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The pathogenesis of autoimmunity remains an enigma; however, growing evidence points to a possible involvement of lymphokines both in the initiation phase and especially in the effector stage of many autoimmune diseases. Although no single experimental approach can accurately mimic the highly complex interplay of genetic, hormonal, and immune factors inherent in the development of autoimmunity, several lines of evidence strongly suggest a major role for lymphokines, in particular interferons (IFN), tumor necrosis factor (TNF), and interleukins 1 and 2 (IL-1, IL-2). These include the pleiotropic biologic activities of lymphokines which often synergize and interact, and can mediate several prominent clinical and laboratory manifestations of autoimmunity. Patients undergoing therapy with IFN or IL-2 may develop varied autoimmune syndromes, often an exacerbation of previously latent autoimmunity. Likewise, the administration of IFN to experimental animals can cause or accelerate autoimmune disease and, more importantly, specific lymphokine blockade was shown to be protective. Moreover, in the animal models of autoimmunity and in many patients with autoimmune diseases, increased lymphokine levels can be demonstrated either in the circulation or locally, often correlating with disease activity. Finally, aberrant MHC class II expression on nonlymphoid cells can be identified in the target organs of most autoimmune diseases and extensive data suggest that it can present autoantigen, activate autoreactive T cells, and initiate a cascade of self-propagating autoimmunity. Thus, a local release of IFN-gamma, the major inducer of MHC class II, may be pivotal to the development of organ-specific autoimmunity. The central role of cytokines in lymphocyte traffic into inflammatory sites as well as a growing understanding of lymphokine production patterns by different T cell subsets important in autoimmunity lends further support for this hypothesis, at the same time revealing that certain lymphokines may have a protective inhibitory effect on autoimmunity (e.g., IL-4, TGF-beta). In conclusion, varied data strongly suggest that several lymphokines, produced mainly locally and interacting with each other, have an important role in the pathogenesis of autoimmunity. Although the initiating events and complex interactions remain largely unclear, recent advances are encouraging, and may lead to specific manipulations of lymphokines in the future treatment of autoimmune diseases.
UNLABELLED: Hepatitis C virus (HCV) was identified in 1989 as a primary aetiologic agent of parenterally transmitted non-A non-B hepatitis and a major cause of acute and chronic hepatitis worldwide [1, 2]. Extrahepatic manifestations that are associated with chronic HCV infection include: type II cryoglobulinaemia, membranoproliferative glomerulonephritis, porphyria cutanea tarda, Sjogren syndrome, autoimmune thyroiditis, lichen planus, etc. [3, 4]. Likewise, there is a very interesting link between HCV and autoimmune hepatitis type I [5-7]. The second generation of immunoassays confirmed positive anti HCV in a relatively low percent of patients (0-5%) with autoimmune hepatitis type I [5-7]. This fact suggests that HCV infection is not an important factor in the pathogenesis of autoimmune hepatitis, but it is not excluded. The examination of autoimmune markers is highly significant for the proper decision of the therapy: interferon therapy leads to exacerbation of autoimmune hepatitis, while corticosteroids enhance virus replication in patients with HCV infection. There is a percentage of patients suffering from both diseases, and in this case the therapeutic strategy is the treatment of predominant disease. The aim of the study was to establish the proper diagnose and make an adequate therapeutic decision in HCV infection combined with positive autoantibody findings. PATIENTS AND METHODS: In our study forty nine patients with HCV infection of autoimmune markers are described. Diagnosis of HCV infection was confirmed by clinical, biochemical, serological and histological examinations. ANA, AMA, and ASMA as non-specific autoimmune markers have been studied. Significant titre of ANA is 1:80, AMA 1:40 and ASMA 1:20 or higher. The patients included in the study were HBsAg negative, anti-HCV positive (at least six months) and had no sign of any other chronic disease, such as Morbus Wilson, alpha-1-antitrypsin deficiency or haemochromatosis. RESULTS: The relevant data on patients are shown in Table 1. It is evident that 45% of patients had no known risk factors. The results of autoantibody are shown in Table 2. Eleven patients (22%) had autoantibodies, of whom one had 1:40 titre of ANA, while three had 1:80 titre of ASMA. Positive titre of AMA 1:40 was found in two patients. The distribution of relative autoantibody concentrations showed insignificant titres. The interferon therapy was used in five HCV RNA positive cases without progression. DISCUSSION: Pathologic immune responses are sometimes the primary cause of autoimmune disorder, and sometimes the second one. The best studied factors that produce autoimmune disorder, are viruses. Probably the best evidence of virus aetiology of autoimmune hepatitis is the presence of anti-HCV antibody in some patients with autoimmune hepatitis type 1. Our clinical trial revealed the presence of autoantibodies in 22% of patients who suffered from HCV infection. These results are very similar to those of other authors [3, 5, 6, 16]. From the clinical point of view all patients can be divided into three groups: 1) The first group consists of patients with false positive results of anti-HCV and "true" autoimmune hepatitis type 1. Corticosteroid treatment is recommended. 2) The second group consists of patients with HCV infection and low percent of autoantibodies titres. These patients should be treated with alpha-interferon. 3) The third group consists of patients suffering from both diseases: chronic hepatitis C and autoimmune hepatitis. In this case, the initial treatment should start with corticosteroids (as low risk therapy) but if the progression is still on, corticosteroids should be substituted by interferon therapy. Our patients belonged to the second group, because of nonspecific titres of relative autoantibody concentrations. Our conclusion was that none of these patients had autoimmune hepatitis but certain autoimmune phenomena. The interferon therapy was used in five HCV RNA positive cases without
To advance understanding of autoimmunity associated with exposure to environmental factors, an "Exploratory Meeting Epidemiology on Occupational and Environmental Factors Associated with Autoimmunity" was organized in Bilthoven, the Netherlands, from May 10-12, 2000. Even if no firm conclusions can be drawn on a role of certain chemicals in the environment and in the work place in causing or exacerbating autoimmune responses and illnesses, many indications of this to occur exist. The aim of the meeting was to determine the optimal methodology for assessment of autoimmunity associated with occupational or environmental exposures in the human population, and to set up interdisciplinary and collaborative epidemiological studies to investigate the association of exposure to silica, hexachlorobenzene, ultraviolet radiation, and other agents with autoimmunity and autoimmune diseases in the human population. These agents were selected as carrying particular suspicion at present. It was concluded that there is a need for experimental studies in laboratory animals and for clinical investigations to improve scientific knowledge about the causes and mechanisms of environmentally-induced autoimmune disorders and their treatment; in addition there is a need for an interdisciplinary approach to epidemiological studies of the environmental and other causes of these disorders in human populations. Specific designs for epidemiological studies in this context, as well as laboratory assays for health outcomes, were reviewed. Several recommendations for the epidemiological approach to evaluating effects of environmental or occupational agents on autoimmunity were made. The prime recommendations are the following: 1) systematic descriptive epidemiological data on autoimmunity and autoimmune disorders are required; 2) the establishment of disease-reporting registries should be encouraged; 3) the development of internationally accepted standard diagnostic criteria for all autoimmune diseases should be encouraged; 4) the social impact of these disorders should be evaluated and estimations of direct and indirect economic costs should also be made; 5) the methods of exposure assessment used in epidemiological studies should be standardized; 6) laboratory methods for measurement of biological responses should be standardized; and 7) the inclusion of indicators of autoimmunity and autoimmune diseases and of relevant environmental exposures in ongoing epidemiological studies should be encouraged. The importance of studying environmental causes of autoimmune diseases and autoimmunity lies in the identification and prevention of risks to the public health, and in improving our knowledge of basic mechanisms of health and disease.
Autoimmunity may be observed in chronic viral hepatitis, in particular hepatitis C and D. The hepatitis C virus (HCV) displays numerous interactions with the immune system. Hepatitis C virus induces a number of diseases of presumed autoimmune background, like mixed cryoglobulinaemia, glomerulonephritis, panarthritis, arthritis, thyroiditis and skin lesions. On the other hand a number of autoantibodies are observed during the course of hepatitis C. Of particular interest are liver/kidney microsomal antibodies (LKM). Their occurrence in viral hepatitis may indicate an increased risk for treatment with interferons. LKM antibodies in chronic hepatitis C recognize several autoepitopes differing from those in autoimmune hepatitis. Hepatitis C-associated LKM antibodies are more heterogeneous. They recognize either conformational or several distinct linear autoepitopes on cytochrome P450 2D6; they may also react with other microsomal proteins. Apart from their molecular weight at 59 and 70 kDa these microsomal antigens are not yet identified. Another model of virus-induced autoimmunity in man is chronic hepatitis D which always requires co-infection with hepatitis B. Hepatitis D is known to be associated with a number of autoantibodies, amongst them LKM-3. LKM-3 antibodies have recently been shown to react with proteins of the UDP glucuronosyltransferase family (UGT). The main antigen is an autoepitope expressed on exon 2-5 of family 1 UGTs. Some hepatitis D sera recognize a minor second epitope on family 2 UGTs. It is interesting that hepatitis C patients recognize proteins of the cytochrome P450 family while hepatitis D sera react with UGTs. There seems to be little overlap between autoimmunity seen in hepatitis C and D as far as autoepitopes are concerned. LKM-3 antibodies against UGT 1 are also seen in a minority of patients with autoimmune hepatitis type 2. However, the autoimmune response against UGTs seen in autoimmune hepatitis differs from that observed in viral hepatitis. Autoantibodies in autoimmune liver disease are usually more homogenous and are directed against precise linear epitopes. Autoepitopes in autoimmune hepatitis usually represent conserved regions of these proteins, the antibody usually is inhibitory and antibody titres are very high. In contrast, autoantibodies in viral hepatitis are more heterogenous, recognize several linear and conformational epitopes; antibody titres are much lower. However, the major LKM autoantigen in chronic hepatitis C also is P450 2D6. Autoimmune hepatitis and autoimmunity in viral hepatitis must be distinguished clinically by all means due to the need for specific therapeutic interventions. These liver diseases may serve as models to study virus induced autoimmunity and autoimmune disease in man.
BACKGROUND: Chronic urticaria has been described in patients with Helicobacter pylori infection. Despite numerous studies, the correlation between H. pylori infection and chronic urticaria is doubtful. Our study was performed to determine the prevalence of H. pylori infection in autoimmune urticaria and in patients suffering from autoimmune urticaria and autoimmune thyroiditis. METHODS: The authors widely investigated 48 patients. The examinations were extended principally to autologous serum skin test, antithyroid antibodies, and the presence of H. pylori infection as well as detection of antibodies against H. pylori. RESULTS: Out of the 48 patients, 26 were regarded as having autoimmune origin. The prevalence of antithyroid antibodies was different in the two groups of patients with urticaria. There were 11 patients (42.3%) in the autoimmune group compared with three patients (13.6%) in the nonautoimmune group with antithyroid peroxidase antibody (P = 0.03). The difference in the prevalence of H. pylori infection was significant between autoimmune urticaria with and without thyroid autoimmunity (90.9% vs. 46.7%; P = 0.02). Autoimmune thyroiditis was connected with CagA +H. pylori strains, as the H. pylori- specific IgG antibodies revealed significant differences in a prevalence of 120 kDa (P < 0.05). CONCLUSIONS: The authors observed a relationship between autoimmune urticaria and autoimmune thyroiditis. The results strengthen the possibility of cross-reactivity being triggered between CagA plus H. pylori strains and some other organ-specific autoimmune diseases such as autoimmune urticaria and autoimmune thyroiditis. This indicates a possible role of H. pylori in triggering autoimmune urticaria in at least a select group of patients.
Autoimmune diseases are traditionally viewed as an outcome of a chaotic situation in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis, a disease of the white matter of the central nervous system (CNS), the immune attack is directed against myelin proteins. In this article, the authors propose a paradigm shift in the perception of autoimmune disease. They suggest that an autoimmune disease may be viewed as a by-product of the malfunctioning of a physiological autoimmune response whose purpose is protective. The proposed view is based on observations by their group suggesting that an autoimmune response is the body's own mechanism for coping with CNS damage. According to this view, all individuals are endowed with the potential ability to evoke an autoimmune response to CNS injuries. However, the inherent ability to control this response so that its beneficial effect will be expressed is limited and is correlated with the individual's inherent ability to resist autoimmune disease induction. The same autoimmune T cells are responsible for neuroprotection and for disease development. In patients with CNS trauma or neurodegenerative disorders, it might be possible to gain maximal autoimmune protection and avoid autoimmune disease induction by boosting the immune response, using myelin-associated peptides that are nonpathogenic or antigens that simulate the activities of such peptides. In patients with multiple sclerosis and other neurodegenerative diseases, where the aim is to block the autoimmune disorder while deriving the potential benefit of the autoimmune response, the effect of treatment should be immunomodulatory rather than immunosuppressive. In this article, the authors present a novel concept of protective autoimmunity and propose that autoimmune disease is a by-product of failure to sustain it. They summarize the basic findings that led them to formulate the new concept and offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals. The therapeutic implications of the new concept and their experimental findings are discussed.
OBJECTIVE: Diverse autoimmune diseases may coexist in the same individual and in families, implying a common etiology. We examined the aggregation of autoimmune diseases among first-degree relatives (FDR) of patients with primary Sjögren's syndrome (pSS). METHODS: This was a population-based case-control family study in which 101 families of women classified as having pSS according to the revised American-European criteria and 124 families of matched controls without autoimmune disease were enrolled to investigate the presence of autoimmune diseases. We performed a genetic analysis that included familial correlation and recurrent risk ratios. RESULTS: In family cases, 38% had at least one FDR with an autoimmune disease, versus 22% in control families [odds ratio (OR) 2.2, 95% confidence interval (CI) 1.2-3.9, p = 0.01]. An autoimmune disease was registered for 7.3% of 876 patients' FDR as compared with 3.85% of 857 controls' FDR (OR 1.97, 95% CI 1.28-3.03, p = 0.002). The most frequent autoimmune diseases registered among the pSS patients' FDR were autoimmune thyroid disease (AITD), systemic lupus erythematosus, and rheumatoid arthritis, which disclosed aggregation. The proband phenotype (i.e., pSS) was correlated with AITD, systemic sclerosis, and all autoimmune diseases when considered together as a trait. Maternal transmission of the autoimmunity trait was observed in cases but not in controls. CONCLUSION: Our results indicate that autoimmune diseases cluster within families of patients with pSS. This familial aggregation of autoimmune diseases adds further evidence that clinically different autoimmune phenotypes might share common susceptibility gene variants, which acting in epistatic pleitropy may represent risk factors for autoimmunity.