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Organ-specific autoimmunity is characterized by the accelerated loss of selected cell types, resulting in specific tissue destruction and disease. The role of different genetic or environmental factors in initiating the autoimmune reactivity is still unclear. However, novel mechanisms responsible for tissue destruction have recently been revealed. Here, Ruggero De Maria and Roberto Testi propose that Fas ligand may represent a common weapon during the destructive phase of organ-specific autoimmunity.
Organ- and tissue-specific metastases have been proposed as an alteration of invasion, translocation through vascular channels, lodgment, and local proliferation. However, experimental metastasis without tumor formation at the primary site can not be explained by these hypotheses. We hypothesize here that tumor cells heterotopically express homeobox genes as a marker of their location, and that they translocate elsewhere according to positional information encoded in these genes.
Earlier we reported that serum contains organ-specific opsonins which selectively enhance recognition of liposomes by macrophages in the specific organs of the reticuloendothelial system (Moghimi, S.M. and Patel, H.M. (1988) FEBS Lett. 233, 143-147). The results presented here describe the properties of these organ-specific opsonins which differentiate between liver-specific and spleen-specific opsonins responsible for the enhancement of phagocytosis of liposomes by Kupffer cells and spleen macrophage, respectively. Liver-specific opsonin is a heat-stable macromolecule which on heating or on freezing and thawing exhibits enhanced opsonic activity. Serum also contains a dialysable factor which inhibits its opsonic activity. On the other hand, the spleen-specific opsonin is a heat-labile macromolecule which is sensitive to freezing and thawing and requires a dialysable serum co-factor for its optimum opsonic activity on spleen macrophages. Removal of this factor from serum brings about an irreversible conformational change in the opsonin. Evidence suggests that the spleen-specific opsonin may be composed of more than one different opsonin molecule. It is suggested that the serum factor(s) that inhibits liver-specific opsonic activity and enhances the spleen-specific activity may not be the same molecule, but in both the cases the factor(s) may mediate its function by modifying the process of the opsonisation of liposomes or by influencing the interaction of the opsonised liposomes with the respective cells. We propose that purification of the organ-specific opsonins may provide an opportunity to target drug carriers selectively to a specific organ of the reticuloendothelial system, and help us to evaluate their role in the altered opsonin states known to exist in certain diseases.
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Quantitative estimation of doses of carcinogens delivered to physiologic targets facilities specification of organ-specific dose-response functions. Typically, exposure measurements, such as air or water concentrations of carcinogens, are used as dose surrogates in epidemiologic studies. An illustrative exception to this usual situation is the case of airborne alpha radiation-emitting radionuclides, for which organ-specific doses can be derived. A metabolic modeling approach for estimating doses delivered to the lung, gastrointestinal tract and bone is described for three classes of radionuclides: soluble uranium, insoluble uranium and plutonium. The dose models are defined in terms of biological retention patterns and organ-specific depositions affinities. Application of the metabolic modeling approach is illustrated with a hypothetical example of excess lung cancer risk projection in a cohort of persons exposed to plutonium. Also, a simple example is presented to demonstrate how adherence to the metabolic model structure can avoid gross overestimation of doses in the case of multiple in vivo lung counting measurements taken in close temporal proximity following a large exposure intake.
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An orthotopic metastatic human renal cell carcinoma model in nude mice was established to evaluate the mechanism of metastasis as a preliminary phase in the development of a treatment to prevent cancer metastasis. The effect of host fibroblasts from different organs on the production of type IV collagenase by human renal cell carcinoma and the factors which influenced the enzyme production and secretion by fibroblasts were also investigated. KG-2 cells were established from human renal cell carcinoma, and produced tumors following implantation to both the subrenal capsular space (orthotopic site) and subcutis (ectopic site). Histologically, the tumors in the subcuit (SC tumors) were well encapsulated with a thick fibrous capsule and did not produce metastasis or invasion, whereas those in the subrenal capsular space (SRC tumors) lacked a fibrous capsule and produced metastasis at the lung or regional lymph nodes. The production of type IV collagenase in conditioned media from metastatic SRC tumors and lung metastatic lesions was larger than that from non-metastatic SC tumors. The conditioned media separated from mouse kidney or lung fibroblasts stimulated the production of type IV collagenase by KG-2 cells, whereas, that separated from mouse skin fibroblasts decreased the enzyme production. The production of type IV collagenase by KG-2 cells was stimulated by cocultured KG-2 cells and fibroblasts from the kidney or lung, whereas it was suppressed by cocultured KG-2 cells and skin fibroblasts.(ABSTRACT TRUNCATED AT 250 WORDS)
Five patients are described who were found to have both systemic lupus erythematosus and autoimmune thyroid disease. The coexistence of nonorgan specific and organ specific autoimmune disease is discussed.
Organ specific autoimmune diseases are predominantly diseases of the endocrine glands and involve amongst others the thyroid (Hashimoto's disease, primary myxoedema, Graves' disease), the islets of Langerhans (type I diabetes mellitus) and the adrenals (Addison's disease). Over the past fifty years the knowledge on the pathogenesis of these diseases has considerably increased, leading to a large number of newly developed diagnostic tools, particularly determination of autoantibodies. Most of these autoimmune diseases have a (long) subclinical latency period. During this latency period a reliable prediction of later clinical manifestation is feasible. Preventive interventions during the latency period to correct underlying abnormalities of the target endocrine gland and/or the immune system are currently being tested in experimental animal models.
Organ-specific antibodies were looked for in 26 patients with lichen sclerosus. Ten of the 25 female patients (40%) had organ-specific antibodies to thyroid cytoplasm and 11 (44%) had organ-specific antibodies to gastric parietal cells. Both values were significantly greater than those obtained in age-matched controls. None of the sera from patients with lichen sclerosus contained antibodies to steroid-producing tissues. No organ-specific antibodies were found in the one male patient.The findings suggest that lichen sclerosus may be related to an autoimmune process.
Human cancers express organ-specific neoantigens (OSNs) which elicit specific cellular immune responses in the cancer patient, as demonstrated by leukocyte adherence inhibition (LAI), an in vitro immune response assay. A purified protein of MW 40,000 (p40) exhibiting OSN (colon specific) activity was cleaved into specific peptide fragments and their partial amino acid sequences determined. This information was used in the polymerase chain reaction (PCR) to obtain a 992 bp cDNA clone (PCR-992) from a human colon adenocarcinoma cell line (LS-180). By comparison of the predicted amino acid sequence of PCR-992 with the known sequence of p40 peptides, PCR-992 was shown to correspond to almost the entire coding region of p40. Nucleotide sequence analysis suggested that the protein was mycoplasmal in origin due to its high A+T content (76%) and the presence of five in frame TGA termination codons; at least two of the latter are actually read as tryptophan, a known feature of mycoplasma translation. We have confirmed this origin by direct isolation of a contaminating mycoplasma species from the LS-180 cell line and demonstration that it could be hybridized with the PCR-992 probe. Northern and PCR analysis of RNA preparations from the contaminated LS-180 cell line showed that p40 was part of the high affinity transport system operon of Mycoplasma hyorhinis (Dudler et al, EMBO J., 7: 3963-3970, 1988). Total protein lysates of Mycoplasma hyorhinis cultivated without animal cells could elicit positive LAI responses when incubated with cancer patient leukocytes but not with normal patient leukocytes. The organ-specific nature of the response was, however, not observed indicating that host cell-mycoplasmal interactions may play a role in determining the organ-specific nature of p40 seen with the LAI. The significance of these findings will be discussed in the context of previous thinking regarding the origin of OSNs.
Nine main organs in the mouse were studied by ESR spectroscopy at 77K. Manganese ions were readily detected in the pancreas, small intestine, stomach and kidney. In particular, the pancreas gave strong ESR signals for the transition metal, suggesting that Mn(II) plays an important role in pancreatic function. All organs reveal different ESR spectra indicating organ specificity. C-centered radical, R-OO radical and C0Q10 or ascorbate radical are stable in the tissue. In the brain, heart and pancreas, N-centered radical heme-NO adduct was detected at 6 and 24 h after excision since common process is involved in tissue degeneration and ESR is sensitive to proteolysis and necrosis of tissues. In endotoxemia and/or CDE-diet-induced pancreatic lesions, R-OO radical and Mn(II) ion were detected in the signal at 77K. By the spin-trapping method (DMPO) at 25 degrees C, DMPO-OH adduct and 3-Line and 6-Line were detected in CDE diet-induced acute pancreatitis. These results suggest that damaged pancreatic tissues are in a highly oxidative environment that probably contains oxygen radicals, and that free radicals are considered to play an important role in the development of pancreatic lesions.
Many cancers display characteristic organ colonization patterns that do not fit simple, anatomical-mechanical trapping theories of tumor cell dissemination. Organ preferences of metastatic spread appear to be mediated partly by the selective attachment of tumor cells to organ-specific, microvascular endothelium. To study these tumor cell-endothelial cell interactions in an efficient and reproducible manner, we have designed a novel in vitro assay system wherein endothelial cells isolated from large vessels (e.g., aorta) can be modulated to assume phenotypic traits of organ-specific, microvascular endothelium. Modulation is achieved by growing bovine aortic endothelial cells (BAEC) on organ-specific matrix components, termed tumor attachment modulators (TAMs). Using monolayers of modulated BAEC in a tumor attachment assay, we show here that tumor cells which metastasize to a given organ, have a significantly higher binding affinity for BAEC grown on TAMs of the preferred, metastasized organ, than they have for BAEC grown on TAMs of any other organ not colonized by these tumor cells. Lung-metastatic tumor cells (R3230AC-MET, B16-F10) adhere preferentially to BAEC monolayers grown on lung-specific TAMs, whereas liver-metastatic tumor cells (RAW117-H10, M5076) selectively adhere to BAEC grown on liver-specific TAMs. In contrast, nonmetastatic tumors cells (R3230AC-LR, RBTCC-1, 647V) show no such adhesion preferences. Preferential tumor cell adherence is increased by growing BAEC for prolonged periods on organ-specific TAMs. Metastatic preference and organ distribution are mediated, at least in part, by urea-extractable endothelial cell surface components that are regulated by the extracellular matrix.
Sera from 13 patients with proven primary biliary cirrhosis (PBC) were studied for the capacity to bind to the adenine nucleotide translocator (ANT) isolated from heart, kidney and liver mitochondria. Antibodies against the ANT from liver were detected in the serum of all PBC patients, while 10 of 13 sera were negative when tested with the ANT from heart. None of the sera showed a significant binding to the ANT from kidney. The specific binding and the organ specificity of the autoantibodies against the ANT from liver were also confirmed by immunoabsorption studies on the isolated proteins. To distinguish between antibody titre and antibody activity, we measured the ability of the antisera to inhibit the adenine nucleotide transport across inner mitochondrial membrane using isolated mitochondria from heart, kidney and liver. Six of 13 patient sera tested inhibited the adenine nucleotide transport from liver mitochondria, however, none of the sera inhibited the transport from heart or kidney mitochondria again indicating the organ specificity of the antigen and the autoantibodies.
We appraised organ-specific toxicokinetics and dose responses of arsenic burdens in tilapia Oreochromis mossambicus. We kinetically linked an Area-under-the-curve (AUC)-based acute toxicity model and a pharmacodynamic model to derive dose-response relationships between equilibrium organ-specific arsenic concentrations and mortality effects. The AUC-based acute toxicity model was also used to derive organ-specific internal effect concentration (IEC)-time-response relationships, which can also be applied to predict a time-mortality profile. We conducted a 7-day exposure experiment to obtain toxicokinetic parameters, whereas the AUC-based acute toxicity model was verified with LC50(t) data obtained from a 7-day acute toxicity bioassay. Our results demonstrated that 96-hour LC50 and incipient LC50 for tilapia exposed to arsenic are 28.68 (95% confidence interval to 24.92 to 32.44) and 25.55 mg L(-1), respectively. Dose-response relationships followed the Hill equation, which could be expressed as organ-specific bioconcentration factors and incipient LC50. Organ-specific dose-response relationships showed that muscle, gill, and liver have a relatively steep sigmoid dose-response profile in that IEC50 were 26.6, 62.5, and 78.5 microg g(-1) dry wt (dw), respectively. Organ-specific arsenic internal lethal burdens were the highest in the gill and the lowest in the muscle in waterborne-exposed tilapia. The IEC and target-organ concentrations derived in this study can be used in site-specific risk assessment.