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At least 289 records · Page 16Linked to original sources
PubMed1993

The origin of the autoimmune disease-resistant LER rat: an outcross between the buffalo and autoimmune disease-prone Lewis inbred rat strains.

The Lewis (LEW) rat strain is highly susceptible to a large number of experimentally induced inflammatory and autoimmune diseases. The Lewis resistant (LER) rat strain, which reportedly arose as a spontaneous mutation in a closed colony of LEW rats, is resistant to many of these disorders. The mechanism of resistance is not yet clear. We report the analysis of 19 simple dinucleotide repeat polymorphisms in 13 rat strains including the LEW/N and LER/N rat strains. The LEW/N and LER/N alleles were the same in only 42% of cases. For all of the other polymorphisms, the LER/N and Buffalo (BUF/N) rat strain alleles were identical. These data provide evidence that the LER strain did not arise as a spontaneous mutation in the LEW strain but is the result of an outcross between the LEW and BUF rat strains. The LER rat strain is now a recombinant inbred rat strain. This information should facilitate the genetic analysis of the loci responsible for resistance to experimental autoimmune disease in the LER rat.

Alleles↗
PubMed2006

By-stander activation in autoimmune thyroiditis: studies on experimental autoimmune thyroiditis in the GFP+ fluorescent mouse.

We have taken advantage of GFP+ fluorescent protein (GFP) tagged lymphocytes to examine by-stander activity in experimental autoimmune thyroiditis in the mouse. To generate GFP-positive EAT-susceptible CBA/J mice (H-2k) (GFP-CBA/J mice), we backcrossed CBA/J (H-2k) with heterozygous GFP+ transgenic mice (C57Bl/6; H-2b). I-Ak and GFP expression on peripheral lymphocytes was used to select the resulting progeny up to the N7 generation. Mixed lymphocyte reactions using spleen cells from N7 GFP-CBA/J mice showed negative responses to spleen cells from CBA/J confirming the inbreeding and with marked reactivity to cells from C57BL/6. Immunization with human thyroglobulin (hTg) in GFP-CBA/J mice induced thyroiditis in 50% of the animals and high titers of Tg antibodies in all the animals. In addition, priming of GFP+ spleen cells in vitro with hTg induced a marked proliferative response (mean stimulation index = 24.7), These proliferating spleen cells were then transferred to CBA/J recipients. Fourteen days after transferring 30 x 10(6) Tg-primed GFP+ spleen cells into irradiated (500 rad) normal syngeneic hosts, a GFP+ lymphocytic infiltration was seen within their thyroid glands along with a GFP- lymphocytic infiltration arising from the host. This suggested that the hTg-specific transferred cells had initiated by-stander activation of naive host lymphocytes. This model of bystander cell detection confirmed that such an effect occurs in EAT and adds weight to the importance of this phenomenon in the initiation of autoimmune thyroid disease.

Adoptive Transfer↗
PubMed2001

[Autoimmune hepatitis with prolonged IGM antibodies to HAV. Are serological markers reliable in ruling out a diagnosis of autoimmune hepatitis?].

We present the case of a 44-year-old woman who was referred to us for jaundice, choluria and acholia. Review of the patient's clinical history revealed that tests for hepatitis A virus (HAV) IgM antibody had been positive 4 and 2 years previously and continued to be so. The patient showed a score of 16 in the International Autoimmune Hepatitis Group's system when the HAV marker was not taken into account and a score of 13 when this marker was taken into account. The persistence of this viral marker for so many years in such patients is probably associated with polyclonal hypergammaglobulinemia. Consequently, we believe that the inclusion of this antibody as a negative datum in the diagnosis of autoimmune virus should be viewed with caution.

Adult↗
PubMed1992

Expression of intercellular adhesion molecule-1 in thyroid follicular cells in autoimmune, non-autoimmune and neoplastic diseases of the thyroid gland: discordance with HLA.

The presence of intercellular adhesion molecule-1 (ICAM-1) on epithelial cells facilitates their recognition by specific T lymphocytes. To assess the possible role of ICAM-1 in the recognition of thyroid follicular cells by T cells in thyroid autoimmune disease, we investigated the expression of ICAM-1 in thyrocytes from thyroid glands affected by Graves' disease, in glands with non-autoimmune pathology and normal glands using immunofluorescence staining on cryostat sections and on dispersed cell preparations. Sequential tissue sections from glands affected by Graves' disease (n = 15), multinodular goitre (MNG, n = 26), benign nodules (n = 11), primary carcinomas (n = 12) and control thyroid glands (n = 5) were stained for ICAM-1, HLA class I, HLA class II, CD3 and thyroid peroxidase (TPO). Weak and patchy ICAM-1 expression was found in the thyrocytes of 4/15 (27%) Graves' disease and of 1/26 (4%) multinodular goitre glands. In contrast, ICAM-1 expression was detected in the thyrocytes of 5/11 (45%) benign nodules and of 8/12 (67%) thyroid carcinomas in which it was sometimes strong. Thyrocytes in the five control glands were negative. These results correlated well with flow cytometry data from 23 of these glands which showed that ICAM-1 expression in thyrocytes from Graves' patients was, when present, 'dull', while in some malignant thyrocytes it was 'bright'. In preparations of thyrocytes from Graves' disease glands we found a striking discordance between the high levels of expression of HLA class I and HLA class II and the low expression of ICAM-1. This is surprising since in vitro the expression of these three molecules is equally induced by IFN-gamma and TNF-alpha. These results suggest that additional factors are involved in the induction of the inappropriate HLA class II expression observed in the thyrocytes of glands affected by Graves' disease.

Antigens, CD↗
PubMed2004

Diagnosing autoimmune hepatitis in children: is the International Autoimmune Hepatitis Group scoring system useful?

BACKGROUND & AIMS: In 1999, the International Autoimmune Hepatitis Group (IAIHG) modified a scoring system to differentiate adult patients with definite or probable autoimmune hepatitis (AIH) from those with other forms of chronic liver disease. We assessed the use of the scoring system in children. METHODS: Twenty-eight pediatric patients with AIH and/or sclerosing cholangitis were reviewed. Clinical, laboratory, and histologic data were collected to score patients both before and after standard treatment. RESULTS: There were 8 boys and 20 girls. The median age at diagnosis was 11 years (range, 2-16 years). Twenty-one of 28 children were diagnosed with AIH, 4 as isolated primary sclerosing cholangitis (PSC), and 3 as overlap syndrome. At presentation, 18 of 21 (86%) with AIH scored as definite AIH and 3 of 21 (14%) scored as probable. No patient clinically diagnosed as AIH scored as other. Seven of 28 patients had proven PSC. All patients with isolated PSC scored as other. The 3 with overlap syndrome scored as definite AIH. When the gamma-glutamyltranspeptidase (GGT) ratio was substituted for the alkaline phosphatase (ALP) ratio, 5 patients were reclassified from definite to probable AIH. Four of these 5 had an incomplete response to therapy, and 2 of 4 have confirmed overlap syndrome. CONCLUSIONS: The IAIHG scoring system has a use in children. Patients who fall into the other category should have cholangiographic imaging. Using the GGT ratio instead of the ALP ratio in the IAIHG score may improve the specificity for children, identifying those likely to have biliary disease. When GGT is used, patients classified as needing probable pretreatment should be considered for biliary imaging.

Adolescent↗
PubMed1993

Proliferative autoimmune glomerulonephritis in rats: a model for autoimmune glomerulonephritis in humans.

Some forms of glomerulonephritis (GN) in humans appear consequent to autoimmunity. Experimental autoimmune GN (EAG) has been described in sheep, but attempts to develop EAG in other mammals have resulted only in antibody and proteinuria but no GN. We have developed a model of EAG in an inbred mammalian species to further study pathogenetic mechanisms. We immunized Brown Norway (BN) and Wistar-Kyoto (WKY) rats with glomerular basement membrane (GBM) or collagenase solubilized GBM (csGBM). Circulating and bound anti-GBM antibody developed in all rats. Only interstitial nephritis occurred in BN rats despite amounts of glomerular and serum anti GBM antibodies similar to WKY animals. One hundred percent of WKY rats immunized with csGBM/acid developed reproducible severe GN at two to three weeks with proteinuria and decreased kidney function which progressed to glomerulosclerosis and interstitial fibrosis. Antigen in acid was a requisite for induction of EAG. EAG rats had positive tests for delayed type hypersensitivity, their T cells underwent antigen specific transformation, and T cells and macrophages were present histologically. Passive transfer of EAG serum to naive rats resulted in fixation to recipient GBM but no proteinuria or GN. This new model of EAG in rats appears dependent on genetic factors, may involve cellular immunity in pathogenesis, requires exposure of the nephritogenic antigen, and is highly similar to rapidly progressive GN in humans.

Animals↗
PubMed1998

Autoimmune thrombocytopenia (AITP) and thyroid autoimmune disease (TAD): overlapping syndromes?

The pathogenesis of thrombocytopenia associated with TAD and the occurrence of overlapping traits between TAD and AITP are still a matter of debate. For this reason, we investigated for the presence and specificity of platelet and thyroid autoantibodies in 18 TAD patients with thrombocytopenia, 19 TAD patients without thrombocytopenia and in 22 patients with primary AITP without clinical signs of TAD. Platelet-associated IgG and/or specific circulating platelet autoantibodies were detected in 83% of patients with TAD and thrombocytopenia, in 10% of patients with TAD without thrombocytopenia and in 86% of patients with primary AITP. The reactivity of serum autoantibodies, assayed by MoAb immobilization of platelet antigens (MAIPA), was directed against platelet glycoproteins Ib and/or IIb/IIIa in 50% of the patients with TAD and thrombocytopenia, as in 46% of the patients with primary AITP. Thyroid autoantibodies were found in 89% of patients with TAD and thrombocytopenia, in 95% of patients with TAD without thrombocytopenia, and in 18% of patients with primary AITP. Thyrotropin (TSH) levels determined in three of four AITP patients with thyroid autoantibodies revealed a subclinical hyperthyroidism in one patient. The present study supports the autoimmune aetiology of thrombocytopenia associated with TAD, since the prevalence and specificity of platelet autoantibodies are similar in TAD and primary AITP. The results indicate also that there exists an overlap between thyroid and platelet autoimmunity with or without clinical manifestations.

Adult↗
PubMed2001

Distinction between autoimmune and non-autoimmune hyperthyroidism by determination of TSH-receptor antibodies in patients with the initial diagnosis of toxic multinodular goiter.

Distinguishing Graves' disease (GD) from a toxic multinodular goiter (TMG) subgroup with a diffuse but uneven Tc-distribution depends on the diagnostic power of the TSH-receptor antibody (TRAb) determination. Bioassays using CHO cell lines expressing the hTSH-receptor or a new TBII assay, which uses the hTSH-receptor as an antigen (DYNOTEST TRAK human, Brahms, Germany), showed a higher sensitivity for the detection of TRAbs in patients with GD than assays using solubilized porcine epithelial cell membranes. The aim of this study was to investigate whether the new Dynotest TRAK human assay has an increased sensitivity to distinguish GD from non-autoimmune hyperthyroidism. Therefore, we examined 21 consecutive patients with the initial diagnosis of TMG for thyroid-stimulating antibodies (TSAbs, JP26 cell assay) and TBII with the new highly sensitive Dynotest TRAK human (Brahms, Germany). The initial diagnosis of TMG was based on suppressed TSH and a patchy Tc-uptake of more than 1 % and less than 7 % or TSH of more than 0.3 mIE/l with a patchy Tc-uptake of more than 1.5 % and less than 7 % and negative TBII values in a displacement assay using solubilized porcine epithelial cell membranes (TRAK, Brahms, Germany). 11 sera from these 21 patients showed TSAb activity. Furthermore, 10 of these 11 TSAb-positive sera were also positive in the Dynotest TRAK human assay, whereas one serum sample was borderline positive. TSAb activity and inhibition of (125)I-bTSH binding in the Dynotest TRAK human assay correlated well (r = 0.7). Therefore, 11 of the 21 investigated patients initially classified as TMG actually had GD, which was undetectable using the porcine TBII assay. In conclusion, TSAbs or TRAbs detected with the Dynotest TRAK human have the highest diagnostic power to differentiate GD from TMG. Because of the less cumbersome assay technique, the Dynotest TRAK human measurements should be obtained for all patients with non-typical TMG to differentiate GD from non-autoimmune hyperthyroidism in order to select the appropriate therapy for these patients.

Adult↗
PubMed2005

NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease.

Mutations in the autoimmune regulator protein AIRE1 cause a monogenic autosomal recessively inherited disease: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE1 is a multidomain protein that harbors two plant homeodomain (PHD)-type zinc fingers. The first PHD finger of AIRE1 is a mutational hot spot, to which several pathological point mutations have been mapped. Using heteronuclear NMR spectroscopy, we determined the solution structure of the first PHD finger of AIRE1 (AIRE1-PHD1), and characterized the peptide backbone mobility of the domain. We performed a conformational analysis of pathological AIRE1-PHD1 mutants that allowed us to rationalize the structural impact of APECED-causing mutations and to identify an interaction site with putative protein ligands of the AIRE1-PHD1 domain. The structure unequivocally exhibits the canonical PHD finger fold, with a highly conserved tryptophan buried inside the structure. The PHD finger is stabilized by two zinc ions coordinated in an interleaved (cross-brace) scheme. This zinc coordination resembles RING finger domains, which can function as E3 ligases in the ubiquitination pathway. Based on this fold similarity, it has been suggested that PHD fingers might also function as E3 ligases, although this hypothesis is controversial. At variance to a previous report, we could not find any evidence that AIRE1-PHD1 has an intrinsic E3 ubiquitin ligase activity, nor detect any direct interaction between AIRE1-PHD1 and its putative cognate E2. Consistently, we show that the AIRE1-PHD1 structure is clearly distinct from the RING finger fold. Our results point to a function of the AIRE1-PHD1 domain in protein-protein interactions, which is impaired in some APECED mutations.

Amino Acid Sequence↗
PubMed1998

Autoimmune enteropathy with severe atrophic gastritis and colitis in an adult: proposal of a generalized autoimmune disorder of the alimentary tract.

BACKGROUND: We describe the case of an adult with autoimmune enteropathy consistent with both severe atrophic gastritis accompanying antral stenosis and colitis. METHODS AND RESULTS: The patient, positive for anti-intrinsic factor antibody, had intractable diarrhea and protein-losing enteropathy. In the ileum inflammatory cells were observed infiltrating the lamina propria along with villus atrophy, and similar inflammation was also found in the lamina propria of the colon and stomach, with complete loss of specialized glands. The myenteric ganglion cells of the hypertrophied muscularis propria in the stenosed antrum showed degeneration with surrounding T-lymphocyte infiltration. There were more CD8+ than CD4 lymphocytes in the lamina propria of the stomach and colon. CONCLUSIONS: The CD8+ (suppressor-cytotoxic) T lymphocytes may have played an important role in the production of lesions in the stomach, small intestine, and colon, so we propose this case as an example of a generalized autoimmune disorder of the alimentary tract.

Autoimmune Diseases↗
PubMed1995

Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity.

Autoantibodies from many patients with systemic lupus erythematosus bind the Sm autoantigen B/B' polypeptide. The binding of serial serum specimens to the 233 overlapping octapeptides of Sm B/B' have shown that of the B/B'-derived octapeptides, PPPGMRPP and PPPGIRGP are early targets of the autoimmune response in some lupus patients. Rabbits immunized with PPPGMRPP and PPPGIRGP develop antibodies which not only bind these octapeptides, but also subsequently bind many other octapeptides of Sm B/B'. Eventually, the rabbits immunized with one octapeptide develop autoantibodies that bind other spliceosomal proteins including D, 70K, A, and C. Any mechanisms that operate to maintain tolerance or anergy for the spliceosome are thus overcome. Features considered typical of human systemic lupus erythematosus are also found in these peptide-immunized animals, such as antinuclear antibodies, anti-Sm precipitins, anti-double-stranded DNA, thrombocytopenia, seizures, and proteinuria. This disease model provides access to a mechanism for the development of humoral autoimmunity and may provide a basis to explain the immunopathogenesis of lupus in humans.

Amino Acid Sequence↗
PubMed1990

Autoimmune syndrome after induction of neonatal tolerance to alloantigens: analysis of the role of donor T cells in the induction of autoimmunity.

The injection of (C57BL/6 x BALB/c) F1 spleen cells into BALB/c newborn mice leads to activation of persisting F1 donor B cells and development of a lupus-like syndrome in tolerized BALB/c mice. This syndrome is characterized by hypergammaglobulinaemia, high levels of anti-DNA and anti-Sm antibodies, circulating immune complexes and deposits of immunoglobulin in renal glomeruli. The role of donor T cells in this model was investigated by injecting the newborn mice with F1 cells depleted in different T cell subsets by using specific monoclonal antibodies (MoAbs). Tolerance, as shown by an absence of H-2b-specific CTL alloreactivity and persistence of immunoglobulin bearing the donor allotype were observed in mice injected with F1 cells previously depleted in the CD4+ and/or CD8+ T cell subsets as well as in those which received Thy-1+-depleted F1 spleen cells. In these mice, a typical autoimmune syndrome was found, including splenomegaly and lymphadenopathy, anti-ssDNA and anti-aortic myosin IgG antibodies and renal deposition of immunoglobulin. However, some quantitative changes were seen: the levels of anti-aortic myosin antibodies were lower in mice tolerized with CD4+-depleted F1 cells than in those receiving untreated F1 cells. Conversely, higher levels of these autoantibodies were observed in mice tolerized with CD8+-depleted F1 cells. These results suggest that mature donor T cells are not necessary neither for the establishment of neonatal tolerance to alloantigens nor for the activation of F1 donor B cells in the production of the autoimmune syndrome in tolerant mice, but they may contribute in the regulation of the expression of autoreactive B cell clones.

Animals↗
PubMed1998

Experimental autoimmune prostatitis: in vivo induction of the autoimmune response to lymphocytic soluble factors. Alterations at the endocrine metabolism level.

PROBLEM: In rats, immunization with male accessory gland (MAG) extract promotes experimental autoimmune vesicle prostatitis. A specific mononuclear cell-mediated immune response and prostate androgen metabolism impairment in MAG-immunized rats were observed. The possibility that lymphocytic soluble factors (SoFs) can regulate the local steroid metabolism in these rats directly was studied. We investigated whether the SoFs released by MAG-sensitized lymphocytes are capable of modifying the prostatic androgen metabolism and whether they induce histologic lesions "in vivo" when they are inoculated, carried by liposomes, into untreated rats. METHOD OF STUDY: "In vitro" enzymatic [3H]-5 alpha-dihydrotestosterone bioconversion and histologic studies were performed with prostates from SoF-treated rats (LK rats). The obtained 3 alpha/beta-hydroxysteroid-oxidoreductase activities showed that LK rat values were significantly lower than in controls: 79.0 +/- 2.5 vs 158.7 +/- 10.2 pmol/min/mg protein, respectively (P < 0.01). RESULTS: In the histologic studies, LK rat prostates showed focalized mononuclear infiltrates of various degrees, whereas control rats showed non-atypic modification of the gland. CONCLUSION: These results indicate that SoFs (probably total lymphokines) contribute significantly to the pathogenesis of experimental autoimmune prostatitis, involving a biochemical relationship between immune reaction and the androgenic enzymatic inhibition in the prostate.

Animals↗
PubMed1991

Ultrastructural pathology of the 'barrier sites' in experimental autoimmune uveitis and experimental autoimmune pinealitis.

Lewis rats were immunised with retinal S-antigen to induce experimental autoimmune uveitis and experimental autoimmune pinealitis. The blood-retinal and blood-pineal 'barrier sites' were examined by transmission electron microscopy. Inflammatory cell movement through Bruch's membrane involved separation of its constituent layers, cell migration through pores in the membrane, and between retinal pigment epithelial cells without causing significant displacement of the retinal pigment epithelial cell layer. The endothelial cells of retinal and pineal vessels with perivascular infiltrates showed morphological features resembling endothelium of 'high endothelial venules'.

Animals↗
PubMed1991

Autoimmune enteropathy and colitis: is there a generalised autoimmune gut disorder?

Children with protracted diarrhoea, circulating enterocyte autoantibodies, and an enteropathy showing features of inappropriate HLA molecule expression on the jejunal crypt epithelium, often present with persistent blood and mucus in their stools. Eight children with autoimmune enteropathy were investigated for the presence of associated colonic disease. Six children with protracted diarrhoea, no circulating autoantibodies, and an enteropathy (in five of them) undergoing colonoscopy were used as control subjects. In all eight patients, but not in the control subjects, there was macroscopic and microscopic evidence of an accompanying colitis of variable severity, thus indicating that a more generalised intestinal disorder was present, which might affect the whole intestine. Aberrant expression of DR molecules on the colonic surface and crypt epithelium was also detected. Autoimmunity may play a role in the colitis.

Autoantibodies↗
PubMed2000

Humoral and cellular autoimmunity in autoimmune bullous skin disorders.

Autoimmune bullous skin diseases, such as pemphigus vulgaris (PV) and bullous pemphigoid (BP), are severe, frequently life-threatening skin disorders. Immunologically, they are characterized by the presence of serum autoantibodies (auto-Ab) targeting distinct adhesion molecules of the epidermis or dermoepidermal basement membrane zone. Antibody (Ab) binding interferes with the adhesive function of these molecules, leading to detachment and subsequently blister formation. PV is the classical example of an Ab-mediated autoimmune disease affecting epidermal adhesion. Auto-Ab against the desmosomal adhesion molecule, desmoglein 3 (Dsg3), are critical in the pathogenesis of this disease, since the transfer of serum IgG Ab reactive with Dsg3 into newborn mice induces a bullous skin disease resembling PV. Autoreactive T cell responses to Dsg3 may be critical in the pathogenesis of PV because: (1) Ab production generally requires T cell help; (2) the involvement of CD4+ T lymphocytes in PV has been suggested by the strong association with distinct HLA class II alleles, and (3) T cell recognition of epitopes of Dsg3 may be crucial for the initiation and perpetuation of the production of Dsg3-specific auto-Ab by B cells. In PV and BP, autoreactive CD4+ T cells recognize distinct epitopes of the extracellular portions of Dsg3 and BP180 [BP antigen 2 (BPAG2) or type XVII collagen], respectively, and produce preferentially T helper type 2 (TH2) cytokines. Auto-Ab of the TH2-dependent IgG4 subtype are preferentially seen in the active stages of both PV and BP, while auto-Ab of the TH1-dependent IgG1 subclass are predominant during the chronic course of these disorders. These observations suggest that autoreactive TH2 cells may provide targets to specifically modulate the T cell-dependent production of pathogenic auto-Ab in these disorders.

Animals↗
PubMed2006

The role of epithelial cells in the initiation and perpetuation of autoimmune lesions: lessons from Sjogren's syndrome (autoimmune epithelitis).

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting epithelial tissues. Exocrine glands are the primary target and their functional impairment comes as a result of immune attack of epithelial cells of the affected organs (autoimmune epithelitis). In this interplay, the role of the epithelial cell is pivotal. Extensive data point to an intrinsically activated status. Moreover, the epithelial cells possess all the features needed in order to act as non-professional antigen presenting cells. Through apoptosis and exosomes release endocellular antigens contributing to tolerance breakdown. In addition, produce cytokines and chemokines that recruit lymphocytes in the immunopathogenic lesion. Herein, we review all the aforementioned aspects of the epithelial activity that lead to the perpetuation of the lesion as well as the probable viral factors for the intrinsic activation. Finally, we propose a model for SS pathogenesis that integrates the knowledge accumulated during the last decade.

Autoimmune Diseases↗