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PubMed1987

[Organ specificity and common factors in latent tumors].

Materials displaying latent tumors were obtained from autopsy cases and from surgically removed organs at our hospital during the past 20 years. Organ specificity and the common factors of these latent tumors indicated the following: a high incidence of latent tumors was found in the small organs and/or endocrine organs (prostate, thyroid, pancreas). In addition, it was found that these tumorous organs are of sufficient interest for clinicopathologic study (stomach, esophagus). Latent tumors show an increasing tendency to manifestation at an advanced age. Further, shade of difference between females and males has been noted in comparing clinically manifested tumors. Also latent tumors occasionally coexist with multiple primary neoplasms in the same and indifferent organs. The histological characteristics of latent tumors is frequently associated with thickened capsules and fibrosis. It has been speculated that the appearances of a reaction are local autoimmune mechanisms and the hosts suppressive effects against the proliferation of tumors. The biological behaviour of latent and clinical tumors should be considered different.

Age Factors↗
PubMed2001

Possible involvement of EBV-mediated alpha-fodrin cleavage for organ-specific autoantigen in Sjogren's syndrome.

A cleavage product of alpha-fodrin may be an important organ-specific autoantigen in the pathogenesis of Sjogren's syndrome (SS), but the mechanisms of alpha-fodrin cleavage remain unclear. Since EBV has been implicated in the pathogenesis of SS, we determined whether EBV activation could induce the SS-specific 120-kDa autoantigen alpha-fodrin. ZEBRA mRNA expression, a marker for activation of the lytic cycle of EBV, was found in the salivary gland tissues from SS patients, but not in those from control individuals. ZEBRA-expressing lymphoid cells were also found in the SS glands in double-stained immunohistochemistry. Furthermore, a significant link between production of Abs against 120-kDa alpha-fodrin and reactivated EBV Ag was found in sera from patients with SS, but not in those from control individuals. EBV-activated lymphoid cells showed specific alpha-fodrin cleavage to the expected 120-kDa fragments in vitro. Pretreatment with caspase inhibitors inhibited cleavage of alpha-fodrin. Thus, an increase in apoptotic protease activities induced by EBV reactivation may be involved in the progression of alpha-fodrin proteolysis in the development of SS.

Amino Acid Chloromethyl Ketones↗
PubMed1986

Organ-specific autoimmunity: a 1986 overview.

The normally functioning immune system is subject to intricate networks of regulatory mechanisms: it is therefore not surprising to find that autoimmune diseases present a complex pathogenic picture in which the relative contributions of various factors probably determine the precise nature and course of disease. This is particularly evident in the effector mechanisms of organ-specific autoimmunity which are described in this chapter. These ultimately give rise to the disease symptoms, and can be directly cytotoxic, or may either stimulate or block functional activity or growth of the target cells. Their various contributions to human diseases are becoming more firmly established, as in Type I diabetes, or are only now being described, as in the case of EC-Ab in protracted diarrhea of infancy and as evidenced by the growing lists of receptor-stimulating or -blocking antibodies. The nature and precise location of relevant autoantigens is also coming under closer scrutiny. The answers to the question of why these diseases arise in the first place remain more elusive. However, it is again likely that a variety of factors can contribute. The attractive possibility of a role for idiotypic interactions is gaining ground, particularly within the context of antibodies to hormones and their receptors. Another potential mechanism which we believe may be of central importance, particularly in the development of organ-specific destructive autoimmunity, and which we have discussed here in detail, is the aberrant expression of HLA Class II molecules by target cells. Whether this is actually an initiating factor is presently not known, but its potential for promoting pathogenesis both early and late in the process is clear. Furthermore, the complex nature of the regulation of epithelial Class II expression may help to explain the heterogeneity of features and course of disease in different patients with the same underlying pathology. All these advances in our basic understanding of the disease processes should ultimately lead to more effective and specific means of therapeutic intervention.

Animals↗
PubMed2005

Dietary retinoic acid alters vitamin A kinetics in both the whole body and in specific organs of rats with low vitamin A status.

To study the effects of exogenous retinoic acid on vitamin A (VA) metabolism, we analyzed previously collected tracer kinetic data on VA dynamics in rats with low vitamin A (LA) status either with (LA+RA) or without (LA) retinoic acid supplementation. In spite of low VA intake ( approximately 7 nmol/d), the LA+RA rats were in a slight positive VA balance (0.325 nmol/d vs. -0.168 for LA) for 35 d after administration of [(3)H]retinol-labeled plasma. Using the Windows version of the Simulation, Analysis and Modeling software, we determined that the VA disposal rate was lower in LA+RA than in LA rats (3.98 vs. 5.00 nmol/d) as was the system fractional catabolic rate (0.0548 vs. 0.110 d(-1)). Model-predicted traced mass and residence times (the average time that a molecule of retinol spends in an organ before irreversible loss) were higher for liver (19.4 vs. 1.8 nmol; 5.0 vs. 0.36 d), kidneys (7.0 vs. 2.1 nmol; 1.4 vs. 0.42 d), small intestine (2.1 vs. 0.42 nmol; 0.43 vs. 0.084 d), and lungs (3.2 vs. 0.10 nmol; 1.6 vs. 0.021 d) in the LA+RA compared with the LA rats; there were no major differences for eyes, testes, adrenal glands, or remaining carcass. We conclude that RA supplementation of rats with low VA status affects VA metabolism at both the whole-body level and in specific organs. These organs (liver, kidneys, small intestine, and lungs) have the enzymatic capability and an appropriate cell type to store retinyl esters.

Animals↗
PubMed2006

Organ-specific metastatic tumor cell adhesion and extravasation of colon carcinoma cells with different metastatic potential.

Adhesive and invasive characteristics appear to be crucial for organ-specific metastasis formation. Using intravital microscopy we investigated the relation between the metastatic potential of colon carcinoma cells and their adhesive and invasive behavior during early steps of metastasis within microvasculatures of rat liver, lung, intestine, skin, muscle, spleen, and kidney in vivo. Colon carcinoma cells with low (HT-29P), intermediate (KM-12C), and high (HT-29LMM, KM-12L4) metastatic potential were injected into nude or Sprague-Dawley rats. Initial interactions with host organ microvasculatures were semiquantitatively analyzed throughout 20 to 30 minutes. Circulating cells passed microvessels in all observed organs without size restriction. All cell lines showed high adhesion rates, independent from their metastatic potential, within liver and lung but very rarely in other organs. Diameters of involved microvessels were larger than diameters of adherent tumor cells. Cell extravasation of highly metastatic HT-29LMM and KM-12L4 cells into liver parenchyma was significantly higher compared to low metastatic cells (P<0.05). Our results indicate that colon carcinoma cells can arrest in target organs without size restriction. Cell adhesion of circulating tumor cells occurred in metastatic target organs only, likely attributable to specific interactions. Migration into target organs correlated with their metastatic potential.

Animals↗
PubMed2005

Infliximab treatment does not induce organ-specific or nonorgan-specific autoantibodies other than antinuclear and anti-double-stranded DNA autoantibodies in Crohn's disease.

BACKGROUND: Treatment of Crohn's disease (CD) by infliximab has been associated with the induction of antinuclear (ANA) and anti-double stranded DNA (dsDNA) autoantibodies. As yet, little is known about the effect of the humoral response induced by infliximab on the production of other organ-specific or nonorgan-specific autoantibodies. METHODS: Thirty-five patients with CD treated with repeated infusions of infliximab were prospectively studied. Thirty-two patients with CD who had never received infliximab served as controls. A large panel of autoantibodies directed against phospholipid, beta2-glycoprotein I, mitochondria, smooth muscle, liver--kidney microsomes, filaggrin, thyroid, adrenals, and rheumatoid factor was tested along with ANA and anti-dsDNA autoantibodies during 1 year of intermittent treatment with infliximab. Autoantibodies were detected using the appropriate methods (i.e., indirect immunofluorescence, a radioimmunological technique, and ELISA assays). RESULTS: Induction of ANA and anti-dsDNA autoantibodies was observed in 53% and 35% of infliximab-treated patients with CD, respectively. Overall, no other organ-specific or nonorgan-specific autoantibodies were detected during follow-up. A single patient who developed ANA and anti-dsDNA autoantibodies showed clinical features consistent with drug-induced lupus, which quickly resolved after discontinuation of infliximab. The other patients with CD receiving infliximab did not develop any clinical symptoms of autoimmunity. CONCLUSIONS: The humoral response induced by infliximab was restricted to ANA and anti-dsDNA autoantibodies, which persist for up to 1 year of follow-up. We confirmed the significant prevalence of such autoantibodies induced by infliximab in CD, but they are not generally associated with clinical signs of autoimmunity.

Adult↗
PubMed2026

COVID-19 multi-omics reveal organ-specific responses and biomarkers.

OBJECTIVE: Post-COVID-19 syndrome is characterised by persistent immune dysfunction and multi-organ sequelae. This study aimed to characterise the systemic blood molecular landscape induced by SARS-CoV-2 infection and identify prognostic markers linked to skeletal muscle mass loss, a key driver of poor outcomes. METHODS: We enrolled 30 healthy controls and 307 COVID-19 patients, collecting 422 plasma samples for integrated proteomic and metabolomic profiling to investigate organ-specific molecular alterations in COVID-19. RESULTS: We comprehensively mapped the molecular landscape of COVID-19, encompassing immune, tissue-specific, and metabolic perturbations, and delineated their interactions. Focusing on organ-damage-related molecular patterns associated with disease progression and mortality, we found that skeletal muscle mass loss contributed to poor clinical outcomes of COVID-19 (p&#x2009;<&#x2009;0.0001). Dysregulated arginine metabolism emerged as a key metabolic signature in fatal COVID-19 cases, with GLUL, GOT1, and citrulline showing significant correlation with skeletal muscle mass loss. Longitudinal analyses further revealed that reduced citrulline levels underlie the poor outcome of COVID-19 patients with muscle mass loss. These findings were robustly supported through multiple approaches: Mendelian randomization confirmed causal relationships between citrulline depletion, sarcopenia/fat-free mass loss, and COVID-19 mortality (p&#x2009;<&#x2009;0.05), transcriptomic analyses of SARS-CoV-2-infected golden hamsters (GSE231910) provided additional support in enrichment of arginine biosynthesis (FDR&#x2009;<&#x2009;0.05), and in vitro experiments further demonstrated that citrulline depletion promotes pro-inflammatory M1 macrophage polarisation &#x2014; a key immunological feature of critical COVID-19. Leveraging these insights, we developed a skeletal muscle loss-specific prognostic prediction model for COVID-19 using GLUL, GOT1, and citrulline. This model effectively stratified patients into high- and low-risk groups (p&#x2009;=&#x2009;0.035). CONCLUSION: Our study advances the understanding of COVID-19-induced organ pathophysiology and provides a foundation for developing targeted therapeutic strategies for post-COVID sequelae.

COVID-19↗
PubMed2007

Microarray analysis of Fusarium graminearum-induced wheat genes: identification of organ-specific and differentially expressed genes.

A wheat cDNA microarray consisting of 5739 expressed sequence tags (ESTs) was used to investigate the transcriptome patterns of the glume, lemma, palea, anther, ovary and rachis dissected from infected wheat spikes after inoculation with the fungus Fusarium graminearum, the causal agent of fusarium head blight (FHB) disease. Stringent conditions were employed to reduce the false discovery rate. The significance analysis of microarrays (SAM) was used to identify transcripts that showed a differential response between fungal-challenged vs. control plants. To verify the microarray data, Northern blot analysis was carried out on randomly selected up-regulated clones. We observed 185 (3.2%) up-regulated and 16 (0.28%) down-regulated ESTs in the six organs constituting the wheat spike. Many up-regulated ESTs (46.67%) showed no homology with sequences of known functions, whereas others showed homology with genes involved in defence and stress responses, the oxidative burst of H(2)O(2), regulatory functions, protein synthesis and the phenylpropanoid pathway. The monitoring of genes in specific organs avoided the averaging of expression values over multiple organs that occurs when using data from the whole spike. Our data allowed us to uncover new up-regulated genes expressed in specific organs. The study revealed that each organ had a defined and distinctive transcriptome pattern in response to F. graminearum infection.

DNA, Complementary↗
PubMed2002

Physiologic bladder evacuation with selective sacral root stimulation: sinusoidal signal and organ-specific frequency.

In patients with spinal cord injury above S2, who characteristically have both detrusor hyperflexia and sphincteric spasm, sacral anterior root stimulation can evacuate the bladder, but sacral deafferentation is needed to eliminate the hyperreflexia for normal bladder filling. The common stimulation parameters for these patients activate the detrusor and the external urethral sphincter simultaneously (detrusor-sphincter dyssynergia), and the resultant post-stimulus voiding is not physiologic. We sought to determine organ-specific stimulation parameters. In 20 male dogs, the rectangular pulse and sinusoidal signal forms were evaluated with a variety of parameters for stimulation of S2 and S3 anterior roots extra- and intradurally (i.e., stimulation frequency and voltage, uni- versus bilateral electrode placement, and degree of bladder filling). New torpedo-shaped bipolar electrodes were used, adjusted to neural diameter. The best results were recorded with intradural bilateral sinusoidal signal. Sphincteric fatigue was produced by pre-stimulating S2 with 104+/-17 Hz and 0.8+/-0.1 V for 10 to 15 seconds before S3 stimulation. S3 stimulation with 16+/- 2.1 Hz and 0.4+/-0.1 V evoked a detrusor pressure of 28.7+/-3.0 cm H2O above the sphincteric pressure. Selective anterior root stimulation with organ-specific stimulation parameters can effect initial sphincteric fatigue to achieve physiologic voiding.

Animals↗
PubMed1999

Anti-cytoplasmic autoantibodies reactive with epithelial cells of the salivary gland in sera from patients with Sjögren's syndrome: their disease- and organ-specificities.

To test whether the autoantibodies reactive with epithelial cells of the salivary gland in sera from Sjögren's syndrome (SS) patients are specific for the organ and the disease, tissue reactivities of serum IgG obtained from the patients with SS and oral lichen planus (OLP), another immune-mediated oral mucosal disease, were examined by immunohistochemistry and Western blotting. IgG purified from the sera of SS patients specifically localized not only on the nuclei but also on the cytoplasm of the salivary gland epithelial cells. On the other hand, no convincing staining of the epithelial cells was observed when IgG purified from the sera of OLP patients or those from healthy controls were used for immunohistochemistry. No cytoplasmic staining was observed when sections of kidneys and pancreas were stained with SS patients' IgG. In Western blotting performed by using lysates of a submandibular gland as antigens, all the IgG prepared from the SS patients reacted prominently with several protein bands, including those specific for the disease and the organ. These results suggest that production of autoantibodies reacting with the cytoplasm of salivary gland epithelial cells is a characteristic of SS, and may play a role in the pathogenesis of the sialadenitis.

Adult↗
PubMed2001

The renin-angiotensin system: from the renal basis to an organ-specific subsystem in the pancreas.

Not only is the renin angiotensin system or its components found morphologically in many organs, it also exerts many different regulatory functions such as contributing to systemic homeostasis as well as to organ-specific regulation. The presence of the components of the renin angiotensin system in the pancreas was discovered only a few years ago. Physiological and pathophysiological stimuli were able to modify, in part, the gene expression and the occurrence of some of these components. Because of the important clinical significance of pancreatic diseases such as pancreatitis, research should follow every traces of the renin angiotensin system in the pancreas: impairment of microcirculation via hypoxia mediated up-regulation with the subsequent further deterioration of the oxygen supply seems to be the most obvious mechanism. There are many possible approaches to a better understanding of problems that are associated with diseases such as different kinds of pancreatitis; basic studies in animal models are oriented toward microcirculation, cellular function and the time course of modified gene expression after stimuli such as hypoxia; a clinical approach must reevaluate different correlations between clinical parameters of hypertension and those of pancreatic diseases.

Animals↗
PubMed1996

Interferon-gamma is required during the initiation of an organ-specific autoimmune disease.

Autoimmune gastritis induced by neonatal thymectomy of mice is a CD4+ T cell-mediated organ-specific autoimmune disease. The characteristic features of autoimmune gastritis, which include a mononuclear infiltrate within the gastric mucosa, loss of parietal and chief cells and circulating autoantibodies to the gastric H+/K+ ATPase, appear 6-10 weeks after thymectomy. Here we have assessed the role of interferon-gamma (IFN-gamma) in the pathogenesis of the gastric lesion. Splenic T cells derived from mice with gastritis produced three- to tenfold more IFN-gamma than T cells from normal animals after stimulation with anti-CD3 antibodies. Treatment of neonatally thymectomized mice at weekly intervals for 6 or 12 weeks with a neutralizing rat monoclonal antibody to mouse IFN-gamma abolished the production of anti-gastric autoantibodies and decreased the incidence of gastric mononuclear infiltrates from the 69% observed in normal rat immunoglobulin (Ig)-injected mice to 16%. Further, in mice treated with only a single dose of anti-IFN-gamma immediately after thymectomy at 3 days after birth, the incidence of autoimmune gastritis was 1/19 compared to 8/19 in normal rat Ig-injected mice. Prevention of autoimmunity by neutralization of IFN-gamma several weeks prior to the detection of a pathological lesion strongly suggests that IFN-gamma plays an essential role in the initiation of the gastric autoimmune response.

Animals↗
PubMed2006

IL-10-deficiency unmasks unique immune system defects and reveals differential regulation of organ-specific autoimmunity in non-obese diabetic mice.

Interleukin (IL)-10 is a potent anti-inflammatory cytokine and ablation of IL-10 exacerbates Th1-type autoimmune diseases. Even though type 1 diabetes (T1D) in NOD mice is believed to be Th1-mediated, the incidence and severity of T1D is unaltered in IL-10-deficient NOD mice raised under pathogen-free conditions. We describe for the first time, the outcome of IL-10 deficiency on islet and other organ-specific autoimmunity in NOD mice raised in a conventional facility. IL-10-deficient NOD mice under such conditions were protected from spontaneous as well as cyclophosphamide-induced diabetes, but were susceptible to diabetes induced by adoptive transfer of splenocytes from spontaneously diabetic NOD mice. Whereas the incidence of rectal prolapse was very high in this NOD.IL-10(-/-) mouse colony, IL-10-deficient C57Bl/6 mice raised under similar conditions seldom developed rectal prolapse. While injection of complete Freund's adjuvant (CFA) significantly reduced insulitis, it did not ameliorate colitis in IL-10-deficient NOD mice indicating differential regulation of organ-specific autoimmunity by CFA. Phenotypic characterization of IL-10(-/-) mice revealed a significant increase in splenic macrophage numbers in NOD but not on the B6 background. This was accompanied by a heightened systemic inflammatory cytokine response and mortality following in vivo challenge with a toll-like receptor 9 agonist, CpG-containing DNA.

Animals↗
PubMed2005

Transcriptional modulations by RXR agonists are only partially subordinated to PPARalpha signaling and attest additional, organ-specific, molecular cross-talks.

Nuclear hormone receptors (NR) are important transcriptional regulators of numerous genes involved in diverse pathophysiological and therapeutic functions. Following ligand activation, class II NR share the ability to heterodimerize with the retinoid X receptor (RXR). It is established that RXR activators, rexinoids, transactivate several peroxisome proliferator-activated receptor alpha (PPARalpha) target genes in a PPARalpha-dependent manner. We hypothesized that, once activated, RXR might signal through quiescent NR other than PPARalpha, in an organ-specific manner. To study this putative phenomenon in vivo, we developed an array of 120 genes relevant to the class II NR field. The genes were selected using both published data and high-density screenings performed on RXR or PPARalpha agonist-treated mice. Wild-type C57BL/6J and PPARalpha-deficient mice were treated with fenofibrate (PPARalpha activator) or LGD1069 (RXR activator). Using our customized array, we studied the hepatic, cardiac, and renal expression of this panel of 120 genes and compared them in both murine genotypes. The results obtained from this study confirmed the ability of an RXR agonist to modulate PPARalpha-restricted target genes in the liver and the kidney. Furthermore, we show that various organ-specific regulations occurring in both genotypes (PPARalpha +/+ or -/-) are highly indicative of the ability of RXR to recruit other class II NR pathways. Further development of this molecular tool may lead to a better understanding of the permissiveness of class II nuclear receptor dimers in vivo.

Animals↗
PubMed1999

Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1.

We have isolated a novel liver-specific organic anion transporter, LST-1, that is expressed exclusively in the human, rat, and mouse liver. LST-1 is a new gene family located between the organic anion transporter family and prostaglandin transporter. LST-1 transports taurocholate (Km = 13.6 microM) in a sodium-independent manner. LST-1 also shows broad substrate specificity. It transports conjugated steroids (dehydroepiandrosterone sulfate, estradiol-17beta-glucuronide, and estrone-3-sulfate), eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, leukotriene E4), and thyroid hormones (thyroxine, Km = 3.0 microM and triiodothyronine, Km = 2.7 microM), reflecting hepatic multispecificity. LST-1 is probably the most important transporter in human liver for clearance of bile acids and organic anions because hepatic levels of another organic anion transporter, OATP, is very low. This is also the first report of the human molecule that transports thyroid hormones.

Amino Acid Sequence↗
PubMed2005

NKT cells mediate organ-specific resistance against Leishmania major infection.

Whereas the acquired T cell-mediated protection against intracellular pathogens such as Leishmania major has been well studied in the past, the cells and mechanisms involved in their innate control are still poorly understood. Here, we investigated the role of natural killer T (NKT) cells in a high dose L. major mouse infection model. In vitro, L. major only weakly stimulated NKT cells and antagonized their response to the prototypic NKT cell ligand alpha-galactosylceramide, indicating that L. major partially escapes the activation of NKT cells. NKT cell deficiency as analyzed by subcutaneous infection of Jalpha281-/- mice (lacking invariant CD1d-restricted NKT cells) and CD1-/- mice (lacking all CD1d-restricted NKT cells) led to a transient increase in skin lesions, but did not impair the clinical cure of the infection, NK cell cytotoxicity, the production of IFN-gamma, the expression of inducible nitric oxide synthase, and the control of the parasites in the lymph node. In the spleen, however, NKT cells were required for NK cell cytotoxicity and early IFN-gamma production, they lowered the parasite burden, and exerted bystander effects on Leishmania antigen-specific T cell responses, most notably after systemic infection. Thus, NKT cells fulfill organ-specific protective functions during infection with L. major, but are not essential for parasite control.

Animals↗
PubMed1993

Site-directed mutagenesis of the organ-specific element in the soybean leghemoglobin lbc3 gene promoter.

The expression of a soybean leghemoglobin 5'lbc3-GUS-3'nos chimeric gene was analyzed in Lotus corniculatus after site-specific mutagenesis of the nodulin consensus sequences, AAAGAT and CTCTT, present in the organ-specific element (OSE) (-139 to -102). Full-length promoters (-1956, +46) carrying clustered point mutations in the CTCTT sequence or in both the AAAGAT and the CTCTT sequences were inactive. Point mutations in the AAAGAT sequence had only minor effects on the expression level. Substitution of the ATTG sequence between the AAAGAT and the CTCTT sequences in the OSE reduced the activity in nodules to 10%. This, together with the conservation of the ATTGT sequence in the same position of leghemoglobin genes from other legumes, indicates that these sequences, in addition to the nodulin consensus sequences of the OSE, are important for high-level nodule-specific expression. Substitution of the CTCTT sequences outside the OSE (-44, -40 and -79, -75) results in promoter activities of approximately 50%.

Base Sequence↗