, such as the membrane ribosomal P-like protein, is at an accessible location.
Polysystemic autoimmune diseases often cause orofacial and stomatognathic symptoms. Inflammation of the temporomandibular joint only rarely and slightly reduces the range of mouth opening (rheumatoid arthritis), which is much more restricted in systemic sclerosis due to fibrosis of perioral soft tissues. Weakness of masticatory and pharyngeal muscles in idiopathic inflammatory myopathies results in dysphagia and dystonia. Ulcerations, petechiae, teleangiectasia, and lichenoid lesions are the characteristic symptoms of oral mucosal involvement, but drugs used in systemic treatment can also cause very similar side effects. Salivary gland hypofunction (Sjögren's syndrome) is common, and in addition to the subjective complaints, leads to objective pathologic alterations such as oral mycotic infections, purulent sialadenitis, and increased caries prevalence. The side effects of steroid administration should be taken into account also during dental treatments. Regular dental follow-up and treatment is a basic part of the complex care of these patients in order to diagnose and cure oral abnormalities and salivary gland hypofunction in time. Impairment of hand functions (rheumatoid arthritis, scleroderma) reduces the oral hygienic activity and therefore special devices, local antiseptics and local fluoride preparations are necessary.
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Gene therapy (GT) is still at the 'experimental' stage and some recent setbacks have cooled the potential use of this therapeutic tool even in life-threatening conditions. However, this therapeutic approach has a potential, which is not limited to disease for which we have not other option. There are increasing evidence that GT will be soon used in diseases that are not life threatening. One group of diseases that can benefit from GT is the autoimmune one. Several experimental animal models have indicated the efficacy (proof of principle) of GT. In the present review, we have addressed the possibility that even extremely benign autoimmune-like diseases such as Celiac Disease (CD) might one day profit from this type of therapy. We further point that in conditions such as CD, where the trigger is well known and the pathogenic cascade is relatively well defined, a situation not common in autoimmunity, we can even have a better situation where to explore and use GT to control disease initiation and progression. Once the risks that are still intrinsic to GT will have been reduced the therapeutic options we outline in the present review might not appear too far from reality.
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