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PubMed1995

Combinatorial libraries: new insights into human organ-specific autoantibodies.

The recent application of immunoglobulin (Ig) gene combinatorial library technology has led to a logarithmic increase in information concerning human, disease-associated, organ-specific autoantibodies of the IgG class. As reviewed here by Basil Rapoport, Stefano Portolano and Sandra McLachlan, the molecular cloning, analysis and expression of the genes for increasing numbers of these human, monoclonal autoantibodies is providing new insight into the genetic background and epitopic repertoires of such molecules.

Antibodies, Monoclonal↗

PubMed2003

Non-organ-specific autoantibodies in nonalcoholic fatty liver disease: prevalence and correlates.

Eighty-four consecutive subjects with nonalcoholic fatty liver disease (NAFLD) were tested for non-organ-specific autoantibodies (NOSA) by indirect immunoflorescence. Indices of insulin resistance and biochemical and anthropometric parameters were assessed. The overall prevalence of anti-nuclear-antibodies (ANA), smooth muscle antibodies (SMA) and anti-mitochondrial-antibodies (AMA) was 35.7% (30/84), 18 subjects (21.4%) being positive for ANA, 4 (4.7%) for SMA, 6 for ANA and SMA, and 2 for AMA. NOSA-positive subjects were older (P < 0.01) and mostly females (63.3%). No significant difference was found in the age-corrected parameters studied, except for copper and ceruloplasmin, which was more elevated in NOSA-positive patients. The subset of high titer (>1:100) ANA-positive patients had significantly (P < 0.05) greater insulin resistance than ANA-negative patients. In contrast, SMA-positive patients had higher gammaglobulin and significantly lower insulin resistance as compared to high-titer ANA-positive patients. In 3 NOSA-positive but not in NOSA-negative patients, liver biopsy disclosed features of overlapping NASH with autoimmune hepatitis, partially responding to diet combined with steroid treatment. In conclusion, NOSA positivity in NAFLD is more prevalent than in the general population. High-titre ANA but not SMA positivity is associated with insulin resistance.

Adult↗

PubMed1992

Evaluation of nonionic nitroxyl lipids as potential organ-specific contrast agents for magnetic resonance imaging.

Considering their intrinsic properties of accumulation in the hepatic tissue, we have synthesized nitroxyl-containing lipids as potential organ-specific contrast agents for magnetic resonance imaging (MRI). Their resistance to reduction by ascorbate and in liver homogenates, and their relaxivity in different media were investigated and compared to those of free carboxyl-Proxyl (3-carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl) and Tempamaine (4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl). With respect to the reduction rates by ascorbate, the lipid derivatives show the same well-known order of reactivity as carboxy-Proxyl and Tempamine, the five-membered nitroxyls being more stable than the six-membered compounds. However the binding of the piperidinoxyl compounds to the fatty acids confers to those lipid derivatives a markedly increased stability. Similarly, in liver homogenates, the nitroxyl lipids remained unchanged more than 20 min, contrarily to carboxy-Proxyl and Tempamine. The measurements of spin-lattice relaxation time (T1) in biological media have demonstrated a higher relaxivity of nitroxyl lipids, which can be related to their interaction with proteins. Tested in vivo, one of the synthesized compounds (0.75 mmol/kg) produced an enhancement of 44 +/- 12% of the hepatic signal 5 min after intraportal injection in T1-weighted images. The potential applicability of the other nitroxyl lipids as contrast agents for MRI was limited in the in vivo studies by an unexpected toxicity. Work is currently in progress to improve the therapeutic index of the present class of nitroxyl lipids.

Animals↗

PubMed2002

The severe G480C cystic fibrosis mutation, when replicated in the mouse, demonstrates mistrafficking, normal survival and organ-specific bioelectrics.

The majority of cystic fibrosis patients produce a mutant form of CFTR (DeltaF508) which has been shown to be mislocalized in both humans and mice. G480C, another clinically 'severe' mutation, has also been demonstrated to be defective in its intracellular processing, but when allowed to traffic in Xenopus oocytes showed similar channel characteristics to that of wild-type CFTR. We have replicated the G480C mutation in the murine Cftr gene using the 'hit and run' double recombination procedure. As expected, the G480C cystic fibrosis mouse model expresses the G480C mutant transcript at a level comparable to that of wild-type CFTR: The homozygous mutant mice were fertile, had normal survival, weight, tooth colour and no evidence of caecal blockage, despite mild goblet cell hypertrophy in the intestine. Analysis of the mutant protein revealed that the majority of G480C CFTR was abnormally processed and no G480C CFTR-specific immunostaining in the apical membranes of intestinal cells was detected. The bioelectric phenotype of these mice revealed organ-specific electrophysiological effects. In contrast to DeltaF508 'hit and run' homozygotes, the classic defect of forskolin-induced chloride ion transport is not replicated in the caecum, but the response to low chloride in the nose is clearly defective in the G480C mutant animals. The mild phenotype of these G480C mutant animals combined with the defective chloride transport in the nose uniquely provides a valuable resource to test novel pharmacological agents aimed at improving trafficking and correcting the electrophysiological defect in the respiratory tract.

Animals↗

PubMed2004

The anthropogenic contribution to the organic load of the Lippe River (Germany). Part II: Quantification of specific organic contaminants.

The major goal of this study was to investigate the organic pollution of a river on a quantitative basis. To this end, 14 anthropogenic contaminants which were identified in Lippe River water samples as reported in part I (Dsikowitzky et al., submitted parallel to this manuscript) were surveyed. Dissolved organic loads of the specific compounds were calculated on the basis of their concentrations in water and river runoff on the day of sampling. The organic loads of each compound were compiled along the longitudinal section of the river in order to generate individual spatial pollution profiles. It was observed that distribution of organic loads along the river showed distinctive patterns, depending upon the input situation and physico-chemical properties of the compound. The compounds were classified into three types of which Type 1, due to their stability in the aqueous phase, are of special interest for potential application as anthropogenic markers.

Environmental Monitoring↗

PubMed2005

Clinical impact of non-organ-specific autoantibodies on the response to combined antiviral treatment in patients with hepatitis C.

BACKGROUND: Hepatitis C virus (HCV)-related chronic hepatitis is frequently associated with non-organ-specific autoantibodies (NOSAs), but available data about the relationship between NOSA positivity and the effect of antiviral therapy in persons with hepatitis C are few and controversial. Our aim was to evaluate the impact of NOSA positivity on the outcome of combined antiviral therapy in HCV-positive patients. METHODS: A total of 143 consecutive adult patients with hepatitis C were studied. Antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), and anti-liver/kidney microsomal antibody type 1 (LKM1) were detected by indirect immunofluorescence. All patients were treatment naive and received combined antiviral therapy (interferon [IFN]-ribavirin) after enrollment in the study. Patients were classified as nonresponders if HCV RNA was detectable after 6 months of therapy, as relapsers if abnormal transaminase levels and reactivation of HCV replication were observed after the end of treatment, and as long-term responders if transaminase levels were persistently normal and HCV RNA was undetectable 6 months after the end of treatment. RESULTS: Thirty-seven patients (25%) were NOSA positive (SMA was detected in 19 patients, ANA in 10, ANA and SMA in 4, LKM1 in 3, and SMA and LKM1 in 1). The prevalence of long-term response was similar between NOSA-positive patients and NOSA-negative patients (48.6% vs. 56.6%; P=not significant). Compared with HCV genotype 1 (HCV-1), HCV genotypes other than 1 were more often associated with long-term response among NOSA-positive patients (93.3% vs. 30%; P=.0017). The overall rate of long-term response, irrespective of NOSA status, was 54.5%. Detection of HCV-1 and elevated gamma-glutamyl transpeptidase serum levels were independent negative prognostic factors of treatment response (P=.007 and P=.026, respectively). CONCLUSIONS: Combined antiviral treatment (IFN-ribavirin) is safe and effective in NOSA-positive patients with hepatitis C, even if long-term response is less likely in those infected with HCV-1.

Adult↗

PubMed2001

Organ-specific characteristics of blood supply in acute hemorrhage in rats with different resistance to circulatory hypoxia.

The present study is aimed toward a comparative real-time analysis of organ-specific characteristics of the liver, kidney and brain blood supply in the dynamics of acute massive hemorrhage in rats with different resistance to circulatory hypoxia. The survival time of experimental animals after the arrest of bleeding was used as a criterion of their resistance to acute blood loss. The rats with high resistance (HR) to hypoxia had the survival time not less than 3 h, while the rats with low resistance (LR) to hypoxia lived not more than 1.5 h. A marked decrease in arterial organ blood flow velocity and tissue perfusion of the liver, kidney and brain in LR and HR rats was observed at the end of acute massive hemorrhage in ultrasonic and Doppler flowmetry. In the post-hemorrhagic period the organ hemodynamics and microcirculation showed a tendency to a further decrease in LR rats. In HR animals the blood flow velocities in hepatic, renal and common carotid arteries were temporarily restored to 115-120, 85-90 and 60-65%, respectively, following the bleeding arrest. In the compensated phase of the post-hemorrhagic period the brain blood flow was maintained at this new post-hemorrhagic level due to autoregulatory changes in the carotid resistance. Such a response of brain blood vessels of HR rats is considered to be an adaptive response which protects the brain from autoreperfusion- and reoxygenation-induced injuries under conditions of posthemorrhagic autorestoration of tissue circulation.

Journal Article↗

PubMed2002

Organ-specific alternative transcripts of KNOX family class 2 homeobox genes of rice.

We identified three genes (HOS58, HOS59 and HOS66) of rice (Oryza sativa), which encode predicted proteins with the KNOX family class 2 homeodomain. These proteins contain three conserved domains, the KNOX domain, ELK domain and homeodomain, from an N-terminus to a C-terminus. In addition to similarity of predicted amino acid sequences, these genes showed a similar exon/intron structure. cDNA cloning and reverse transcription-polymerase chain reaction analyses of these genes indicated tissue-specific expression of alternative transcripts. The expression of the longer mRNAs of HOS58 (HOS58L) and HOS59L was detected in all organs examined such as roots, leaf blades, leaf sheaths, flowers and calli, whereas the shorter mRNAs of HOS58 (HOS58S) and HOS59S were expressed in leaf blades, leaf sheaths and flowers. The expression of HOS66L was detected in roots, leaf blades, leaf sheaths and flowers, whereas the expression of HOS66S was detected in roots and flowers. The alternative transcripts of HOS66 arose by use of alternative transcription start sites. The longer transcripts contained an exon 1 which encodes an alanine/glycine-rich region, whereas the shorter ones lacked it. These results suggest that the expression of the alternative transcripts is organ-specific, and their products have different degrees of abilities for activation or repression of transcription.

Alternative Splicing↗

PubMed2000

Cloning of the full-length coding sequence of rat liver-specific organic anion transporter-1 (rlst-1) and a splice variant and partial characterization of the rat lst-1 gene.

The full-length coding sequence of rat liver-specific organic anion transporter-1 (lst-1) and its splice variant have been cloned. The full-length rat lst-1 (designated rlst-1a) encodes a protein containing 687 amino acids and has 12-putative transmembrane domains, multiple potential N-glycosylation and phosphorylation sites. Therefore, rat lst-1a has 35 additional amino acid residues compared to the previously reported rat lst-1. A splice variant (designated rlst-1c) reported in this communication encodes a protein containing 654 amino acids and has 10-putative transmembrane domains. PCR analysis suggests that rlst-1a is the most abundant form in liver. Phylogenetic analysis reveals that rat lst-1a is an ortholog of human LST-1 (hLST-1) and mouse lst-1 (mlst-1). The rlst-1 gene is composed of 15 exons and 14 introns. Analysis of exon-intron boundary reveals that the splice variant rlst-1c lacks the entire exon 7, while the previously reported rat lst-1 (designated herein as rlst-1b) lacks approximately half of exon 10, and the splicing has occurred through alternative usage of a splice donor site within exon 10.

Alternative Splicing↗

PubMed1979

Donor- and organ-specific evaluation of antibodies eluted from canine lung allografts rejected by immunosuppressively treated and untreated recipients.

Using elution techniques, the humoral lung allograft rejection in immunosuppressively treated versus untreated recipients is analyzed at the donor organ specific level. The antibodies were evaluated quantitatively and qualitatively by elution of lung graft bound immunoglobulins and by testing the eluates against donor lung antigen using passive hemagglutination and indirect immunofluorescence. By correlating the results in those assays, a considerable amount of humoral anti-donor lung antibodies could be proved only in dogs not treated immunosuppressively, and there was no accordance with the results of direct immunofluorescence by quantification. The difference in the organ-bound antibodies between immunosuppressively treated and untreated lung grafts seems to be remarkable because of a similar mononuclear infiltration. Thus, enabling a specific improvement of some previous speculations about the lung-specific humoral alloimmune reaction, this type of rejection seems to be similar to rather stereotypical allograft rejection, but may be modified by a standard immunosuppression with methylprednisolone and azathioprine.

Animals↗

PubMed1985

Involvement of sialic acid on endothelial cells in organ-specific lymphocyte recirculation.

Mouse lymphocytes incubated on cryostat-cut sections of lymphoid organs (lymph nodes and Peyer's patches) specifically adhere to the endothelium of high endothelial venules (HEV), the specialized blood vessels to which recirculating lymphocytes attach as they migrate from the blood into the parenchyma of the lymphoid organs. Treatment of sections with sialidase eliminated the binding of lymphocytes to peripheral lymph node HEV, had no effect on binding to Peyer's patch HEV, and had an intermediate effect on mesenteric lymph node HEV. These results suggest that sialic acid on endothelial cells may be an organ-specific recognition determinant for lymphocyte attachment.

Animals↗

PubMed1997

Biases among hospital personnel concerning donation of specific organs and tissues: implications for the donation discussion and education.

Previous research has established that healthcare professionals who are being trained to talk with families about donation have strong personal preferences for and aversions to the donation of specific organs and tissues. This article examines the possible reasons for such preferences and/or aversions. Among the population studied, strong personal preferences for donation of specific anatomical gifts predominantly were associated with pragmatic and moral or ethical justifications. Strong aversions were associated with pragmatic reasoning and mystical thinking, represented as ancient fears. The findings suggest the need for changes in the way the donation option is offered to families and the way hospital personnel are educated.

Attitude of Health Personnel↗

PubMed2002

Pathogenic effects of anti-Fc gamma receptor IIIb (CD16) on polymorphonuclear neutrophils in non-organ-specific autoimmune diseases.

The receptors FcgammaRIIIb and FcgammaRIIa for the Fc portion of IgG are naturally expressed in polymorphonuclear neutrophils (PMN). Autoantibodies (Ab) against FcgammaRIIIb exist in patients with non-organ-specific disease. These may be categorized, based on the results of an indirect immunofluorescence (IIF) test for the detection of anti-membrane-bound FcgammaRIIIb autoAbs, and an enzyme-linked immunosorbent assay for that of soluble FcgammaRIIIb-recognizing autoAbs. The IIF+ autoAbs are not cytotoxic, and prolong the survival of the cells. The autoAb-triggered anti-apoptotic signal may be transduced through FcgammaRIIa and/or CD11b, the beta-chain of the neighboring complement receptor type 3. However, FcgammaRIIIb appears to be as competent as FcgammaRIIa, because the results obtained using the respective monoclonal Abs are additive. Soluble FcgammaRIIIb binds to CD11b and produces similar effects, suggesting that autoAb-stimulated FcgammaRIIIb can work in concert with CD11b. Anti-FcgammaRIIIb-conditioned supernatant of PMNs induces the transcription of messenger RNA for granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF, followed by the release of these anti-apoptotic factors. The delay in apoptosis is accompanied by a down-regulated expression of Bax. Thus, apoptosis of aged PMNs can be modulated by signaling through FcgammaRIIIb, which may occur in patients with PMN-binding anti-FcgammaRIIIb autoAbs.

Animals↗

PubMedDate not supplied

[Specific organic compounds in the human waste products].

It is for the first time that chromato-mass-spectrometry has been used to examine human wastes. The data on the excretion rate of specific organic compounds can be employed to predict the content of toxic metabolites in the enclosed environment, to give their biomedical characterization, and to diagnose unfavorable changes in the body.

Feces↗

PubMed1999

Prevalence of non-organ-specific autoantibodies and chronic liver disease in the general population: a nested case-control study of the Dionysos cohort.

BACKGROUND: Several retrospective and prospective studies report an increased prevalence of non-organ-specific autoantibodies (NOSAs) in patients with hepatitis C virus (HCV) related chronic liver disease (CLD). Some of the data so far available are controversial and the true prevalence of NOSAs in the general population is still not known. AIM: To explore the prevalence of NOSAs, their relation to different HCV genotypes, and the presence and severity of CLD in the general population of Northern Italy. PATIENTS: All 226 anti-HCV positive and 87 hepatitis B surface antigen (HBsAg) positive patients of the Dionysos cohort study were analysed and compared with sex and age matched cases (226) negative for both anti-HCV antibody and HBsAg selected from the same cohort. METHODS: Sera tested for the presence of NOSAs (anti-nuclear antibody (ANA), anti-smooth muscle antibody (SMA), and anti-liver/kidney microsomes type 1 antibody (LKM1)) were screened by indirect immunofluorescence at a 1:40 serum dilution. HCV RNA and HCV genotypes were also determined by nested polymerase chain reaction (PCR) of the 5' non-coding region and by PCR amplification of the core region with type specific primers. RESULTS: The overall prevalence of NOSA reactivity was significantly higher in anti-HCV positive subjects than in both normal and pathological controls (25% v 6% and 7% respectively, p<0.05). ANA, SMA, and LKM1 occurred in 16, 10, and 1. 3% of cases respectively. No specific association between NOSAs and a specific HCV genotype was found. NOSAs were found more often associated with more than one genotype (35.7%) and with untypable genotypes (34.6%), although the association was not statistically significant. NOSAs were associated with HCV RNA and CLD but not with the presence of cirrhosis and/or hepatocellular carcinoma. On univariate analysis, NOSA reactivity was independently associated with abnormal alanine aminotransferase (p<0.01) and gamma-glutamyltranspeptidase levels (p<0.05). The risk for the presence of NOSAs was 5.1 times higher in anti-HCV subjects than in controls. CONCLUSIONS: In the general population the prevalence of NOSAs is higher in anti-HCV positive subjects than in normal or disease controls. Moreover NOSAs are associated with CLD and with a more active disease in terms of alanine aminotransferase activity.

Adolescent↗

PubMed2003

Organ-specific expression of brassinosteroid-biosynthetic genes and distribution of endogenous brassinosteroids in Arabidopsis.

Brassinosteroids (BRs) are steroidal plant hormones that are essential for growth and development. There is only limited information on where BRs are synthesized and used. We studied the organ specificity of BR biosynthesis in Arabidopsis, using two different approaches: We analyzed the expression of BR-related genes using real-time quantitative reverse transcriptase-polymerase chain reaction, and analyzed endogenous BRs using gas chromatography-mass spectrometry. Before starting this study, we cloned the second BR-6-oxidase (BR6ox2) gene from Arabidopsis and found that the encoded enzyme has the same substrate specificity as the enzyme encoded by the previously isolated 6-oxidase gene (BR6ox1) of Arabidopsis. Endogenous BRs and the expression of BR-related genes were detected in all organs tested. The highest level of endogenous BRs and the highest expression of the BR6ox1, BR6ox2, and DWF4 genes were observed in apical shoots, which contain actively developing tissues. These genes are important in BR biosynthesis because they encode the rate-limiting or farthest downstream enzyme in the BR biosynthesis pathway. The second highest level of endogenous BRs and expression of BR6ox1 and DWF4 were observed in siliques, which contains actively developing embryos and seeds. These findings indicate that BRs are synthesized in all organs tested, but are most actively synthesized in young, actively developing organs. In contrast, synthesis was limited in mature organs. Our observations are consistent with the idea that BRs function as the growth-promoting hormone in plants.

Amino Acid Sequence↗

PubMed1993

[Insulin-dependent diabetes and organ specific autoimmune diseases: a retrospective clinical and immunogenetic study of 165 consecutive cases].

We analysed clinical and immunological indexes in 165 caucasian adult patients presenting insulin-dependent diabetes mellitus associated with other organ-specific autoimmune diseases (type Ib IDDM). As diagnostic strategy, we recommend testing thyrogastric autoantibodies at diabetes onset and islet-cells antibodies three years after.

Adolescent↗

PubMed2001

Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects.

OBJECTIVE: In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders. RESEARCH DESIGN AND METHODS: In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method): insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies (radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence); anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay). RESULTS: The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes-associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P < 0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients (P < 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recentonset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive-specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P < 0.05). CONCLUSIONS: We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre-type 1 diabetes.

Adolescent↗