SEARCH · PubMed Health

Results for “Autoimmunity”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 757 records · Page 42Linked to original sources

PubMed2005

Coeliac disease, autoimmune diseases and gluten exposure.

OBJECTIVE: Gluten-free diet treatment has been proposed to prevent the development of autoimmune diseases in coeliac subjects. The aim here was to investigate the occurrence of autoimmune disorders in relation to gluten intake in coeliac patients in a well-defined area. MATERIAL AND METHODS: The frequency of autoimmune disorders was evaluated in 703 adults and children with coeliac disease and in 299 controls with normal duodenal histology. Incidence figures were given per 10,000 person-years. In logistic regression analysis, where the prevalence of autoimmune disorders was a dependent variable, the effect of age at end of follow-up, age at diagnosis of coeliac disease, actual gluten exposure time, gender and diagnostic delay were assessed. RESULTS: The prevalence of autoimmune diseases was significantly higher in coeliac subjects than in controls. In logistic regression analysis, age at end of follow-up, age at diagnosis of coeliac disease and female gender increased the risk of autoimmune disorders, whereas actual gluten exposure time reduced the risk; diagnostic delay had no effect. A similar, though not statistically significant, trend was seen in childhood coeliac disease to that in the whole study group. CONCLUSIONS: Despite that fact that patients with coeliac disease are at increased risk of various autoimmune conditions, the duration of gluten exposure seems not to be of crucial importance in the development of autoimmune diseases.

Adolescent↗

PubMed2003

Autoimmunity as the most frequent cause of idiopathic secondary adrenal insufficiency: report of 111 cases.

The origin of the isolated secondary adrenal insufficiency is unknown in most cases. An observation of a group of over 100 patients with secondary adrenal insufficiency and coexisting autoimmune abnormalities suggests that autoimmunity could be a frequent cause of idiopathic secondary failure, similarly as in Addison's disease. We studied 176 patients with idiopathic isolated secondary adrenal insufficiency. The methods included clinical examination and measurements of pituitary, adrenal, thyroid and gonadal hormones in all the cases. Since thyroid autoimmunity has been the most frequent finding in Addison's disease we have also chosen thyroid autoantibodies as markers of an autoimmune process in our material. Anti-peroxidase, anti-microsomal and anti-thyroglobulin autoantibodies were determined in 151 patients. In 111 out of 151 patients (73%) coexisting autoimmune diseases and/or presence of thyroid autoantibodies were detected. The most frequent autoimmune diseases associated with secondary adrenal insufficiency were primary hypothyroidism, hyperthyroidism (mainly in the past) and premature ovarian failure. Thyroid autoantibodies, especially antiperoxidase autoantibodies, were present in 106 patients. Thus, coexistence of isolated secondary adrenal insufficiency with some autoimmune disorders in 73% of the patients under study suggests that autoimmunity is the most frequent cause of the idiopathic form of this disease.

Adolescent↗

PubMed1985

Polyglandular autoimmune syndromes.

Dysfunction of multiple endocrine glands may develop as the result of hypopituitarism, various infiltrative disorders, or an organ-specific autoimmune mechanism. When dysfunction of two or more endocrine glands occurs in association with circulating organ-specific antibodies directed against the involved glands, the term polyglandular autoimmune syndrome is applied. Characteristics of polyglandular autoimmunity include specific patterns of disease association and frequently a family history of similar involvement. The principal endocrine components of these syndromes are adrenal insufficiency, autoimmune thyroid disease, insulin-dependent diabetes mellitus, and premature gonadal failure. In addition, primary hypoparathyroidism is a key feature of one form of polyglandular autoimmunity that occurs in children. Several nonendocrine organ-specific autoimmune disorders are also associated with polyglandular autoimmunity, of which pernicious anemia is the most frequent. The underlying abnormality responsible for polyglandular autoimmunity is most likely a defect in T suppressor cell function, but there is evidence that aberrant expression of HLA DR antigens also plays an important role in the pathogenesis of these disorders.

Addison Disease↗

PubMed1995

Recent-onset autoimmune hepatitis. Biopsy findings and clinical correlations.

Whereas the histologic findings in clinically "chronic" autoimmune hepatitis have been well established, with piecemeal necrosis as a hallmark lesion, the histologic findings of clinically "acute" or recent-onset autoimmune hepatitis remain undefined. The goal of this study was to define more fully the liver histomorphology in patients with recent-onset autoimmune hepatitis. Twenty-six patients were identified at our institution who had well-characterized autoimmune hepatitis and had undergone a liver biopsy within 6 months of clinical presentation. A detailed histologic evaluation revealed evidence of chronic liver disease in 25 (of 26) patients despite the lack of correlating clinical chronicity. The histologic evidence of chronicity included, in addition to a portal lymphoplasmacytic infiltrate, bridging (septal) fibrosis (11 patients) and overt cirrhosis (four patients). Eighteen of these 25 cases with evidence of chronicity also showed zone 2 and 3 lobular hepatitis, including disarray and hepatocyte necrosis. A single case showed lobular hepatitis with confluent hepatocyte necrosis (submassive hepatocellular necrosis), but no evidence of chronic liver disease. Although autoimmune hepatitis remains in the differential diagnosis of lobular hepatitis, these data show that most patients with autoimmune hepatitis who undergo biopsy early in its clinical course will have histologic evidence of chronic liver disease. Most of these patients probably have a lobular "flare" in disease activity, which likely precipitated the clinical presentation. The findings herein reinforce the concept that autoimmune hepatitis is by definition a chronic disease and supports the proposal that the modifier "chronic" be eliminated from autoimmune hepatitis.

Adult↗

PubMed2001

Autoimmune hepatitis as a late complication of liver transplantation.

BACKGROUND: The development of de novo autoimmune hepatitis as a long-term complication after liver transplantation has been recently reported. The authors describe five liver allograft recipients who developed chronic hepatitis associated with autoimmune features. METHODS: Five of 155 liver transplant recipients at risk (2.5%) developed this particular form of graft dysfunction. The authors review the clinical records, liver histology, therapy, and outcome of these five patients. RESULTS: Patients included two boys and three girls. Median age at transplantation was 3.5 years (range, 0.5-14 years), median age at presentation was 9 years (range, 2-17 years), and median interval after transplantation was 5.1 years (range, 1.5-9 years). Indications for liver transplant included biliary atresia in four patients and primary sclerosing cholangitis in one patient. At the time of presentation, all patients were receiving cyclosporine as their primary immunosuppressive agent. Only one patient had a history of rejection, which had resolved. All patients presented with increased transaminase levels, and one had a mildly elevated conjugated bilirubin level. Only one patient had constitutional complaints. Acute and chronic rejection, viral hepatitis, vascular insufficiency, and biliary tract obstruction were excluded. Antinuclear antibody levels were elevated in four patients (titer range, 1:160-1:640), one of whom also had positive antismooth muscle antibody (titer 1:80) results. The fifth patient had an elevated serum total protein level. Histologic analysis of liver biopsy samples from the five patients showed findings consistent with chronic autoimmune hepatitis. All patients were treated with standard therapy for autoimmune hepatitis, which included daily steroids and azathioprine. Cyclosporine doses were reduced in three patients and eliminated in two. All patients responded with normalization (n = 2) or improvement (n = 3) of liver transaminases within the first 3 months of therapy. Histologic analysis of the 3-month follow-up liver biopsy was normal (n = 2) or showed improvement in inflammation (n = 2). Two patients developed acute allograft rejection within 6 to 12 months after discontinuation or reduction in cyclosporine. CONCLUSIONS: Autoimmune hepatitis occurs after liver transplantation in patients without a previous history of autoimmune hepatitis. The risk of developing autoimmune hepatitis appears to be greater in children after liver transplantation than in the general pediatric population. Standard therapy for autoimmune hepatitis is effective.

Adolescent↗

PubMed2003

Increased prevalence of autoimmune diseases in first-degree relatives of patients with celiac disease.

BACKGROUND: The prevalence of autoimmune disorders is increased in patients with celiac disease (CD), and it is unknown whether their first-degree relatives also have a high risk of autoimmune disorders. METHODS: To assess the prevalence of autoimmune diseases in first-degree relatives of CD patients, the authors looked for autoimmune disorders in 225 first-degree relatives of 66 children with CD (group A) and in 232 first-degree relatives of 68 healthy children (group B). For both groups, serologic screening for CD was performed through antiendomysium (EMA) and tissue transglutaminase autoantibodies (tTGAA). EMA- and tTGAA-positive subjects were offered an intestinal biopsy. The age at onset of autoimmune diseases was also recorded in group A. RESULTS: The prevalence of autoimmune disorders was significantly (P = 0.028) higher in group A (11 of 225, 4.8%) than in group B (2 of 232, 0.86%). In relatives of CD patients, the prevalence increased with age (chi2 for trend, 43.5; P < 0.0001). Serologic screening for CD was only positive in group A (15 of 225 subjects). An intestinal biopsy was performed in 13 of these 15 relatives (2 refused biopsy). Eleven of 13 had flat mucosa, with subclinical or silent forms of CD. The prevalence of autoimmune diseases in the EMA- and tTGAA-positive relatives of CD patients was significantly higher (3 of 15, 20%; P = 0.028; odds ratio, 6.3; 95% CI, 1/0.21-1/0.11, 4.9-7.6) than in those who were EMA and tTGAA negative (8/210, 3.8%). CONCLUSIONS: The first-degree relatives of CD patients have an increased risk of autoimmune diseases, most likely connected with unrecognized subclinical or silent forms of CD.

Adolescent↗

PubMed2001

Decreased cochlear DNA receptor staining in MRL.MpJ-Fas(lpr) autoimmune mice with hearing loss.

OBJECTIVES: Previous studies of decreased cochlear DNA binding in autoimmune mice suggested that antibodies against a cochlear cell surface DNA receptor cause autoimmune hearing loss. However, the presence of a cochlear DNA receptor has not been determined. Therefore, immunohistochemistry with an anti-DNA receptor antibody was performed on MRL.MpJ-Fas(lpr) (MRL/lpr) autoimmune mice to determine 1) which inner ear structures contain DNA receptors and 2) whether the receptor staining pattern changes as autoimmune disease progresses and hearing thresholds increase. STUDY DESIGN: A prospective study of the progression of hearing loss in autoimmune mice and correlated alterations in immunostaining for the inner ear DNA receptor. METHODS: One group of MRL/lpr mice (n = 10) was allowed to develop autoimmune disease, and auditory brainstem response (ABR) audiometry was performed at 4, 6, and 9 months of age to measure the progression of hearing loss. A second group (n = 5) was tested for ABR thresholds at 2 months of age and immediately killed to assess receptor staining before the onset of autoimmune disease and hearing loss. The inner ears from all mice were immunohistochemically stained with an anti-DNA receptor antibody, and a qualitative analysis of the staining of cochlear structures was performed. RESULTS: Auditory brainstem response audiometry revealed a significant 20- to 30-dB elevation of thresholds as systemic disease progressed. Anti-DNA receptor staining was heaviest in the spiral ligament and less intense in the spiral ganglion and cochlear nerve. Both groups showed a similar pattern of staining in these structures. The stria vascularis and hair cells also stained in both groups. However, the stria cells of normal-hearing mice showed diffuse intracellular immunoreactivity, whereas older mice displayed less staining that was confined to the cell membranes. CONCLUSIONS: The inner ears of MRL/lpr mice contain DNA receptors. Autoimmune hearing loss was correlated with weaker overall intracellular staining in the stria vascularis and hair cells but increased staining of the cell membranes. This suggested DNA receptors have impaired endocytosis and more receptors remain on the cell membrane, possibly as a result of binding by circulating autoantibodies.

Age Factors↗

PubMed1989

Biologic false-positive serologic tests for syphilis and other serologic abnormalities in autoimmune hemolytic anemia and thrombocytopenic purpura.

Autoimmune hemolytic anemia (AIHA), the first autoimmune disease to be recognized, is a manifestation of defective immune regulation. Although often associated with a lymphoid neoplasm or an overt immunologic disorder, AIHA frequently appears without apparent cause. Many patients with the "idiopathic" disease have been found to have various immunologic abnormalities in addition to the antibodies reacting with red cells. Although familial AIHA is uncommon, other autoimmune diseases and serologic abnormalities have been encountered in relatives of numerous patients. Few detailed family studies have been performed, but the available data suggest that predisposition to AIHA and to the associated immunologic disorders often is genetically transmitted. Less information is available about autoimmune thrombocytopenic purpura, in part because of the historic difficulty in recognizing autoantibodies that react with platelets. However, there is good evidence for genetically determined predisposing factors in some cases. Using the BFP reaction as an indicator, we add to the evidence that AIHA and autoimmune thrombocytopenia, like SLE, tend to occur in persons with a long-standing occult immunologic defect that often has a genetic basis. In our studies, 11 patients with AIHA or ITP had BFP reactions. The serologic abnormality in 4 had been known to precede the blood disorder by 6 to 44 years. Five of the patients had an additional disease believed to have an immunologic pathogenesis. Serologic abnormalities apart from the BFP reaction and the red cell or platelet antibodies were demonstrated in 9. Autoimmune diseases or serologic changes are known to have affected relatives of 5 patients, including 4 who had 1 or more relatives with BFP reactions. Serologic tests for syphilis were negative in 2 sibs with autoimmune thrombocytopenic purpura whose father had a chronic BFP reaction and thyroiditis, but all 3 had low levels of IgA and IgM. Lymphoproliferative disorders appeared in 3 of the patients with BFP reactions, and 2 had relatives with lymphoid neoplasms. A lymphoma occurred in a woman with cold agglutinin disease 21 years after the discovery of the erythrocyte antibody. Our observations support the view that an abnormality of cells of the immune system, often genetically determined, may predispose to serologic changes, immune deficiency, autoimmune diseases and neoplasia.

Adult↗

PubMed2000

Successful prevention of autoimmune disease by transplantation of adequate number of fully allogeneic hematopoietic stem cells.

BACKGROUND: We have previously shown successful engraftment of allogeneic hematopoietic stem cells (HSCs) when transplanted across the major histocompatibility antigen barriers if transplanted along with a preparation of facilitator cells (osteoblasts). We have investigated whether or not fully allogeneic HSCs from healthy mouse donors prevent the development of autoimmunities in the autoimmune-prone W/B F1 mice. METHODS: W/B F1 is a strain of mice that spontaneously develop autoimmunities, a coronary vascular disease, thrombocytopenia, and systemic lupus-like syndrome. The 6- to 8-week-old (before the onset of the disease) W/B F1 mice have been transplanted with either a preparation of HSCs alone, or along with facilitator cells from MHC-incompatible autoimmune-resistant BALB/c mice, then followed to determine longterm survival and whether or not they developed signs of the autoimmune disease. RESULTS: The number of the transplanted HSCs acts as the determining factor in achieving successful and durable engraftment. Survival of the W/B F1 mice significantly improved by transplantation of increasing numbers of HSCs, either alone or along with facilitator cells. When W/B F1 mice were transplanted with 2-5 million HSCs, more than 1-year survival was 100%, all the transplanted mice were fully engrafted with allogeneic HSCs, and were free of signs of the autoimmune disease. Histological sections of the hearts, lungs, and kidneys of the transplanted mice showed absence of the autoimmune-associated pathology. CONCLUSIONS: We thus report herein the successful prevention of autoimmune disease by transplantation of a sufficiently large number of purified fully allogeneic HSCs in W/B F1 mice.

Animals↗

PubMed2004

AIRE and immunological tolerance: insights from the study of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy.

PURPOSE OF REVIEW: To review the clinical and molecular features of autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy and discuss recent advances in the function of the AIRE protein. We will summarize how AIRE contributes to immunological tolerance, and thus to the prevention of autoimmunity. RECENT FINDINGS: The organization of a well-structured thymic microenvironment and the interaction between nascent thymocytes and thymic epithelial cells have been shown to be essential for AIRE expression. AIRE is involved in the expression of ectopic proteins by medullary thymic epithelial cells. This allows the establishment of central tolerance and contributes to the prevention of organ-specific autoimmunity, as shown by findings in patients with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy (a disease caused by AIRE gene mutations) and in aire (-/-) mice. SUMMARY: Autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy represents a unique model to investigate the cellular and molecular mechanisms that govern central tolerance and help prevent autoimmunity. Recent findings indicate that the compartmentalization of AIRE and interaction with other proteins are involved in this mechanism. The disturbance of AIRE expression may also be responsible for autoimmune manifestations in disorders with disrupted thymic structure other than autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy alone.

Candidiasis↗

PubMed2006

Autoimmune diseases co-occurring within individuals and within families: a systematic review.

BACKGROUND: Autoimmune diseases have been observed to coexist both within individuals and within families. It is unclear whether clinical reports of comorbid autoimmune diseases represent chance findings or true associations. This systematic review evaluates the current level of evidence on the coexistence of selected autoimmune diseases within individuals and families. We reviewed the associations among 4 TH1-associated autoimmune diseases: insulin-dependent diabetes mellitus, autoimmune (Hashimoto) thyroiditis, rheumatoid arthritis, and multiple sclerosis. METHODS: Studies quantifying the coexistence between the selected diseases, published through March 2004, were identified from Medline and Embase searches. Study eligibility was determined on the basis of preestablished criteria, and relevant data were extracted according to a fixed protocol. We determined the prevalence of comorbid autoimmune disease according to index disease and then compiled summary statistics. Heterogeneity among studies was assessed by exact likelihood ratio tests and Monte Carlo inference. RESULTS: We found 54 studies that met the eligibility criteria. Of these, 52 studies examined the coexistence of disease within individuals and 9 studies examined within-family associations. The majority of studies were uncontrolled and did not account for confounding factors. There was substantial evidence for heterogeneity among studies. Although inconclusive, the data appear to support an increased prevalence of autoimmune thyroiditis among patients with rheumatoid arthritis and those with insulin-dependent diabetes mellitus, and an inverse association between rheumatoid arthritis and multiple sclerosis. CONCLUSION: Although the available evidence does not permit firm conclusions regarding comorbidities among the selected autoimmune diseases, results are sufficiently suggestive to warrant further study.

Arthritis, Rheumatoid↗

PubMed2005

Characterization of antipituitary antibodies targeting pituitary hormone-secreting cells in idiopathic growth hormone deficiency and autoimmune endocrine diseases.

OBJECTIVE: In order to investigate whether somatotrophs are the target of antipituitary antibodies (APA) in adult patients with growth hormone deficiency (GHD), we studied the sera of 37 APA positive patients. PATIENTS: Patients were grouped as follows: nine patients with APA at high titre (> 1 : 8) affected by apparently idiopathic GHD; four of them (group 1a) with isolated GHD diagnosed during childhood and five with GHD diagnosed during adulthood associated with autoimmune endocrine diseases (group 1b), and 28 patients with autoimmune endocrine diseases without pituitary impairment, previously found positive for APA at low titre (1 : 8, group 2). MEASUREMENTS: APA were evaluated by a four-layer double indirect immunofluorescence technique. RESULTS: In group 1a patients, APA immunostained exclusively GH-producing cells. In group 1b patients, APA were directed not only to GH- but also to other pituitary hormone-producing cells. In group 2 patients, APA were directed selectively to PRL-producing cells and rarely to some GH-producing cells. CONCLUSIONS: In the present study, we demonstrated that GH-secreting cells are the target of the autoimmune reaction in autoimmune GHD and that the immunostaining of only the somatotrophs is typical of isolated GHD. In contrast, the finding of diffuse staining of APA indicates the need to search for other autoimmune diseases. Finally, the presence of APA at low titre directed against PRL-secreting cells in patients with autoimmune endocrine diseases in the absence of pituitary impairment, seems to be only a nonspecific marker of pituitary autoimmunity. A longitudinal study would be useful to clarify the relationship between the different pituitary cell involvement and the natural history of pituitary dysfunction in autoimmune hypophysitis.

Adult↗

PubMed1985

Susceptibility to acute Trypanosoma cruzi infection in autoimmune strains of mice.

We previously observed that mice bearing the autoimmune associated lpr gene exhibit increased susceptibility to challenge with Trypanosoma cruzi, the causative agent of Chagas' disease. We have now tested two other autoimmune prone strains of mice, BXSB and NZB, and found that these animals also show increased sensitivity to acute T. cruzi infection. When challenged with a standard dose (10(2)) of Y strain trypomastigotes, BXSB males (BXSB-YSB), which develop early onset autoimmune disease, suffered high mortality, while late onset autoimmune BXSB females and minimally autoimmune male BXSB mice whose Y chromosome was derived from C57BL/6J mice (BXSB-YB/6) also recover. NZB mice were found to be highly susceptible to challenge while NZW and NZB/W were resistant. A finding common to all groups of susceptible autoimmune mice was increased plasma levels of T. cruzi specific antibody, especially IgM. The data indicate that in two of the three autoimmune prone strains examined, increased T. cruzi susceptibility appears to be linked to restricted genetic elements (i.e. lpr gene and the YSB associated factor) which also influence the rapidity of onset of autoimmunity.

Animals↗

PubMed2002

Prevalence of autoimmune liver disease in Alaska Natives.

OBJECTIVE: There is limited information on the prevalence of autoimmune liver disease in nonwhite populations. We conducted a population-based study on the prevalence of autoimmune liver diseases in Alaska natives. METHODS: Clinical records from 1984 to July, 2000 were reviewed to identify Alaska natives with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, autoimmune cholangitis, and overlap syndromes of two of the above. AIH was defined as definite or probable, based on criteria established by the International Autoimmune Hepatitis Group. The diagnosis of PBC was based on a positive antimitochondrial antibody of > or = 1: 40, biochemical evidence of cholestasis, and compatible liver biopsy. Autoimmune cholangitis was defined as PBC but without a positive antimitochondrial antibody. Primary sclerosing cholangitis was diagnosed on the basis of cholangiogram. RESULTS: Seventy-seven patients with possible autoimmune liver disease were identified. Of these, 42 had definite and seven probable AIH. At presentation, 34.7% of patients with AIH presented with acute icteric hepatitis, and 65.3% were asymptomatic. Persons presenting with mild or no symptoms were more likely to have moderate to severe fibrosis on liver biopsy than those presenting with jaundice. Eighteen persons were diagnosed with PBC, five with autoimmune cholangitis, five with overlap syndrome, and none with primary sclerosing cholangitis. The combined point prevalence of AIH Alaska natives was 42.9/100,000 (95% CI = 31-57.7). The prevalence of PBC was 16/100,000 (95% CI = 12.9-25.4). CONCLUSIONS: This population-based study demonstrates that the prevalence rates of AIH and PBC in Alaska natives are comparable with reported rates in other populations.

Adolescent↗

PubMedDate not supplied

A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis.

Autoimmune pancreatitis, an inflammatory process of the pancreas due to an autoimmune mechanism establishing etiology of chronic pancreatitis, is characterized by the presence of autoantibodies, hypergammaglobulinemia, pancreatic enlargement, pancreatic duct strictures, and pathologic features of fibrotic changes with intense, mainly lymphocytic infiltrations, which may contribute to tissue destruction probably by apoptosis. In almost 60% of the cases, this type of pancreatitis coexists with other autoimmune diseases such as Sjogren's syndrome, sclerosing extrahepatic cholangitis, primary biliary cirrhosis, autoimmune hepatitis, or other extrapancreatic disorders, and recently with gastric peptic ulceration. The diversity of extrapancreatic lesions with similar histopathologic findings suggests general involvement of the digestive system in this disease, although the presence of such involvement has not been fully elucidated. Similarly, Helicobacter pylori (H. pylori) infection, a well known cause of gastric ulcer, has been associated, via molecular mimicry of host structures by its constituents with the same autoimmune conditions, also characterized by fibrotic changes and/or lymphoplasmacytic inflammations, accompanied by aberrations of T cell apoptosis that contribute to hepatobiliary- or extrahepatic-tissue destruction. Considering that H. pylori is involved in the pathogenesis and pathophysiology of these autoimmune disorders, we propose that this organism might trigger autoimmune pancreatitis through induction of autoimmunity and apoptosis.

Apoptosis↗

PubMed1999

Role of dendritic cells in the induction and maintenance of autoimmune diseases.

Autoimmune diseases are characterised by the loss of tolerance against self-determinants, activation of autoreactive lymphocytes and pathological damage to single or multiple organs. The mechanisms by which autoimmune responses are triggered and activation of autoreactive lymphocytes is initiated and maintained are not yet fully understood. Translocation of previously immunologically ignored antigens from the periphery to secondary lymphoid organs is probably a key step in the initiation of autoimmunity. Antigen transport and primary sensitisation of T lymphocytes is mainly mediated by dendritic cells which reside in peripheral non-lymphoid tissues and maintain a continuous gradient of antigens towards secondary lymphoid tissues. In the transgenic rat insulin promoter-glycoprotein model of autoimmune diabetes, dendritic cell (DC)-mediated antigen transport initiates an autoimmune response against a pancreatic neoself-antigen. Dose and timing of antigen delivery by DC and turnover of antigenic peptides presented by DC are the main parameters regulating the outcome of autoimmune diabetes in this model system. An important sequel of continued antigenic stimulation via DC is the formation of lymphoid structures in the pancreas. Thus, appropriate and repeated activation of cytotoxic T lymphocytes by DC, in concert with local inflammatory processes leading to formation of organised lymphoid tissue in the target organ, is likely to be crucial in the development of destructive autoimmunity. Therapeutic intervention to selectively manipulate antigen transport by dendritic cells or to influence antigen presentation may prove beneficial for the treatment of autoimmune diseases. Furthermore, the capacity of DC to induce potent antiself responses might have implications for the use of DC presenting self-antigens in treatment of established tumours.

Animals↗

PubMed1996

Susceptibility to murine experimental autoimmune oophoritis is associated with genes outside the major histocompatibility complex (MHC).

PROBLEM: Neonatal thymectomy induces experimental autoimmune oophoritis in certain strains of mice, and this serves as a model for human autoimmune oophoritis. Because strong MHC associations have been noted in human autoimmune conditions, we investigated the role of MHC in determining susceptibility to murine experimental autoimmune oophoritis. Strain A mice are highly susceptible to post-thymectomy autoimmunity, whereas strain B10 mice are relatively resistant. The availability of congenic strains of mice makes it possible to separate the effects of genetic background and specific H-2 haplotype METHODS: We neonatally thymectomized A and B10 background female mice, and their H-2 congenic counterparts, and then evaluated the resulting ovarian disease at age 6 weeks. RESULTS: A. By mice, which have the A background and the H-2b haplotype, developed severe disease equivalent to strain A mice. Similarly, B10.A mice, which have the B background and the H-2a haplotype, failed to develop disease. Thus, H-2a haplotype did not convey disease susceptibility. CONCLUSIONS: Our findings suggest that immune-regulatory regions outside the H-2 locus play an important role in determining susceptibility to murine post-thymectomy autoimmune oophoritis. This is in accord with our previous findings in women that showed no association between MHC and premature ovarian failure. Thus, in this respect this model is similar to human autoimmune ovarian failure. This suggests that the non-MHC genes conveying susceptibility to autoimmune oophoritis in mice might represent similar predisposing genes for premature ovarian failure in women.

Animals↗

PubMed2000

Susceptibility to autoimmune disease and drug addiction in inbred rats. Are there mechanistic factors in common related to abnormalities in hypothalamic-pituitary-adrenal axis and stress response function?

DA and LEW inbred rats are extraordinarily susceptible to a wide range of experimental autoimmune diseases. These diseases include rheumatoid arthritis models such as collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA), multiple sclerosis models such as myelin-basic-protein (MBP)-induced experimental autoimmune encephalomyelitis (MBP-EAE), and autoimmune uveitis models such as retinal S antigen (SAG) and interphotoreceptor-retinoid-binding-protein (IRBP)-induced experimental autoimmune uveitis (SAG-EAU and IRBP-EAU, respectively). DA and LEW rats are also addiction-prone to various drugs of abuse, such as cocaine. Moreover, they exhibit a variety of behavioral and biochemical characteristics that appear to be related to their susceptibility to addiction. By contrast, F344 and BN rats show quite different phenotypes. They are relatively resistant to CIA, AIA, MBP-EAE, SAG-EAU, and IRBP-EAU, and they are relatively resistant to addiction. Interestingly, both DA and LEW rats, in contrast to F344 and BN rats, have abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function. For example, circadian production of corticosteroids is very abnormal in DA and LEW rats; that is, they exhibit minimal circadian variation in corticosterone levels. Since corticosteroids potentially have significant influences on immune function and autoimmune disease susceptibility and may also influence sensitivity to drugs of abuse, we have begun to dissect genetic control of these various phenotypic differences, focusing initially on the regulation of autoimmune disease expression. Using genomewide scanning techniques involving F2 crosses of DA x F344 (CIA and AIA), DA x BN (CIA), and LEW x F344 [IRBP-EAU and streptococcal-cell-wall arthritis (SCWA)], we have identified, to date, 14 genomic regions [quantitative trait loci (QTL)] that regulate disease expression in these crosses. Development and analysis of QTL-congenic rats involving these loci are in progress and should permit us to address the relationships among autoimmune disease susceptibility, drug addiction, and HPA axis and stress response function. These initial data, however, indicate that the genetic control of the autoimmune disease traits is highly complex.

Animals↗