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PubMed1977

Localization of organ-specific antigens in the nervous system of the rat.

Localization of organ-specific brain antigens in the central nervous system of the rat has been studied by means of indirect immunofluorescence. Rabbit antiserum against homogenate of rat brain, previously absorbed with normal serum and homogenates of rat organs (kidney, liver, spleen), reacted with the water-soluble antigens of rat brain prepared by extraction with phosphate buffer (pH 7.3) and ultracentrifugation at 50 000 X g to give one band in the immunodiffusion test and 2--3 precipitation arcs in immunoelectrophoresis. There was also a positive reaction with peripheral nerve. The antigen was detectable in all regions of the CNS. Cells with distinct cytoplasmic immunofluorescence were most frequently observed in cerebellar white matter, pons, cerebellar pedunculi, longitudinal tracts of the brain stem. Positive immunofluorecence reaction has appeared in the outer plexiform layer and granular layer of the retina, satelite cells of the spinal root ganglia and Schwann cells. A similar reaction was observed in human, mouse and guinea pig brain slices. Both the morphological and immunochemical reactions are indicative of glial localization of this antigen.

Animals↗
PubMed1985

Maize mitochondria synthesize organ-specific polypeptides.

We detected both quantitative and qualitative organ-specific differences in the total protein composition of mitochondria of maize. Labeling of isolated mitochondria from each organ demonstrated that a few protein differences are due to changes in the polypeptides synthesized by the organelle. The synthesis of developmental stage-specific mitochondrial polypeptides was found in the scutella of developing and germinating kernels. The approximately 13-kDa polypeptide synthesized by mitochondria from seedlings of the Texas (T) male-sterile cytoplasm was shown to be constitutively expressed in all organs of line B37T tested. Methomyl, an insecticide known to inhibit the growth of T sterile plants, was shown to be an effective inhibitor of protein synthesis in mitochondria from T plants.

Electrophoresis, Polyacrylamide Gel↗
PubMed2005

Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors.

We used bioluminescence imaging to reveal patterns of metastasis formation by human breast cancer cells in immunodeficient mice. Individual cells from a population established in culture from the pleural effusion of a breast cancer patient showed distinct patterns of organ-specific metastasis. Single-cell progenies derived from this population exhibited markedly different abilities to metastasize to the bone, lung, or adrenal medulla, which suggests that metastases to different organs have different requirements. Transcriptomic profiling revealed that these different single-cell progenies similarly express a previously described "poor-prognosis" gene expression signature. Unsupervised classification using the transcriptomic data set supported the hypothesis that organ-specific metastasis by breast cancer cells is controlled by metastasis-specific genes that are separate from a general poor-prognosis gene expression signature. Furthermore, by using a gene expression signature associated with the ability of these cells to metastasize to bone, we were able to distinguish primary breast carcinomas that preferentially metastasized to bone from those that preferentially metastasized elsewhere. These results suggest that the bone-specific metastatic phenotypes and gene expression signature identified in a mouse model may be clinically relevant.

Animals↗
PubMed1985

An isolated enriched organ-specific cancer neoantigen of human lung cancer for leukocyte adherence inhibition assays.

Until now, measurement of human antitumor immunity to organ-specific cancer neoantigen (OSN) by the leukocyte adherence inhibition (LAI) assay depended on using crude extracts of cancer. In this study, a new method is presented to generate and to isolate a highly enriched OSN from spent medium of a lung cancer cell line, NCI-H69, grown in chemically defined medium. Production of large quantities of OSN with minimal contamination by extraneous proteins was possible. Four physicochemical steps were used to give a 1000-fold enrichment of OSN activity: anion-exchange and molecular-sieve chromatography; Blue Sepharose affinity chromatography; and finally anion-exchange high-pressure liquid chromatography. The enriched OSN isolates showed dose-response antigenicity when tested in LAI assay with leukocytes from lung cancer patients but had no antigenicity with leukocytes from control subjects or patients having malignant melanoma, colon cancer, or pancreatic cancer. Cross-reactive antigenicity was observed with leukocytes from patients with breast cancer and slight reactivity with leukocytes from bladder cancer patients. The final isolate from the four-step separation procedure as well as the isolates produced using additional separation techniques consistently had antigenicity at less than 10 ng in blocking LAI and 500 ng in the direct assay and showed components with molecular weights of about 62,000 +/- 3,000 (SD) (p62), 40,000 +/- 3,000 (p40), and 25,000 +/- 1,000 (p25) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The OSN isolates on two-dimensional gels showed p40 to have microheterogeneity (seven spots), with a pl from 6.2 to 7.6, and p62 and p25 as even more basic streaks. The polypeptide bearing the antigenic determinant was not purified, although we tried to separate p62, p40, and p25 to determine whether they carried the OSN determinant. The results of this study are important in showing that an isolate of an organ-specific tumor antigen containing 5 to 13 components, as determined by highly sensitive silver stains and radiolabeled patterns on single and two-dimensional gels, can be used successfully in LAI to measure tumor immune responses.

Antigens, Neoplasm↗
PubMed1989

Cis-acting regulatory elements controlling temporal and organ-specific activity of nopaline synthase promoter.

Regulatory elements controlling temporal and organ-specific expression of the nopaline (nos) gene were identified by analyzing deletion mutants of the promoter. As observed in cultured cells, the TATA box element was required for efficient promoter function and the 29 bp upstream promoter region between -130 and -101 was necessary for the nos promoter activity in various vegetative organs. This 29 bp region includes ten nucleotides of a potential Z-DNA-forming sequence (Z element) and eight nucleotides of a repeated element (b element). Duplication of b elements significantly enhanced the promoter strength, revealing the importance of the element in all plant organs. Unlike the results in the cultured cells, however, deletion of the b element or CCAAT box region completely inactivated the promoter function in regenerated organs. Therefore, it appears that transcription initiation is more tightly controlled in differentiated plant cells than in cultured cells.

Amino Acid Oxidoreductases↗
PubMed1977

A human-specific mitochondrial antibody its importance in the identification of organ-specific reactions.

A previously unrecognized autoantibody, detected by immunofluorescence, reacted with all human organs but gave negative results on tissues from rat, mouse, rabbit, guinea-pig, calf and chicken. From its predilection for mitochondria-rich cells (oncocytes) and its selective absorption with human but not animal mitochondria, it was identified as an anti-human mitochondrial antibody and named AHMA. The antibody is found in about 1% of normal subjects and is mostly of IgG class and of low titres. Its prevalence is increased in primary biliary cirrhosis where it may be associated with the standard non-species-specific AMA used for the differential diagnosis of this disease. The importance of AHMA is mainly in possible confusion with organ-specific reactions in submaxillary duct, parathyroid oxyphil cells and in trying to identify new endocrine cells such as those producing pancreatic polypeptide (HPP) in human tissues. Animals immunized with human hormones develop reactions to human mitochondria and thus produce misleading immunofluorescence reactions when used in low dilutions.

Animals↗
PubMed2002

Endothelial cell heterogeneity and organ specificity.

Endothelial cells consist of a heterogeneous population covering the entire inner surface of blood vessels. This review will focus on the factors influencing this heterogeneity including: (1) morphological and functional differences between large and small vessels and between cells derived from various microvascular endothelial beds; (2) the microenvironment and extracellular matrix modulating the phenotype; (3) different response to growth factors; (4) organ specificity reflecting the cumulative expression of post-translation modifications and also the expression of unique genes under the control of organ-specific regulatory elements; and (5) pathological conditions, such as tumor growth, which is accompanied by the development of a characteristic tumor vasculature and tumors formed by endothelial cells.

Animals↗
PubMed1996

Organ specific, protocol dependent modulation of 7,12-dimethylbenz[a]anthracene carcinogenesis in rainbow trout (Oncorhynchus mykiss) by dietary ellagic acid.

This study investigated pre-initiation and post-initiation effects of dietary ellagic acid (EA) on 7,12-dimethylbenz[a]anthracene (DMBA) multi-organ carcinogenesis in rainbow trout (Oncorhynchus mykiss). EA at 100, 250 (study 2), 1000 and 2000 (study 1) p.p.m. suppressed stomach adenopapilloma incidence by 33, 60, 70 and 78% (P < or = 0.001), respectively, as well as tumor multiplicity (P < 0.01) and size (P < 0.001) when fed continuously following DMBA initiation. However, continuous EA feeding also produced modest (250 p.p.m.) to extensive (1000, 2000 p.p.m.) growth rate suppression in these studies. Retrospective logistic regression modeling of the data allowed separation of growth-related from non-growth-related inhibitory effects. By this approach: (i) tumor development showed a similarly strong dependence (same regression slope) on animal growth rate in all treatment groups; (ii) EA-mediated reduction in mean population growth contributed to suppressed stomach tumor response above 250 p.p.m. EA; and (iii) even at high, toxic doses EA displayed inhibitory mechanisms additional to, and distinct from, growth suppression effect. The effects of post-initiation EA were organ specific. Chronic EA treatment significantly suppressed swim-bladder as well as stomach tumor incidence at doses > or = 1000 p.p.m., but increased liver tumor incidence at doses > or = 250 p.p.m. Three protocols examined EA effects on the initiation process. EA fed at 1000 p.p.m. concurrently with 750 p.p.m. dietary DMBA for 7 weeks modestly reduced stomach tumor incidence (from 85 to 78%, P < 0.05) and multiplicity (from 6.3 +/- 4.3 to 4.9 +/- 2.9, P < 0.01), but did not alter swim-bladder or liver response. The effect of EA pretreatment prior to DMBA single-dose initiation by gill uptake was also examined. When fed for 1 week prior to initiation, 2000 p.p.m. EA again imposed a small reduction in stomach adenoma incidence (from 88 to 78%; P < 0.05) and multiplicity (from 5.5 +/- 3.2 to 4.4 +/- 3.2; P < 0.01). However, when EA was pre-fed for 3 weeks instead of 1 week, protection in the stomach was lost and response in liver and swim-bladder significantly increased. In sum, these studies demonstrate that EA influence on DMBA tumorigenesis in this multi-organ model is highly protocol dependent and organ specific. Post-initiation dietary EA consistently suppressed stomach tumor development in trout, at EA doses far lower than those required for protection in rodents. At higher doses, however, EA also displayed toxicity and a potential in some protocols to enhance tumor response in other organs.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2005

Sugarbeet sucrose synthase genes differ in organ-specific and developmental expression.

A full-length sucrose synthase (SBSS2) cDNA clone was isolated from sugarbeet. Comparison of its composition and organ-specific and developmental expression with a previously isolated sugarbeet sucrose synthase gene (SBSS1) revealed distinct differences between the two genes. The two genes share 80% similarity in deduced amino acid sequence but belong to different sucrose synthase subclasses based on phylogenic analysis. Both sucrose synthases were highly expressed in roots, and had low levels of expression in leaf tissue. Transcript abundance of SBSS2, relative to SBSS1, was greater in young vegetative and floral tissues, and reduced in mature vegetative tissues. The organ-specific and developmental expression of SBSS1 and SBSS2 proteins was similar to SBSS1 and SBSS2 transcript levels, although developmental changes in protein abundance lagged transcriptional changes by many weeks. The similarities and differences in transcript and protein abundance suggest that both transcriptional and post-transcriptional regulatory mechanisms are likely to contribute to sucrose synthase expression in sugarbeet.

Base Sequence↗
PubMed2006

Organ-specific role of MyD88 for gene regulation during polymicrobial peritonitis.

Sepsis leads to the rapid induction of proinflammatory signaling cascades by activation of the innate immune system through Toll-like receptors (TLR). To characterize the role of TLR signaling through MyD88 for sepsis-induced transcriptional activation, we investigated gene expression during polymicrobial septic peritonitis by microarray analysis. Comparison of gene expression profiles for spleens and livers from septic wild-type and MyD88-deficient mice revealed striking organ-specific differences. Whereas MyD88 deficiency strongly reduced sepsis-induced gene expression in the liver, gene expression in the spleen was largely independent of MyD88, indicating organ-specific transcriptional regulation during polymicrobial sepsis. In addition to genes regulated by MyD88 in an organ-dependent manner, we also identified genes that exhibited an organ-independent influence of MyD88 and mostly encoded cytokines and chemokines. Notably, the expression of interferon (IFN)-regulated genes was markedly increased in septic MyD88-deficient mice compared to that in septic wild-type controls. Expression of IFN-regulated genes was dependent on the adapter protein TRIF. These results suggest that the influence of MyD88 on gene expression during sepsis strongly depends on the organ compartment affected by inflammation and that the lack of MyD88 may lead to disbalance of the expression of IFN-regulated genes.

Adaptor Proteins, Signal Transducing↗
PubMed1983

Effects of partial hepatectomy on organ-specific toxic response to 1,2-dibromo-3-chloropropane (DBCP).

The organ-specific toxic potency of subcutaneously administered 1,2-dibromo-3-chloropropane (DBCP) was compared in partially hepatectomized and sham-operated rats over a dose range of 20--80 mg kg-1 to assess the roles of hepatic and extrahepatic metabolism in protection against acute renal and gonadal injury. Relative kidney weight and the severity of DBCP-induced renal proximal tubular cell necrosis were increased in rats subjected to a partial (70%) surgical hepatectomy 48 h prior to treatment with DBCP at 80 mg kg-1. Relative liver weight was reduced by DBCP in the hepatectomized, but not in the sham-operated rats. The severity of DBCP-induced (80 mg kg-1) hepatocellular centrilobular necrosis was greater in hepatectomized than in sham rats. DBCP reduced the relative weights of the testis and epididymis in a progressive manner and produced dose-dependent seminiferous tubular atrophy within 12 days of treatment. The morphologically apparent lesions of the testis and epididymis were enhanced by hepatectomy. The concentration of non-protein sulfhydryl groups (NPS) in rat liver was increased by partial hepatectomy. Because of the resulting decrease in liver size, however, the total amount of hepatic NPS per kg body weight 48 h post-surgery was lower than in sham rats. The surgery had no effect on renal, testicular or epididymal NPS concentrations of organ weights. Partial hepatectomy greatly increased pentobarbital and ethanol sleeping times, while sleep induction time for pentobarbital was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Altered melanoma cell surface glycosylation mediates organ specific adhesion and metastasis via lectin receptors on the lung vascular endothelium.

Adhesive interactions between the molecules on cancer cells and the target organ are one of the key determinants of the organ specific metastasis. In this communication we show that b1,6 branched N-oligosaccharides which are expressed in a metastasis-dependent manner on B16-melanoma metastatic cell lines, participate in the adhesion process. We demonstrate that high metastatic cells show significantly increased translocation of one of the major carriers of these oligosaccharides, lysosome associated membrane protein (LAMP1), to the cell surface. LAMP1 on high metastatic cells, carry very high levels of these oligosaccharides, which are further substituted with poly N-acetyl lactosamine (polylacNAc), resulting in the expression of high density of very high affinity ligands for galectin-3 on the cell surface. We show that galectin-3 is expressed in highest amount in the lungs as compared to other representative organs. Blocking galectin-3 by pre-incubating the frozen sections of the lungs with 100 mM lactose, substantially inhibited the adhesion of high metastatic cells, while pre-incubation with sucrose had no effect. Finally, by in situ labeling and immunoprecipitation experiment, we demonstrated that the lung vascular endothelial cells express galectin-3 constitutively on their surface. Galectin-3 on the organ endothelium could thus serve as the first anchor for the circulating cancer cells, expressing high density of very high affinity ligands on their surface, and facilitate organ specific metastasis.

Animals↗
PubMed1982

A study of the immune response to the organ-specific neoantigen of human bladder cancer.

The antitumor immune response of monocytes armed with cytophilic antitumor antibody to an organ-specific neoantigen of human bladder cancer was measured by the tube leukocyte adherence inhibition assay. Of 29 patients with Stage A bladder cancer, 27 had positive tests, whereas of 11 patients with Stage B, C and D bladder cancer, 2 had positive tests. If the leukocytes from advanced bladder cancer patients were preincubated briefly with prostaglandin E2, the negative response was converted to positive. Of 189 patients with diseases of other organs, 2 had positive tests. Patients with acute or chronic cystitis had negative tests. The sensitivity of the assay was 88 per cent; specificity was 95 per cent. The bladder cancer extracts prepared from metastatic tissue or the tissue-cultured cell line, T24, had similar activity in the assay. Normal bladder tissue did not share the bladder cancer organ-specific neoantigen nor did cancers of other organs. Bladder epithelial cells expressed the OSN before they acquired invasive properties since patients with dysplastic bladder epithelium or in-situ cancer had positive tests. Antitumor immunity was often detectable before a recurrence became obvious by cystoscopy or cytology of urine and became undetectable quickly after removal of the bladder cancer. Of 100 patients with prior bladder cancer without evidence of exophytic tumor, 18 had positive tests; the possibility must be considered seriously that some had precancerous changes which formed no visible gross abnormalities. The results suggested that antitumor immunity to bladder cancer was a sensitive indicator of precancerous or cancerous changes existing in epithelial cells.

Antibodies, Neoplasm↗
PubMed1993

Human organ-specific autoimmune disease. Molecular cloning and expression of an autoantibody gene repertoire for a major autoantigen reveals an antigenic immunodominant region and restricted immunoglobulin gene usage in the target organ.

The most common organ-specific autoimmune disease in humans involves the thyroid. Autoantibodies against thyroid peroxidase (TPO) are present in the sera of virtually all patients with active disease. We report the molecular cloning of the genes for 30 high-affinity, IgG-class human autoantibodies to TPO from thyroid-infiltrating B cells. Analysis of the putative germline genes used for the TPO human autoantibodies suggests the use of only five different H and L chain combinations involving four H chains and three L chains. In addition, the same combination of H and L chains was found in multiple patients. The F(ab) proteins expressed by these genes define two major, closely associated domains (A and B) in an immunodominant region on TPO. These A and B domains contain the binding sites of approximately 80% of IgG-class TPO autoantibodies in the sera of patients with autoimmune thyroid disease. The present information permits analysis, not previously possible, of the relationship between autoantibody H and L chain genes and the antigenic domains on an autoantigen. Our data, obtained using target organ-derived autoantibodies, indicate that there is restriction in H and L chain usage in relation to the interaction with specific antigenic domains in human, organ-specific autoimmune disease.

Antibody Affinity↗
PubMed1996

Non-organ specific autoantibodies in children with chronic hepatitis C.

BACKGROUND/AIMS: Recent studies in adult patients have established a relationship between hepatitis C virus infection and the presence of liver-kidney microsomal autoantibody type 1 (LKM1). Conversely, little is known regarding the relationship between hepatitis C and autoimmunity in children. In this study, we investigated non-organ specific autoantibodies in 40 otherwise healthy Italian children with chronic hepatitis C. METHODS: All but four patients included in the study were asymptomatic. Liver histology, obtained in 35, showed features ranging from minimal to mild chronic hepatitis. Autoantibodies were investigated by indirect immunofluorescence. HCV RNA was assayed by the polymerase chain reaction in 34 cases and viral genotypes were determined. RESULTS: Antinuclear antibodies were detected in three (7.5%) cases, one with a homogeneous pattern; smooth muscle autoantibodies in seven (17.5%) cases, always with V (vessels only) specificity and LKM1 in four (10%), at titers ranging from 1:20 and 1:2560. Clinical and virologic features did not significantly differ between autoantibody positive and negative cases, although infections with HCV genotypes 1a and 2 were more frequent in LKM1-positive patients. During observation, the child with the highest LKM1 titre was unsuccessfully treated with alpha interferon but responded to steroids. Twelve LKM1 negative children were also treated with interferon and one developed low LKM1 titers concomitant with an alanine aminotransferase flare. The sera of the five LKM1-positive children with investigated by immunoblotting with a human microsomal fraction and peptide 257-269 of cytochrome P450IID6. Only the serum of the child with the highest LKM1 titers was reactive. CONCLUSIONS: These results show that a consistent proportion of children with chronic hepatitis C circulate non-organ specific autoantibodies. The prevalence of LKM1 is greater than in adults and this could raise problems for the treatment of the disease with interferon. The analysis of LKM1 target antigens might help to identify putative cases of "true" autoimmune hepatitis with concomitant HCV infection that could benefit from steroid treatment.

Adolescent↗
PubMed2001

Neonatal immunity develops in a transgenic TCR transfer model and reveals a requirement for elevated cell input to achieve organ-specific responses.

In recent years, it has become clear that neonatal exposure to Ag induces rather than ablates T cell immunity. Moreover, rechallenge with the Ag at adult age can trigger secondary responses that are distinct in the lymph node vs the spleen. The question addressed in this report is whether organ-specific secondary responses occur as a result of the diversity of the T cell repertoire or could they arise with homogeneous TCR-transgenic T cells. To test this premise, we used the OVA-specific DO11.10 TCR-transgenic T cells and established a neonatal T cell transfer system suitable for these investigations. In this system, neonatal T cells transferred from 1-day-old DO11.10/SCID mice into newborn (1-day-old) BALB/c mice migrate to the host's spleen and maintain stable frequency. The newborn BALB/c hosts were then given Ig-OVA, an Ig molecule carrying the OVA peptide, and challenged with the OVA peptide in CFA at the age of 7 wk; then their secondary responses were analyzed. The findings show that the lymph node T cells were deviated and produced IL-4 instead of IFN-gamma and the splenic T cells, although unable to proliferate or produce IFN-gamma, secreted a significant level of IL-2. Supply of exogenous IL-12 during Ag stimulation restores both proliferation and IFN-gamma production by the splenic T cells. This restorable form of splenic unresponsiveness referred to as IFN-gamma-dependent anergy required a transfer of a high number of neonatal DO11.10/SCID T cells to develop. Thus, the frequency of neonatal T cell precursors rather than repertoire diversity exerts control on the development of organ-specific neonatal immunity.

Amino Acid Sequence↗
PubMed2002

Link between organ-specific antigen processing by 20S proteasomes and CD8(+) T cell-mediated autoimmunity.

Adoptive transfer of cross-reactive HSP60-specific CD8(+) T cells into immunodeficient mice causes autoimmune intestinal pathology restricted to the small intestine. We wondered whether local immunopathology induced by CD8(+) T cells can be explained by tissue-specific differences in proteasome-mediated processing of major histocompatibility complex class I T cell epitopes. Our experiments demonstrate that 20S proteasomes of different organs display a characteristic composition of alpha and beta chain subunits and produce distinct peptide fragments with respect to both quality and quantity. Digests of HSP60 polypeptides by 20S proteasomes show most efficient generation of the pathology related CD8(+) T cell epitope in the small intestine. Further, we demonstrate that the organ-specific potential to produce defined T cell epitopes reflects quantities that are relevant for cytotoxic T lymphocyte recognition. We propose tissue-specific antigen processing by 20S proteasomes as a potential mechanism to control organ-specific immune responses.

Amino Acid Sequence↗
PubMed1981

[Immunoglobulins and non-organ-specific antibodies in alcoholic liver cirrhosis].

The quantitative alterations of serum immunoglobulins and their relationship with functional liver alterations, and the incidence of non organ-specific antibodies have been studied in patients with alcoholic cirrhosis. The study was performed in 52 patients with alcoholic cirrhosis, and 30 healthy subjects were used as controls. Main findings were: increased serum IgA, IgG, and IgM in cirrhosis (p less than 0.001), increased IgA in liver failure (p less than 0.005), and increased IgM in patients with portal hypertension (p less than 0.001). Regarding non organ-specific antibodies, antinuclear antibodies were found in 28 % of the cases, and anti-smooth muscle antibodies in 9 %. No relationship could be established between antibody positivity and quantitative alterations of the serum immunoglobulins.

Antibodies, Antinuclear↗