Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group.
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Antigen-Antibody Reactions↗
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Burst of autoimmunity with the emergence of primary Sjogren syndrome, cholestatic autoimmune hepatitis and latent autoimmune diabetes of adults (LADA).
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Adult↗
Autoimmunity: concepts and diagnosis at the cutting edge. Proceedings of the Fourth International Congress on Autoimmunity supported by the American Autoimmune Related Diseases Association and the Associazione Patologie Autoimmuni Internazionale. November 3-7, 2004. Budapest, Hungary.
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Animals↗
Contemporary concepts of autoimmunity and autoimmune diseases.
No single theory or mechanism can explain the phenomenon of autoimmunity and autoimmune diseases. Not all autoimmune responses are harmful or "forbidden." Considerable research has indicated that autoimmune response may be normal and important in the regulation of the immune system. Autoimmunity may play a role in a wide range of clinical states including physiological clearance of dead cells, and cell components, aging, response to viral and microbial infections, and generalized immunological diseases. There are many factors involved in autoimmunity including genetic, hormonal, immunological, and environmental factors. The susceptibility to autoimmune diseases is multifactorial and polygenic. There is a definite association of the autoimmune diseases with MHC alleles. Also, non-MHC genes are involved in disease susceptibility. Numerous mechanisms of autoimmunity have been discussed. There may be an alteration with dysregulation of the immune system with defective generation of normal suppressor mechanisms or an altered neuroendocrine regulation. The altered immune system will make the host more susceptible to autoimmune disease. Autoimmune reactions can occur in a host with a normal immune system. Some examples are as follows: 1. Infection or damage to host target organ with release or alteration of autoantigen 2. Molecular mimicry or cross-reactivity between virus or bacteria and host autoantigens 3. Abnormal expression of MHC molecules by antigen-presenting cells in target cells resulting in activation of autoreactive T-cells. 4. Drug administration
Autoantigens↗
[Fatal bleeding complications caused by Evans syndrome (autoimmune thrombocytopenia and hemolytic anemia) and type II autoimmune hepatitis in a 56-year-old patient].
BACKGROUND: Autoimmune hepatitis is a rare form of hepatitis of nonviral origin. Two main subentities have been described. The classical lupoid hepatitis (type I) is characterized by hypergammaglobulinemia and the presence of lupus erythematosus cells due to antinuclear antibodies. Autoimmune hepatitis type II, which is associated with antiliver/kidney microsomal antibodies type 1 (LKM 1) shows a more aggressive clinical course than autoimmune hepatitis type I and is frequently (41% of cases) associated with other immunologic diseases. CASE REPORT: In the present study we report a case of autoimmune hepatitis Type II, associated with autoimmune thrombocytopenia and hemolytic anemia, in a 56-year-old patient. The patient's death was caused by a fatal association of a failing coagulation system due to liver dysfunction and a severe autoimmune thrombocytopenia. The aggressive course of the thrombocytopenia even after splenectomy demonstrated that the splenic enlargement due to the portal hypertension was only a minor factor in the destruction of the thrombocytes. Interestingly, some findings of this case such as the advanced age, the presence of anti-smooth muscle antibodies and HLA-DR4 are usually associated with autoimmune hepatitis type I. CONCLUSION: The findings of this case indicate that concomitant autoimmune diseases can worsen the prognosis of autoimmune hepatitis. Prednisolone and azathioprine might not be sufficient to treat aggressive forms of autoimmune hepatitis. Immunosuppressive regimens administered to recipients after organ transplantation might be used as a therapy of autoimmune hepatitis in multicenter clinical trials.
Anemia, Hemolytic, Autoimmune↗
Virus and autoimmunity: induction of autoimmune disease in mice by mouse T lymphotropic virus (MTLV) destroying CD4+ T cells.
Neonatal infection of the mouse T lymphotropic virus (MTLV), a member of herpes viridae, causes various organ-specific autoimmune diseases, such as autoimmune gastritis, in selected strains of normal mice. The infection selectively depletes CD4+ T cells in the thymus and periphery for 2-3 wk from 1 wk after infection. Thymectomy 3 wk after neonatal MTLV infection enhances the autoimmune responses and produces autoimmune diseases at higher incidences and in a wider spectrum of organs than MTLV infection alone. On the other hand, inoculation of peripheral CD4+ cells from syngeneic noninfected adult mice prevents the autoimmune development. These autoimmune diseases can be adoptively transferred to syngeneic athymic nude mice by CD4+ T cells. The virus is not detected by bioassay in the organs/tissues damaged by the autoimmune responses. Furthermore, similar autoimmune diseases can be induced in normal mice by manipulating the neonatal thymus/T cells (e.g., by neonatal thymectomy) without virus infection. These results taken together indicate that neonatal MTLV infection elicits autoimmune disease by primarily affecting thymocytes/T cells, not self Ags. It may provoke or enhance thymic production of CD4+ pathogenic self-reactive T cells by altering the thymic clonal deletion mechanism, or reduce the production of CD4+ regulatory T cells controlling self-reactive T cells, or both. The possibility is discussed that other T cell-tropic viruses may cause autoimmunity in humans and animals by affecting the T cell immune system, not the self Ags to be targeted by the autoimmunity.
Adoptive Transfer↗
[Usefulness of autoantibodies in the study of autoimmune liver diseases and prevalence of autoimmune extrahepatic manifestations].
BACKGROUND: Autoantibodies are prominent findings in the diagnosis of autoimmune liver diseases. However, their usefulness is limited due to the high reported prevalence in others nonautoimmune disorders. The purpose of this report was to assess the significance of these markers in patients with autoimmune liver diseases and to determine the prevalence of extrahepatic autoimmune phenomena. METHODS: We evaluated the samples from all the patients with altered biochemical liver parameters (ALT, AST, alkaline phosphatase or bilirubin) and a complete profile of autoimmunity [Anti-nuclear (ANA), anti-mitocondrial (AMA), anti-smooth muscle (SMA) and anti-liver/kidney microsomes (LKM1) antibodies] received in the Immunology Laboratory from 1993 to 1996. The records of the patients with at least one positive serologic marker were retrospectively reviewed. Autoimmune liver diseases (Autoimmune hepatitis (AIH), Primary biliary cirrhosis (PBC) and Overlap syndromes) were diagnosed according to composite clinical, analytical, histological or response-to-treatment parameters. RESULTS: Samples from 548 patients were analyzed. Of these 85 (15.5%) were positive for at least one antibody. Disorders and autoantibodies were: Autoimmune liver diseases: 18 (4 AIH, 11 PBC, 3 Overlap syndromes); alcohol-induced liver disease: 14 (5 ANA, 9 SMA), Chronic HCV infection: 28 (9 ANA, 17 SMA, 2 ANA + SMA), Chronic HCV + AIH: 2 (1 ANA, 1 ANA + SMA); other liver diseases: 7 (4 ANA, 1 AMA, 2 SMA); other diseases with liver involvement: 10 (8 ANA, 2 SMA); no liver disease (normal): 6 (3 ANA, 1 AMA, 2 SMA). In 75% (64/85) of the positivities processes regarded as immunological liver disease were not found. We identified in 12 out of 20 patients with autoimmune liver diseases others autoimmune extrahepatic processes; in 4 before a diagnosis of liver disease was made. CONCLUSIONS: Autoimmune serologic markers are useful in the study of liver diseases. However, due to inespecifity each individual patient deserves a careful evaluation. Autoimmune extrahepatic manifestations are often found and in some cases allow to recognize the hepatic involvement.
Autoantibodies↗
Infection, autoimmunity and autoimmune disease.
Studies of the immune response of mammals to infectious agents have revealed that members of the hsp60 and hsp 70 family are highly immunodominant. Given their high conservation during evolution this was surprising, because of the apparent risk of triggering of autoimmunity and autoimmune disease during the defense of a mammal against infection. However, detailed studies of the immune responses to HSP in models of autoimmune diseases in animals resulted in a change of the view that autoimmunity necessarily leads to autoimmune disease. It has been found that modulation of autoimmunity to HSP is one way to prevent autoimmune disease. At least in some cases even treatment of autoimmune diseases by immunization with heat shock protein appears feasible. This was shown in adjuvant arthritis in Lewis rats and insulin dependent diabetes in NOD mice. Hsp60 and hsp70 are ubiquitous proteins. Their involvement in regulatory loops of autoimmunity may serve as basis for the development of strategies, to prevent and/or treat autoimmune diseases even without knowledge of the causative (auto-)antigen.
Animals↗
Comparison of differentially expressed genes in T lymphocytes between human autoimmune disease and murine models of autoimmune disease.
A general view is that critical genes involved in biological pathways are highly conserved among species. To understand human autoimmune diseases, a great deal of effort has been devoted to the study of murine models that mirror many pathologic properties observed in the human disease. We have found that lymphocytes from humans with different autoimmune disease all carry a common conserved gene expression profile. Therefore, we wanted to determine if lymphocytes from common murine models of autoimmune disease carried a gene expression profile similar to the human profile and if both mouse models carried a shared gene expression profile. We identified numerous differentially expressed genes (DEGs) in the autoimmune strains compared to non-autoimmune strains. However, we found very little overlap in the gene expression profile between human autoimmune disease and murine models of autoimmune disease and between different murine autoimmune models. Our research further confirms that murine models of autoimmunity do not perfectly match human autoimmune diseases.
Animals↗
Elucidation of autoimmune disease mechanism based on testicular and ovarian autoimmune disease models.
This paper describes several selected models of autoimmune disease of the gonads. Based on these findings, I have reviewed current knowledge concerning the tolerance mechanisms that normally prevent gonadal autoimmunity, the potential events that can overcome such mechanism to trigger autoimmune diseases. In addition we also summarize the immunopathology of orchitis and our understanding of the mechanisms responsible for the immunopathology of the disease. Recent studies indicate that pathogenic T cells capable of eliciting autoimmune diseases in these organs develop in both the neonatal and adult thymuses and they persist in the normal peripheral immune system. However, the function of the pathogenic T cells in adult mice is normally under the control of regulatory T cells which maintain peripheral tolerance, and important phenotypic differences are being defined between these two functional CD4+ T cell subsets. When the clonal balance of these T cell subsets is tipped in favor of pathogenic T cells, autoimmune diseases of the gonads could ensue. Pathogenic T cells responsible for autoimmune oophoritis can be activated through stimulation by non-ovarian peptides that cross-react with self ovarian peptides at the level of the T cell receptor. This novel form of antigen mimicry depends in part on the sharing, between unrelated peptides, the few critical amino acids required for activation of pathogenic T cells. Antibodies can bind to the ovarian target antigens during the development of autoimmune orchitis and autoimmune oophoritis. However, the precise role of antibody in these autoimmune diseases has not been critically explored. In this study, I have described a novel mechanism of autoantibody induction. Immunization of female mice with a pure T cell peptide from ZP3 can lead to the production of antibodies against ZP3 domains outside the immunogenic ZP3 peptide. Evidently, endogenous antigens from normal and pathologic ovaries may reach peripheral immune tissues, and provide the antigenic stimulus to trigger an autoantibody response. This occurs at the same time when activation of ZP3 specific T cells is detected, and it is not simply a consequence of tissue injury. Importantly, the autoantibodies react with native antigenic determinants, and are potentially important in autoimmune disease pathogenesis.
Animals↗
Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used.
Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)-a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.
Adult↗
Latent autoimmune diabetes in adults (LADA) and autoimmune thyroiditis.
Latent autoimmune diabetes in adults (LADA) is characterized by clinical presentation as type 2 diabetes after 25 years of age, initial control achieved with diet or oral hypoglycaemic agents during at least 6 months, presence of autoantibodies (first of all GADA) and some immunogenetic features of diabetes mellitus type 1. In patients with an autoimmune endocrine disease, which could be also autoimmune diabetes, there is a high risk of development of another autoimmune endocrine disorder. The coexistence of two or more autoimmune endocrine diseases is pathognomonic for autoimmune polyglandular syndrome. Autoimmune thyroiditis and type 1 diabetes mellitus are the most common combination of autoimmune endocrine diseases reported. Most studies reported the prevalence of autoimmune thyroiditis in "typical" type 1 adult diabetic subjects about 20 - 40%. Little is known about the prevalence of autoimmune thyroiditis in subjects with LADA. Only a few studies confirmed a high prevalence of thyroid autoantibodies in type 2 diabetic subjects with GADA compared to type 2 diabetic subjects without GADA and compared to non-diabetic population too.
Adult↗
The coexistence of systemic lupus erythematosus with other autoimmune diseases: the kaleidoscope of autoimmunity.
Patients with systemic lupus erythematosis (SLE) often manifest features of other autoimmune diseases. In this review, we provide a detailed compendium of features of SLE that overlap with other conditions. This compendium is important because a critical feature in our understanding of autoimmunity has been the clustering of coexisting/different autoimmune diseases both within an affected patient and within a pedigree. Indeed, autoimmune disorders share a variety of similar clinical and serological defects. For example, all autoimmune disorders are associated with the elaboration of autoantibodies and/or the production of self-reactive mononuclear cell populations; many have high levels of immune complexes and defects in cell-mediated immunity. Several diseases share similar genetic backgrounds, as reflected by study of loci within the major histocompatibility complex. In part the coassociation is due to common genetic tendencies with different environmental precipitating agents (trigger mechanisms). It is likely that many factors can modulate the immune system to autoimmunity in the presence of an appropriate genetic background, eg, drugs, viral infections, UV irradiation, and toxins, ie, toxic oil syndrome and L-tryptophan-induced eosinophilic myalgia. The coexistence of SLE with other autoimmune diseases is an excellent venue to understand these events, and we believe that the presence of other autoimmune diseases in patients with SLE can be called the kaleidoscope of autoimmunity.
Autoimmune Diseases↗
Thymus and autoimmunity: capacity of the normal thymus to produce pathogenic self-reactive T cells and conditions required for their induction of autoimmune disease.
BALB/c athymic nu/nu mice spontaneously developed organ-specific (gastritis, thyroiditis, oophoritis, or orchitis) and systemic (arteritis, glomerulonephritis, and polyarthritis) autoimmune diseases when transplanted with neonatal BALB/c thymuses. Transplantation of thymuses from adult BALB/c mice was far less effective in inducing histologically evident organ-specific autoimmune disease in nu/nu mice. Autoimmune disease developed, however, when adult thymuses were irradiated at a T cell-depleting dose before transplantation. Engrafting newborn thymuses into BALB/c mice T cell depleted by thymectomy, irradiation, and bone marrow transplantation produced similar organ-specific autoimmune disease as well, but thymus engrafting into T cell-nondepleted BALB/c mice (i.e., mice thymectomized as adults, but not irradiated) did not, despite the fact that transplanted thymuses grew well in both groups of mice. The mice with organ-specific autoimmune disease produced autoantibodies specific for the respective organ components, such as gastric parietal cells, thyroglobulins, oocytes, or sperm. The thymus-transplanted nu/nu mice also had hypergammaglobulinemia and developed anti-DNA autoantibodies, rheumatoid factors, and immune complexes in the circulation. These results indicate that: (a) the thymus of a murine strain that does not develop spontaneous autoimmune disease can produce pathogenic self-reactive T cells that mediate organ-specific and/or systemic autoimmune diseases; and (b) such self-reactive T cells, especially those mediating organ-specific autoimmune disease, spontaneously expand and cause autoimmune disease when released to the T cell-deficient or -eliminated periphery.
Animals↗
Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells.
Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4+ T cells mediated the autoimmune prevention but CD8+ T cells did not. CD4+ T cells also appeared to mediate the TLI-induced autoimmune disease because CD4+ T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells.
Animals↗
Autoimmune diabetes: the involvement of benign and malignant autoimmunity.
Our studies in the NOD mouse demonstrate that the autoimmune response can be either benign or malignant. In the former case </=10% of the islets in the pancreas are damaged. The latter is associated with massive islet damage which leads to the development of clinical disease within 2-3 weeks. From the time of weaning up to 70-80 days of age all male and female NOD mice are in a benign state of autoimmunity. After that time animals move, in an unpredictable way, into the malignant state of autoimmunity. As a result, animals >/=100 days of age make up a heterogeneous group where some are in a benign state of autoimmunity, which can continue for a further |LX200 days, others are in a state of transition to the malignant state of autoimmunity, and others have a fully malignant autoimmune response and are diabetic. This heterogeneity developing within members of the population, in terms of pancreatic damage, is not consistent with the proposal that autoimmune islet damage in the NOD mouse is a slow, progressive process affecting all disease prone members of the population. In the NOD mouse, massive islet destruction is a late event in the autoimmune process and only develops following the conversion of the autoimmune response from the benign to the malignant state.
Animals↗
Maternal-fetal immunology and autoimmune disease: is some autoimmune disease auto-alloimmune or allo-autoimmune?
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Autoantigens↗
[Symposium on clinical aspects and pathogenesis of autoimmune diseases. (2). Autoimmune diseases of the hematopoietic system with special reference to autoimmunity to red blood cells].
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Adolescent↗