Evidence for spontaneous immunosuppression in autoimmune hepatitis
ABSTRACT Autoimmune hepatitis (AIH) runs a variable clinical course. Slow disease progression or even spontaneous remissions can be observed and suggest that the autoimmune process can, at least to a certain extent, be controlled by regulatory elements of the patient's own immune system. In experimental autoimmune hepatitis (EAH) spontaneous recovery is regularly observed and associated with antigen-specific and antigen-nonspecific suppression. The aim of the current study was to search for similar immunoregulatory phenomena in patients with AIH. We examined T-cell reactivity to soluble human liver antigens in 11 patients with active autoimmune hepatitis and 30 patients with other liver diseases (chronic viral hepatitis, primary biliary cirrhosis, fatty liver). T-cell reactivity to liver antigens was almost exclusively confined to the AIH patients. In 9 of these 11 patients we were able to compare the T-cell response in active untreated disease, directly after initiation of immunosuppressive therapy and in remission, at which point T-cell reactivity was found to be markedly reduced. Addition of irradiated peripheral blood cells from the active disease phase or the remission phase to the responding cells taken before treatment showed that in eight of the nine patients there was marked suppression of the liver-specific T-cell response by cells from the remission phase. Study of the in vivo immune responsiveness by giving a tetanus toxoid booster immunization to nine patients with active untreated AIH as well as healthy controls and patients with other liver diseases showed that none of the patients with AIH showed a response to the tetanus immunization, whereas almost all the other patients showed marked responses. Taken together these results show the presence of active suppression of T-cell autoreactivity in vitro in AIH and marked nonresponsiveness to in vivo challenge with an unrelated antigen, suggesting generalized spontaneous immunosuppression that is more pronounced in vivo than what can be measured in vitro. Spontaneous immunosuppression, however, is not sufficient to effectively suppress the disease process. Immunosuppressive therapy is required for remission induction, but is apparently helped by the patient's own immunoregulatory activity. These observations support the concept of peripheral control mechanisms being operative in patients with AIH, and these could be the basis for a more effective and specific immunotherapy of this condition in the future. (Hepatology 1995;22:381–388.)
- SourceAvailable from: Matthias Hardtke-Wolenski[Show abstract] [Hide abstract]
ABSTRACT: Autoimmune hepatitis (AIH) is a chronic liver disease which is normally recognized during late stage of the disease. Due to limited knowledge about the onset and course of disease and need for chronic immunosuppression with significant side-effects there is a requirement for a good preclinical animal model, mirroring main characteristics of AIH. In addition to the exclusion of other liver diseases, AIH is characterized by elevated serum transaminases, specific autoantibodies and elevated gammaglobulins as well as a specific liver histopathology. A good preclinical model should mirror most of these criteria. In the last decades several models have been published using different approaches to break hepatic tolerance and induce liver damage. The induction of a chronic hepatitis similar to the human disease remained a difficult challenge. Nevertheless, these models helped to get more information about the aspects of AIH induction and liver immunology.Best practice & research. Clinical gastroenterology 12/2011; 25(6):643-51. · 2.48 Impact Factor
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ABSTRACT: Autoimmune liver diseases in humans are characterized by chronic active hepatitis with serum autoantibodies, hypergammaglobulinemia and liver pathology showing necroinflammatory disease and fibrosis. There are an increasing number of autoantigens believed to be associated with various autoimmune liver diseases. This review will briefly outline human autoimmune hepatitis and the immunology of the liver. Various murine models of liver inflammation will be discussed, including transgenic and non-transgenic models, with emphasis on how these models aid in our knowledge of the mechanisms of disease development and chronicity. There are limitations with all of the models, including a preponderance of T-cell-focused responses. Murine models do not easily develop fibrosis, a hallmark of autoimmune hepatitis in humans. Different experimental models may not reach the same conclusions with differences between immune responses. However, this multiplicity of responses does not necessarily imply that these models are inappropriate for the study of liver immunology and autoimmune liver diseases, as different autoantigens may induce different liver responses. Knowledge of how the liver differs from other immune organs is essential to further our understanding of liver-specific autoimmunity. The plethora of antigens implicated in autoimmune hepatitis in humans predicts that multiple mechanisms may play a role in precipitating disease in the susceptible individual.Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 05/2010; 18(5):397-400.
Article: Autoimmune hepatitis[Show abstract] [Hide abstract]
ABSTRACT: Autoimmune hepatitis (AIH) is a distinct form of acute and chronic inflammatory liver disease in which immune reactions against host antigens are found to be the major pathological mechanism. If left untreated it carries an unfavourable prognosis, and the diagnosis should be made as soon as possible. The diagnostic approach has been greatly facilitated by the establishment of a panel of marker autoantibodies, which do not define distinct therapeutic groups of AIH, but do allow a subgrouping based on differences in patient populations, some clinical features and prognosis. The characterization of organ-specific components of the liver cell surface as targets of cellular and humoral autoimmune reactions give new insights into the pathogenesis of the disease, even though the primary event triggering the disease remains to be defined. The most important diseasepromoting factor seems to be a genetically determined background for autoimmunity. Without this different environmental factors, including viruses, toxins, cytokines and drugs, are only able to induce transient autoimmune phenomena and not autoimmune disease. The histopathology of AIH is in keeping with the present pathogenetic concept. Although there is no pathognomonic feature distinguishing this type of hepatitis from virus-induced forms, some distinct morphological lesions are regarded as characteristic. Clinical research on AIH has benefited greatly from observations of experimental AIH in mice. Recognition of the critical role of autoreactive T-lymphocytes in the pathogenesis and the observation of spontaneous recovery from AIH in the animal model associated with antigen-specific and antigen-non-specific T-cell suppression have made basic contributions to our improved understanding of the natural course of AIH in humans.Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 08/1996; 429(1):1-12. · 2.68 Impact Factor