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PubMed1997

Stiff-man syndrome associated with antecedent myasthenia gravis and organ-specific autoimmunopathy.

We describe a case of stiff-man syndrome accompanied by diabetes mellitus, Hashimoto's thyroiditis and the antecedent myasthenia gravis. The diagnosis of stiff-man syndrome was made based on not only clinical findings and the characteristic electromyographic pattern but also the presence of antibodies to glutamic acid decarboxylase in the serum and cerebrospinal fluid. Stiff-man syndrome is known to be associated with organ-specific autoimmunopathy including insulin-dependent diabetes mellitus. The present case is the first one that stiff-man syndrome was preceded by myasthenia gravis of organ-specific autoimmunopathy. Stiff-man syndrome in the present case probably represents the one of fully expressed manifestations from the broad spectrum of organ-specific autoimmunopathy caused by the loss of self-tolerance.

Adult↗
PubMed2000

Organ-specific manifestations of HIV disease in children.

The clinical manifestations of HIV disease in children affect multiple organ systems. The severity of each manifestation varies by organ system and can be related in many cases to multifactorial causes, namely HIV replication in affected tissue, concomitant opportunistic infection of the organ, effect of concurrent immunodeficiency or autoimmune mechanisms on the organ, or adverse end-organ drug effect (primary HIV therapy or prophylaxis regimens). More information is needed to understand the pathogenesis of the systemic effect of HIV on different organ systems, especially the CNS. Most clinicians hope that advances in therapeutic interventions for primary HIV will halt the progression of the organ-specific manifestations that have been outlined in this article, but such potent therapies will probably have their own unique and new effects on HIV-infected organ systems. Vigilance for organ-specific manifestations in the era of HAART is imperative to provide the best clinical outcome for HIV-infected children.

AIDS-Related Opportunistic Infections↗
PubMed1984

Effect of glycolipids contained in liposomes on the incorporation of beta-galactosidase into specific organs.

A series of glycolipids were examined to find a system capable of targeting liposomes into specific organs of rats. Sulfatide was found to be the best among the components of liposomes examined for delivering the entrapped enzyme, beta-galactosidase from Aspergillus oryzae, into the brain and liver; gangliosides, for the spleen; and sphingomyelin, for the lung. To introduce the enzyme into the liver, galactocerebroside was far better than glucocerebroside. These data suggest that the sugar residues of glycolipids function to target the liposomes into specific organs.

Animals↗
PubMed1989

In vitro formation of organ-specific ultimate carcinogens of 4-dimethylaminoazobenzene and urethan by microsomes.

In order to determine the organ-specific carcinogenicity of 4-dimethylaminoazobenzene (4-DAB) and urethan, their metabolites formed in vitro by incubation with the microsomes from liver, lungs, brain and kidneys of rats were isolated by thin-layer chromatography. 4-DAB was found to be metabolized to give two major products, 4-aminoazobenzene and N-hydroxy-4-aminoazobenzene, only when incubated with liver microsomes. These metabolites were not detected when microsomal suspensions of lungs, brain and kidneys were used. Similarly, urethan was found to yield three metabolites, N-hydroxy derivative of ethyl carbamate, N-hydroxyvinyl carbamate, and epoxy derivative of ethyl carbamate, on incubation with lung microsomes, but not with the microsomes from liver, brain and kidneys. As the potential carcinogenic moieties were only formed by incubating these two compounds with the microsomes of their target organs, their organ-specific carcinogenicity may be explained.

Animals↗
PubMed1993

Floral organ-specific and constitutive expression of an Arabidopsis thaliana heat-shock HSP18.2::GUS fusion gene is retained even after homeotic conversion of flowers by mutation.

Organ-specific and constitutive expression of the Arabidopsis HSP18.2 gene under normal growth conditions (22 degrees C) was observed in transgenic A. thaliana, which carried a fusion gene composed of the promoter region of HSP18.2, one of the genes for low molecular weight heat-shock proteins in Arabidopsis, and the gene for beta-glucuronidase (GUS) from Escherichia coli. In order to clarify the organ-specific nature of promoter expression, various mutations that affect flower morphology were introduced into the transgenic Arabidopsis line, AHS9. The results show that the pattern of expression observed in sepals, filaments, and styles is regulated in a structure-dependent manner, and suggest that the HSP18.2 gene might have an important role in the process of differentiation of flower buds, as do several other stress-related genes.

Arabidopsis↗
PubMed1999

Cutting edge: Role of C-C chemokine receptor 5 in organ-specific and innate immunity to Cryptococcus neoformans.

After intratracheal inoculation of the AIDS-associated pathogen Cryptococcus neoformans, 12-wk survival was >90% for CCR5+/+ mice but <25% for CCR5-/- mice. There were no defects in lung leukocyte recruitment (wk 5), pulmonary clearance, or delayed-type hypersensitivity in CCR5-/- mice. However, CCR5-/- mice had defects in leukocyte recruitment into the brain and, strikingly, in elimination of cryptococcal polysaccharide from the brain. In nonimmune CCR5-/- mice, there was a significant defect in macrophage recruitment after challenge with shed cryptococcal products (C. neoformans filtrate Ag) but not other nonspecific stimuli. Thus, CCR5 plays specific roles in innate immunity and organ-specific leukocyte trafficking during host defense against C. neoformans.

Animals↗
PubMed1987

Organ-specific expression of maize Adh1 is altered after a Mu transposon insertion.

A new, unstable, organ-specific Adh1 mutant was isolated from a Robertson's mutator line by germinating kernels under partial anaerobic conditions. Families of kernels which showed segregation of a conditional anaerobic lethal phenotype were identified. One mutant, Adh1-3F1124, was shown to express approximately 6% normal levels of ADH1 in seed and anaerobically treated seedlings but expresses normal levels of ADH1 in pollen, the male gametophyte. The ADH1 polypeptide encoded by the mutant allele was found to be indistinguishable from that encoded by the Adh1-3F progenitor but its message levels were lower in seed and seedlings. Robertson's mutator lines are known to carry Mu transposons that cause increased mutation rates. Genomic Southern analysis of Adh1-3F1124 and Adh1-3F showed the presence of a 1.85 kbp insertion at the 5' region of Adh1. Comparison of the DNA sequences revealed that a Mu 1-like element was inserted 31 bp 5' from the transcriptional start site of Adh1-3F1124 gene. The insertion of the Mu element creates an additional TATA box by duplicating the 9 bp genomic sequence--ATATAAATC--at the site of insertion. Consequently, there are two potentially functional TATA sequences, separated by the 1.85 kbp Mu element, 5' to the transcriptional start site. It is not yet understood how such an arrangement alters the organ-specific expression of Adh1.

Alcohol Dehydrogenase↗
PubMed2002

[Organ specific MRI contrast media in general practice].

Conventional MR imaging with non-specific gadolinium contrast agents is useful in the detection and staging of malignancies. With the development of organ-specific MR contrast agents, MR imaging is assuming an even larger role in body imaging. Two different classes of liver-specific agents, hepato-biliary agents targeted to the hepatocytes, and reticulo-endothelial agents (or Kupffer cell agents) targeted to the reticuloendothelial system in the liver and spleen, have been developed. MRI with liver-specific contrast agents is superior to helical CT for detection of liver metastases. Mangafodipir, which was originally developed as a liver-specific agent, has been shown to accumulate in the pancreas as well. Recent studies have revealed that mangafodipir-enhanced MRI is at least equal to spiral CT in the staging of pancreatic cancer and may be superior to CT in the detection of small cancers. Blood-pool contrast agents with a long blood half-life, such as ultrasmall iron oxide particles (USPIO), have been developed for MR angiography. After the clearance from the vascular system, USPIO are taken up by phagocytes and accumulate in normal lymph, but not in metastatic nodes. This effect can be exploited to increase the accuracy of MRI in lymph node staging of cancer of head-neck, lung or pelvis. In conclusion, various organ-specific MR contrast agents with a wide range of clinical applications have been developed. Future studies will demonstrate the role of contrast-enhanced MRI in comparison with multi-detector array CT.

Contrast Media↗
PubMed2002

Interindividual variation and organ-specific patterns of glutathione S-transferase alpha, mu, and pi expression in gastrointestinal tract mucosa of normal individuals.

Glutathione S-transferase (GST) protein in gastrointestinal (GI) tracts of 16 organ donors, from whom all or substantial portions of the GI tract (stomach-colon) were available, was quantitated by HPLC and examined for interindividual variability/consistency of organ-specific patterns of expression. GSTP1, GSTA1, and GSTA2 were major components, and GSTM1 and GSTM3 were minor components. Consistent patterns of organ-specific expression were evident despite a high degree of interindividual variation of expression. GSTP1 was expressed throughout the GI tract and showed a decrease of expression from stomach to colon. GSTA1 and GSTA2 were expressed at high levels in duodenum and small intestine and expression decreased from proximal to distal small intestine. In contrast, GSTA1 and GSTA2 expression in colon and stomach of all subjects was low, particularly for colon where GSTA1 expression was 20- to 800-fold lower than that in corresponding small intestine. These consistent patterns of expression would suggest that compared to duodenum and small intestine, colon and to a lesser extent stomach always have low potential for GST-dependent detoxification of chemical carcinogens and are therefore at greater risk of genotoxic effects, particularly via substrates that are specific for GSTA1. This may be a factor in the greater susceptibility of stomach and colon to cancers compared to duodenum/small intestine.

Adolescent↗
PubMed1991

Evaluation of the DNA-repair host-mediated assay. III. Relationship between metabolic activation of dimethylnitrosamine and organ-specific differential lethality induced in E. coli indicator strains.

In the present study the sensitivity of differential lethality as an endpoint for monitoring the presence of organ-specific genotoxic factors within the DNA-repair host-mediated assay (HMA) was determined. The induction of differential lethality in chemically exposed animals was assessed by measuring the recovery ratio Q, i.e., the relative survival of a repair-deficient E. coli K-12 derivative in comparison with its repair-proficient counterpart. Using untreated animals the interindividual fluctuation of the recovery ratio Q was first quantified and then used to determine the level below which it could be considered indicative of chemically induced differential lethality. This Q value was found to be 0.65 or lower. Using this criterion, a significant decrease of the Q value was observed in mice exposed to DMNA at a dose level as low as 15-30 mumole/kg, i.p. Inter-organ transport (liver----extrahepatic organs) of indicator bacteria was studied in reconstruction experiments using the direct-acting methylating agent MNU. These studies showed that inter-organ transport of indicator bacteria did not interfere with MNU-induced differential lethality. Time-related experiments were used to study the effects of inter-organ transport of genotoxic DMNA metabolites. In these studies significant, time-related differences were found in the induction of differential lethality in various organs of mice treated with DMNA. At a dose level of 200 mumole/kg (i.p.) genotoxic factors appeared within 25 min after administration in the liver. In the lungs and kidneys such factors appeared at a substantially slower rate, e.g., 20-120 min after DMNA administration. In persistence experiments differential lethality reached a maximum 30 min after DMNA treatment. No residual effects were detected 60 min after the injection of the carcinogen. These experiments showed that DMNA-derived genotoxic factors diffused from the liver into the bloodstream. The diffusion of these reactive species followed by their transport via the bloodstream to the lungs accounted for maximally 50% of differential lethality observed in bacteria recovered from the latter organ. In contrast, no indications were found for the transport of genotoxic DMNA metabolites from the liver via the bloodstream to the spleen and the kidneys. These results show that organ-specific effects observed in the DNA-repair HMA procedure after DMNA exposure can be primarily attributed to in situ metabolism, rather than diffusion of genotoxic metabolites from the liver to extrahepatic organs.

Animals↗
PubMed1980

[Organ-specific human prostate beta-globulin during tumor growth].

An organ specific protein antigen having an electrophoretic mobility of beta-globulin was demonstrated in human prostate. Its physicochemical properties (relative electrophoretic mobility, diffusion coefficient, molecular weight and relation to different precipitating agents) were determined. The indirect immunofluorescence technique revealed that this antigen is synthesized by the glandular epithelium of the main glands. A statistically significant decrease was found in the concentration of prostatic beta-globulin in tumors of the prostate. The synthesis of this protein was shown to start only in the period of puberty.

Antigens↗
PubMed1999

Role of autoreactive CD8+ T cells in organ-specific autoimmune diseases: insight from transgenic mouse models.

There is now convincing evidence that autoreactive CD8+ T cells can contribute to the pathogenesis of organ-specific autoimmune diseases. In the non-obese diabetic mouse, there is direct evidence that beta-islet cell-specific CD8+ cytotoxic T cells have a pathogenic effect. In human diseases such as autoimmune diabetes and multiple sclerosis, indirect evidence also suggests a role for CD8+ T cells in tissue damage, although their antigen specificity is unknown. Transgenic mouse models as well as the use of knockout mice have been instrumental in the identification of the role of autoreactive CD8+ T cells. Spontaneous models of CD8+ T-cell-mediated autoimmunity generated through transgenesis should help delineate the effector mechanisms leading to tissue destruction. The study of autoreactive CD8+ T cells and the characterization of their antigenic specificity should help unravel the pathophysiology of organ-specific autoimmune diseases, help identify exacerbating foreign antigens, and allow the design of antigen-specific immunotherapy targeting the pathogenic autoreactive T cells.

Animals↗
PubMed1984

A monoclonal antibody directed against an organ-specific liver cell membrane antigen in rabbits.

We generated monoclonal antibodies after immunization of mice with rabbit liver-specific protein (LSP) preparations. One of these antibodies (2D3) showed an organ-specific and species-specific binding pattern as determined by immunohistological and ELISA techniques. Immunoelectron microscopy studies demonstrated that this antibody is bound exclusively to the liver cell membrane except in the region of the bile canaliculi. We further describe a simple ELISA technique for the detection of anti-LSP antibodies. Our study clearly demonstrates the presence of at least 1 organ-specific liver cell membrane antigen in rabbit LSP and shows antigenic differences between areas of the plasma membrane of hepatocytes.

Animals↗
PubMed2003

Aire regulates negative selection of organ-specific T cells.

Autoimmune polyendocrinopathy syndrome type 1 is a recessive Mendelian disorder resulting from mutations in a novel gene, AIRE, and is characterized by a spectrum of organ-specific autoimmune diseases. It is not known what tolerance mechanisms are defective as a result of AIRE mutation. By tracing the fate of autoreactive CD4+ T cells with high affinity for a pancreatic antigen in transgenic mice with an Aire mutation, we show here that Aire deficiency causes almost complete failure to delete the organ-specific cells in the thymus. These results indicate that autoimmune polyendocrinopathy syndrome 1 is caused by failure of a specialized mechanism for deleting forbidden T cell clones, establishing a central role for this tolerance mechanism.

Animals↗
PubMed2001

The promoter of a basic PR1-like gene, AtPRB1, from Arabidopsis establishes an organ-specific expression pattern and responsiveness to ethylene and methyl jasmonate.

Antimicrobial proteins are a key feature underlying the deployment of both pre-formed and inducible defence responses. Probably the most well characterised class are the pathogenesis-related (PR) proteins, which are found in both basic and acidic isoforms. Here we describe the isolation and characterisation of a gene, designated AtPRB1, encoding a basic PR1-like protein from Arabidopsis. This protein showed high amino acid sequence identity with basic and acidic PR1 proteins from other plant species, for example PRB1 from Nicotiana tabacum and PR1 from Brassica napus, at 64% and 78% identity respectively. A genomic DNA fragment containing 2345 bp upstream from the putative transcriptional start site was fused to the gene encoding the luciferase (LUC) gene from Photinus pyralis in order to test for promoter activity. The resulting construct was transformed into Arabidopsis accession Col-0 and analysis of LUC activity, using an ultra-low-light imaging camera system, revealed that the AtPRB1 promoter established an exquisite organ-specific expression pattern. LUC activity was observed in flowers, stems and roots but not in leaf tissue. Superimposed upon this organ-specific expression pattern was responsiveness, in root tissue, to ethylene and methyl jasmonate (MeJA), important cues during the establishment of plant disease resistance. In contrast, AtPRB1::LUC gene expression was repressed in response to salicylic acid treatment. Analysis of a limited series of AtPRB1 5'-promoter deletion mutants, identified a number of promoter regions important for both the establishment of organ-specific expression and responsiveness to ethylene and MeJA. While AtPRB1 gene expression was not induced in response to an avirulent isolate of Peronospora parasitica in leaf tissue, this gene may contribute to horizontal resistance in other tissues and/or to MeJA- and ethylene-dependent defence responses engaged against necrotrophic pathogens in root tissue. It is anticipated that transgenic plants containing AtPRB1-based promoter::reporter constructs will provide useful tools for the future dissection of the cognate signalling networks regulating the expression of this gene.

Acetates↗
PubMed1994

Early adrenal hypofunction in patients with organ-specific autoantibodies and no clinical adrenal insufficiency.

Idiopathic Addison's disease occurs frequently in association with other organ-specific autoimmune diseases, and autoantibodies to adrenal cortex are markers of this condition. A variable asymptomatic period with subtle adrenal dysfunction may precede the onset of clinical manifestations. We studied the pituitary-adrenal axis by measuring plasma ACTH, cortisol, and 17 alpha-hydroxyprogesterone after ovine CRH (100 micrograms as an iv bolus) stimulation in 19 patients with organ-specific autoimmune disease and adrenal autoantibodies, in whom adrenal steroids were normal under baseline conditions and normally responsive to a standard ACTH stimulation test (250 micrograms). In all subjects, oCRH produced a normal increase in plasma ACTH. Plasma cortisol, which was normoresponsive in 11 subjects, showed little or no increase in 8 subjects. Two of these patients developed overt adrenal failure after 1 yr. The 17 alpha-hydroxyprogesterone response to oCRH, tested in 10 of 19 patients, paralleled that of plasma cortisol, excluding a steroidogenic block at the 21-hydroxylase site. Our data demonstrate the existence of a very early phase of Addison's disease in which adrenal function shows an impaired response to ovine CRH-stimulated ACTH.

17-alpha-Hydroxyprogesterone↗
PubMed1990

Islet cell and other organ-specific autoantibodies in Chinese children with insulin-dependent diabetes mellitus.

Islet cell autoantibodies (ICA) and other organ-specific autoantibodies were detected in 27 Chinese children with insulin-dependent diabetes mellitus (IDDM). The frequency of ICA within the first year of diagnosis was 67%, and it declined as the duration of the disease increased. The frequencies of thyroid microsomal autoantibodies and gastric parietal cell autoantibodies were 26% and 11%, respectively. None of the patients had adrenal autoantibodies. These results are comparable to those reported in Caucasian patients. Similar frequencies of islet cell autoantibodies and other organ-specific autoantibodies in children with IDDM between Chinese and Caucasians suggest that the autoimmune process may play an important role in the pathogenesis of Chinese children with IDDM.

Adolescent↗
PubMed1988

The induction of organ-specific antibodies during the graft-vs.-host reaction.

During the parent (P) into F1 hybrid graft-vs.-host reaction (GVHR), nuclear, leukocyte and erythrocyte autoantibodies are commonly seen. The specificity of these autoantibodies is reminiscent of those found in systemic lupus erythematosus (SLE) patients and SLE-prone mice. Organ-specific antibodies, however, including thyro-globulin (Tg) antibodies do not arise spontaneously. There have been conflicting reports about the ability of exogenous Tg to induce an anti-Tg response during the GVHR. We have re-examined this question in greater detail. Using the murine P----F1 GVHR system, the results of this work demonstrate that mouse thyroglobulin (MTg)-specific antibodies can be induced during a GVHR. However, mice must both be undergoing a GVHR, and have received exogenous MTg. The highest autoantibody response occurs if mice are injected with mouse thyroid extract or purified MTg at the time of P----F1 cell transfer. The anti-MTg response is MTg dose dependent. The ability to induce anti-MTg antibody was not major histocompatibility complex restricted, for both the DBA/2----B6D2F1 (low responder H-2 haplotypes to MTg), and AKR or DBA/2----AKD2F1 (high/low responder----high responder haplotype) GVHR gave similar responses. The anti-MTg titers peaked between days 7-10 and declined thereafter. In contrast, antibodies to dsDNA were not present at this early time, but developed after several weeks. We conclude that organ-specific autoantibodies can be induced during a GVHR if the appropriate antigen(s) are presented near the time of GVHR induction.

Acute Disease↗