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1.
Gut ; 55(2): 197-204, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16407385

ABSTRACT

BACKGROUND AND AIMS: Intralumenal bile acid (BA) concentrations have a profound effect on cholesterol absorption. We performed studies to assess the effects of markedly reduced lumenal BA on cholesterol absorption in children with inborn errors in BA synthesis and the role of micellar solubilisation of cholesterol on its absorption in an animal model using human intestinal contents. METHODS: We studied five subjects: two with 3beta hydroxy-C27 steroid dehydrogenase isomerase deficiency (3-HSD), two with Delta(4)-3-oxosteroid 5beta reductase deficiency (5beta reductase), and one with 2-methylacyl CoA racemase deficiency (racemase). Subjects were studied on supplemental BA therapy and three weeks after withdrawal of supplements. During each treatment period a liquid meal was consumed. Duodenal samples were collected and analysed, and cholesterol absorption and cholesterol fractional synthetic rates were measured. Human intralumenal contents were infused in a bile diverted rat lymph fistula model to assess micellar versus vesicular absorption of cholesterol. RESULTS: Without BA supplementation, intralumenal BA concentrations were below the critical micellar concentration (CMC) whereas intralumenal BAs increased to above the CMC in all subjects on BA supplementation. Lumenal cholesterol was carried primarily as vesicles in untreated subjects whereas it was carried as both micelles and vesicles in treated subjects. Cholesterol absorption increased approximately 55% in treated compared with untreated subjects (p=0.041), with a simultaneous 70% decrease in synthesis rates (p=0.029). In the rat lymph fistula model, minimal vesicular cholesterol was absorbed whereas vesicular and micellar fatty acid and phospholipid were comparably absorbed. CONCLUSIONS: Increasing micellar cholesterol solubilisation by supplemental BA in subjects with inborn errors of BA synthesis leads to an improvement in cholesterol absorption and reduction in cholesterol synthesis due to improved micellar solubilisation of cholesterol.


Subject(s)
Bile Acids and Salts/biosynthesis , Cholesterol/pharmacokinetics , Steroid Metabolism, Inborn Errors/metabolism , 3-Hydroxysteroid Dehydrogenases/deficiency , Adolescent , Adult , Animals , Bile Acids and Salts/metabolism , Bile Acids and Salts/therapeutic use , Child , Cholesterol/administration & dosage , Cholesterol/biosynthesis , Duodenum/metabolism , Female , Humans , Intestinal Absorption , Lymph/metabolism , Male , Micelles , Oxidoreductases/deficiency , Racemases and Epimerases/deficiency , Rats , Rats, Sprague-Dawley , Solubility , Steroid Metabolism, Inborn Errors/physiopathology , Steroid Metabolism, Inborn Errors/therapy
2.
J Parasitol ; 89(3): 493-5, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12880247

ABSTRACT

The main purpose of this study was to determine the effects of cortisone on the number and size of primary Echinococcus multilocularis cysts developing in a moderately resistant strain of mice, i.e., C3H/HeJ. Computerized image analysis was used to measure the surface area occupied by hydatid cysts 10 wk after inoculation of the mice with E. multilocularis eggs. Our second objective was to compare the infectivity of primary E. multilocularis hydatid cysts in C57BL/6J-Ay/a (lethal yellow) mice with that in C57BL/6J-a/a (non-agouti black) mice. The data obtained show no difference between the C3H/HeJ and C57BL/6J-a/a strains of mice; yet, the image analysis method was able to detect a slight increase in the total cyst size within the Ay/a mutant of the C57BL/6J strain. Treatment of C3H/HeJ mice with cortisone drastically increased both the number of cysts and the average size of each cyst when the treatment occurred early in the infection.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Cortisone/therapeutic use , Echinococcosis/drug therapy , Animals , Anti-Inflammatory Agents/pharmacology , Carnivora , Cortisone/pharmacology , Echinococcosis/immunology , Echinococcosis/pathology , Echinococcus/drug effects , Echinococcus/growth & development , Echinococcus/immunology , Genes, Lethal/immunology , Image Processing, Computer-Assisted , Immunity, Innate/drug effects , Immunity, Innate/genetics , Immunity, Innate/immunology , Liver/parasitology , Liver/pathology , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Mutant Strains
4.
Gastroenterology ; 120(5): 1193-202, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11266383

ABSTRACT

BACKGROUND AND AIMS: Numerous studies have suggested phospholipid inhibition of dietary cholesterol absorption through the gastrointestinal tract. This study addressed the importance of luminal phospholipid hydrolysis in this process. METHODS: The effect of phospholipase inhibition on cholesterol transport from intestinal lumen to the lymphatics was evaluated in lymph fistula rats. Cholesterol and phospholipid absorption efficiency in intact animals was evaluated in control and phospholipase A(2) (PLA2) gene-targeted mice. RESULTS: The PLA2 inhibitor FPL 67047XX retarded cholesterol absorption in a lymph fistula rat model. Under basal chow-fed dietary conditions, cholesterol absorption efficiency from a single bolus meal, and plasma lipid levels, were similar among PLA2+/+, PLA2+/-, and PLA2-/- mice. Interestingly, the nonhydrolyzable phospholipid dioleoyl ether phosphatidylcholine suppressed cholesterol absorption by 10% to 18% in mice without regard to their PLA2 genotype. When 1-palmitoyl-2-[(14)C]oleoyl-phosphatidylcholine was used as the substrate, the radiolabeled phospholipid was found to be hydrolyzed and absorbed with equal efficiency in PLA2+/+, PLA2+/-, and PLA2-/- mice. CONCLUSIONS: These results suggested that although phospholipid digestion in the intestinal lumen is a prerequisite for efficient cholesterol absorption, additional enzyme(s) can compensate for pancreatic PLA2 in catalyzing phospholipid digestion and facilitating cholesterol absorption in PLA2 knockout mice.


Subject(s)
Cholesterol, Dietary/pharmacokinetics , Intestinal Absorption/physiology , Phospholipases A/genetics , Animals , Carbon Radioisotopes , Digestive System Fistula/metabolism , Female , Lymph/metabolism , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , Phospholipases A/metabolism , Phospholipases A2 , Pregnancy , Rats , Rats, Sprague-Dawley , Triglycerides/pharmacokinetics
5.
Arterioscler Thromb Vasc Biol ; 20(4): 1020-6, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10764667

ABSTRACT

Initial experiments revealed that low concentrations of apolipoprotein (apo) E (0.1 to 5 microg/mL) were effective in inhibiting platelet-derived growth factor (PDGF)-directed smooth muscle cell (SMC) migration by 60% to 80%. In contrast, higher concentrations of apoE, at 25 and 50 microg/mL, were necessary to achieve similar inhibition of PDGF-induced SMC proliferation. The potential role of nitric oxide (NO) in mediating the inhibitory effects of apoE was explored. Results showed that, although 0.1 to 5 microg/mL of apoE had no effect on NO production by SMCs, physiological concentrations of apoE (25 to 50 microg/mL) enhanced NO synthesis by 2-fold in a dose-dependent manner (P<0.001). Reverse transcription-polymerase chain reaction amplification of RNA obtained from control and apoE-treated SMCs demonstrated a direct role of apoE in activating inducible nitric oxide synthase (iNOS) gene expression. The apoE-induced nitric oxide production was significantly reduced by coincubation of the cells with aminoguanidine or N(G)-monomethyl-L-arginine (P<0.05) or with antisense iNOS oligodeoxynucleotides (P<0.01). Moreover, the inhibition of iNOS was shown to overcome apoE suppression of PDGF-induced vascular SMC proliferation. However, apoE suppression of PDGF-directed SMC migration was not affected by these treatments. Taken together, these results document that apoE exerts its inhibitory effects on cell proliferation via activation of iNOS. However, apoE inhibition of cell migration is mediated by a mechanism independent of iNOS activation.


Subject(s)
Apolipoproteins E/pharmacology , Cell Division/drug effects , Cell Movement/drug effects , Muscle, Smooth, Vascular/cytology , Nitric Oxide Synthase/metabolism , Cell Line , Enzyme Activation/drug effects , Humans , Nitric Oxide/metabolism , Nitric Oxide Synthase Type II , Platelet-Derived Growth Factor/pharmacology , Reverse Transcriptase Polymerase Chain Reaction
6.
J Lipid Res ; 41(3): 424-32, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10706590

ABSTRACT

Previous studies have shown that antibodies to cubulin, a receptor on the yolk sac that binds high density lipoproteins (HDL) and cobalamin, induce fetal abnormalities. Mice with markedly low concentrations of plasma HDL-cholesterol (HDL-C) give birth to healthy pups, however. To establish whether maternal HDL-C has a role in fetal development, sterol metabolism was studied in the fetus and extra-embryonic fetal tissues in wild-type and apolipoprotein A-I-deficient mice (apoAI-/-). Maternal HDL-C content was markedly greater in apoAI+/+ mice prior to pregnancy and at 13 days into gestation. By 17 days into gestation, HDL-C content was similar between both types of mice. Fetuses from apoAI (-/- x -/-) matings were 16;-25% smaller than control mice at 13 and 17 days of gestation and contained less cholesterol. The differences in size and cholesterol content were not due to a lack of cholesterol synthesis or apoA-I in the fetus. In the yolk sac and placenta, sterol synthesis rates were approximately 50% greater in the 13-day-old apoAI-/- mice as compared to the apoAI+/+ mice. Even though synthesis rates were greater, cholesterol concentrations were 22% lower in the yolk sac and similar in the placenta of apoAI-/- mice as compared to tissues of wild-type mice. These data suggest that a difference in maternal HDL-C concentration or composition can affect the size of the fetus and sterol metabolism of the yolk sac and placenta in the mouse.


Subject(s)
Fetal Weight , Fetus/abnormalities , Lipoproteins, HDL/metabolism , Sterols/metabolism , Animals , Apolipoprotein A-I/genetics , Base Sequence , DNA Primers , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Pregnancy , Receptors, Cell Surface/immunology , Receptors, Cell Surface/metabolism
7.
Pigment Cell Res ; 11(3): 155-7, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9730323

ABSTRACT

In order to isolate, clone, and sequence agouti exon 2 of the pig (Yorkshire), we used an interspecific hybridization strategy. Primers from the 5' and 3' borders of the known human agouti exon 2 sequence were used to amplify (PCR) pig agouti exon 2. Following Southern blotting using a human exon 2 internal primer to authenticate that our PCR amplified product was truly pig exon 2 (PorAex2), the fragment was cloned and sequenced. PorAex2 exhibits 79.1 and 75.7% DNA sequence and 85 and 74% deduced amino acid sequence homologies with human and mouse agouti exon 2 and agouti protein, respectively. With the isolation of PorAex2, we can now map, sequence, and clarify the modus operandi of the porcine agouti gene. The GenBank Accession number of PorAex 2 is AF018166.


Subject(s)
Exons , Intercellular Signaling Peptides and Proteins , Proteins/genetics , Agouti Signaling Protein , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , Humans , Mice , Molecular Sequence Data , Proteins/isolation & purification , Swine
8.
J Biol Chem ; 273(32): 20156-61, 1998 Aug 07.
Article in English | MEDLINE | ID: mdl-9685360

ABSTRACT

The anti-atherogenic effects of apolipoprotein (apo) E have been attributed to its ability to reduce plasma cholesterol level and to limit foam cell formation. The purpose of this study was to ascertain if apoE also may have cytostatic functions that could attenuate vascular occlusive diseases. Purified apoE inhibited smooth muscle cell migration directed to platelet-derived growth factor (PDGF) or oxidized LDL (oxLDL) (p < 0.0001). The purified apoE also suppressed PDGF- and oxLDL-induced smooth muscle cell proliferation (p < 0.001). These apoE inhibitory effects were not because of suppression of PDGF binding to its receptors on the smooth muscle cells, but was correlated with a significant reduction in agonist-stimulated mitogen-activated protein kinase activity (p < 0.01). ApoE also inhibited PDGF-induced cyclin D1 mRNA expression, suggesting that the apoE effect was mediated by growth arrest at the G0 to G1 phase. Taken together, these results suggest that apoE has cytostatic functions in the vessel wall and may protect against vascular diseases through inhibition of cell signaling events associated with growth factor-induced smooth muscle cell migration and proliferation.


Subject(s)
Apolipoproteins E/pharmacology , Cell Cycle/drug effects , Cell Movement/drug effects , Muscle, Smooth, Vascular/drug effects , Platelet-Derived Growth Factor/antagonists & inhibitors , Signal Transduction/drug effects , Animals , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Cell Division/drug effects , Cell Line , Cyclin D1/pharmacology , Gene Expression Regulation/drug effects , Humans , Lipoproteins, LDL/pharmacology , Phosphorylation/drug effects , RNA, Messenger/metabolism , Rats
9.
Pigment Cell Res ; 11(5): 310-3, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9877102

ABSTRACT

Because of ectopic overproduction of agouti protein, yellow alleles (A(y) and A(vy)) of the murine agouti gene may secondarily modulate the synthesis, maturation (i.e., acetylation), and/or tissue deployment of alpha-Melanocyte Stimulating Hormone (MSH). We used HPLC to test the hypothesis that A(y)/a mice exhibit altered concentrations of desacetyl-, monoacetyl-, and diacetyl-alpha-MSH in pituitaries, sera, and telogen hair bulbs when compared to black (a/a) mice. We also used RIA to measure total MSH in those same tissues of A(y)a,a/a, and white-bellied agouti (A(wJ)/A(wJ)) mice (Strain C57BL/6J). We found no evidence that A(y)/a mice possessed an imbalance of des-, mono-, and diacetylated alpha-MSH species. However, radioimmunoassay (RIA) analyses of total MSH suggest that wild-type agouti mice (A(wJ)/A(wJ)) exhibited significantly decreased (P < 0.05) tissue levels of total alpha-MSH in pituitaries, sera, and regenerating hair bulbs when compared to those of mutant A(y)/a and a/a mice.


Subject(s)
Intercellular Signaling Peptides and Proteins , Proteins/metabolism , alpha-MSH/genetics , alpha-MSH/metabolism , Acetylation , Agouti Signaling Protein , Animals , Chromatography, High Pressure Liquid , Hair/metabolism , Mice , Mice, Inbred C57BL , Mutation , Pigmentation/genetics , Pituitary Gland/metabolism , Tissue Distribution , alpha-MSH/blood
10.
J Invest Dermatol ; 106(3): 559-63, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8648194

ABSTRACT

Ectopic overexpression of the agouti protein in the lethal yellow (A y/a) mouse causes a yellow coat as well as the lethal yellow syndrome. Presence of thiols like glutathione (GSH) or cysteine (Cys) may regulate the conversion of dopaquinone to phaeomelanin in hair follicle melanocytes. GSH also plays important roles in cellular health and maintenance. Cys and GSH were measured using high-performance liquid chromatography in hair follicles and serum of A wJ/A wJ (agouti), A y/a (yellow), and a/a (black) mice over a 20-d hair growth regeneration period. Agouti alleles modulate thiol concentrations. A y/a hair follicles exhibited higher total thiol levels and an increased ratio of Cys to GSH. A wJ/A wJ mice showed intermediate levels, while a/a mice had lowest total thiol concentrations and a decreased ratio of Cys to GSH. Hair follicle cysteine concentrations showed yellow > agouti > black (p < 0.01). In all genotypes, unplucked skin and day 0 hair follicles showed GSH as the major thiol, but a shift to predominantly Cys on peak melanogenic days was seen. Presence of high concentrations of free cysteine support the hypothesis of phaeomelanin synthesis via cysteinyldopas. The A y/a mouse had the most dramatic follicular thiol changes as well as a depression in serum thiols. An altered thiol metabolism in these and other A y/a tissues might impair normal cell functioning to contribute to the lethal yellow syndrome.


Subject(s)
Cysteine/metabolism , Glutathione/metabolism , Hair Follicle/metabolism , Intercellular Signaling Peptides and Proteins , Proteins/genetics , Agouti Signaling Protein , Alleles , Animals , Cysteine/blood , Female , Genes, Lethal , Genotype , Glutathione/blood , Hair Color/genetics , Mice , Mice, Mutant Strains , Phenotype , Syndrome
11.
Pigment Cell Res ; 8(6): 302-6, 1995 Dec.
Article in English | MEDLINE | ID: mdl-8789738

ABSTRACT

Agouti protein (AP) expression in the wild-type agouti mouse (AwJ/AwJ) coincides with a switch in hair follicle melanogenesis from black (eumelanin) to yellow (pheomelanin). Ectopic overexpression of AP in the lethal yellow (Ay/a) mouse cause a pure yellow coat and the lethal yellow syndrome. Thiol concentrations may control the conversion of dopaquinone to pheomelanin in hair follicle melanocytes. Glutathione (GSH) also plays important roles in cellular health and protection. Using HPLC, cysteine and GSH were measured in 1) hair follicles, liver and serum of Ay/a, AwJ/AwJ, and a/a (black) mice, and 2) adipose and spleen tissues of Ay/a and a/a mice on day 9 of regenerating hair growth (late pheomelanin phase). Agouti locus alleles influence thiol metabolism in hair follicles and in other systemic tissues. Ay/a hair follicles and serum showed highest cysteine and lowest GSH levels. AwJ/AwJ mice showed intermediate levels, while a/a hair follicles and serum had lowest cysteine and highest GSH concentrations. In the hair follicle, cysteine (likely derived from enzymatic degradation of GSH) appears to be the primary pheomelanogenic thiol. Agouti locus alleles may also directly or indirectly affect thiol concentrations in systemic tissues like liver and spleen. Cysteine in spleen extracts showed Ay/a > a/a (P < 0.01). An Ay-induced imbalance of thiol metabolism (altering GSH concentrations in multiple tissues) may contribute to the pleiotropic defects of the lethal yellow syndrome.


Subject(s)
Cysteine/analysis , Glutathione/analysis , Hair Follicle/chemistry , Intercellular Signaling Peptides and Proteins , Proteins/genetics , Adipose Tissue/chemistry , Agouti Signaling Protein , Alleles , Animals , Cysteine/blood , Female , Glutathione/blood , Glutathione Reductase/metabolism , Hair/growth & development , Hair Follicle/enzymology , Liver/chemistry , Mice , Mice, Inbred C57BL , Skin Pigmentation/genetics , Spleen/chemistry
12.
Lupus ; 4(5): 339-47, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8563727

ABSTRACT

The mechanism, or mechanisms, responsible for enhancement of renal disease after episodes of infection are poorly understood. We used the BXSB mouse as a lupus model of autoimmune disease and we used bacterial lipopolysaccharide (LPS) as a surrogate infectious agent to gain some insight into the mechanism by which infections promote enhancement of autoimmune disease to chronicity. BXSB mice were exposed to LPS for 5 weeks, LPS was withdrawn and various tests and measurements were performed 6 weeks thereafter. Matched BXSB mice exposed to vehicle injections for 5 weeks served as controls. We verified that previous exposure to LPS enhances polyclonal B cell activation, impairs carrier function of blood cells for immune complexes, increases deposition of immune complexes in the microcirculation and promotes glomerular inflammation and sclerosis. These changes occurred at 6 weeks after withdrawal of LPS in the presence of unimpaired function of mononuclear phagocytes. Some of the effects of LPS are reversible, others are partially so and others are irreversible. Altered immune functions elicited by prior exposure to LPS can result in enhanced involvement of various renal compartments and can result in renal insufficiency.


Subject(s)
Antigen-Antibody Complex/blood , Kidney Diseases/immunology , Lipopolysaccharides , Lupus Erythematosus, Systemic/immunology , Animals , B-Lymphocytes/immunology , Disease Susceptibility , Kidney Cortex/immunology , Kidney Cortex/pathology , Kidney Diseases/complications , Kidney Diseases/pathology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/pathology , Lymphocyte Activation , Mice , Mice, Mutant Strains , Neutrophils/pathology , Neutrophils/physiology , Phagocytes/physiology , Time Factors
13.
Lupus ; 3(6): 507-14, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7704009

ABSTRACT

Lupus prone NZB/W mice repeatedly exposed to bacterial lipopolysaccharide (LPS) develop enhanced polyclonal B cell activation and exacerbated nephritis by a mechanism that results in increased deposits of immunoreactants in kidneys without measurable impairment of mononuclear phagocyte function. In this paper, we investigate whether the referenced effects of LPS are reversible after withdrawal of LPS, or whether their persistence could contribute to progression of nephritis to chronicity. In NZB/W mice previously exposed to LPS, features of enhanced polyclonal B cell activation, more severe glomerulonephritis with tubulointerstitial involvement, increased deposits of immunoreactants in glomeruli, and altered protein excretion persisted 6 weeks after LPS was discontinued. Additionally, mononuclear phagocyte function, assessed through liver uptake of radiolabeled immune complexes, was found to be impaired. The results indicate that some of the effects of prior exposure to LPS may be partially reversible; however, they last long after LPS has been discontinued, and additional impairment of immune function develops together with permanent glomerular dysfunction, thereby contributing to progression of nephritis to chronicity.


Subject(s)
Lipopolysaccharides/toxicity , Lupus Nephritis/etiology , Animals , Antigen-Antibody Complex/metabolism , B-Lymphocytes/immunology , Lupus Nephritis/immunology , Lupus Nephritis/pathology , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Inbred NZB
14.
Autoimmunity ; 17(3): 195-202, 1994.
Article in English | MEDLINE | ID: mdl-7948604

ABSTRACT

We investigated the relative roles of B cell activity, circulating immune complexes, complement concentration and kinetics of disappearance and uptake of immune complexes from the circulation in the pathogenesis of early nephritis of MRL/lpr mice. In comparison to data in control (C57BL/6J) mice, B cell activity was enhanced and the concentration of autoantibodies and endogenous immune complexes in plasma were increased, whereas complement (C3) concentration was not significantly different in MRL/lpr mice. The kinetics of disappearance of radiolabeled immune complexes from the circulation were similar in MRL/lpr and control mice, whereas uptake of radiolabeled immune complexes by the liver was decreased in MRL/lpr mice. Features of polyclonal B cell activation and impaired mononuclear phagocyte function are early events that may set the stage for progressive systemic involvement in MRL/lpr mice.


Subject(s)
Lupus Nephritis/immunology , Animals , Antigen-Antibody Complex/blood , Antigen-Antibody Complex/metabolism , Autoantibodies/blood , B-Lymphocytes/immunology , Complement System Proteins/metabolism , Lupus Nephritis/pathology , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Organ Specificity/immunology , Phagocytosis/physiology
15.
Lupus ; 1(4): 255-61, 1992 Aug.
Article in English | MEDLINE | ID: mdl-1301989

ABSTRACT

We investigated the role of immunoglobulin isotypes in the exacerbation of lupus nephritis associated with exposure to bacterial lipopolysaccharide. The data indicate that enhanced polyclonal B-cell activation and exacerbated autoimmune disease evoked by lipopolysaccharide are associated with an increase in the concentration of isotypes in plasma and in renal eluate, that this isotype response is polyclonal and preferential but not restrictive, that all B cells are responsive but all are not equally sensitive to the effects of lipopolysaccharide, and that some expanded isotypes may be more nephritogenic in certain strains of lupus-prone mice.


Subject(s)
Immunoglobulin Isotypes/metabolism , Kidney/immunology , Lipopolysaccharides/toxicity , Lupus Nephritis/etiology , Animals , Antigen-Antibody Complex/metabolism , Autoantibodies/metabolism , B-Lymphocytes/immunology , Female , Immunoglobulin G/metabolism , Immunoglobulin M/metabolism , Lupus Nephritis/immunology , Lymphocyte Activation , Male , Mice , Species Specificity
16.
Lupus ; 1(2): 63-74, 1992 Feb.
Article in English | MEDLINE | ID: mdl-1301966

ABSTRACT

It is widely believed that autoimmunity is an integral part of the immune system, and that genetic, immunologic, hormonal, environmental and other factors contribute to the pathogenesis of autoimmune disease. Thus, autoimmune disease may represent an abnormal expression of immune functions instead of loss of tolerance to self, and it can be organ specific or systemic in its manifestations. We review the various factors that contribute to the development of autoimmune disease; we also review the mechanisms of polyclonal B-cell activation, with emphasis on the role of infectious agents. We consider systemic lupus erythematosus in humans and in experimental animals as prototypic autoimmune disease, and we summarize data to indicate that polyclonal B-cell activation is central to the pathogenesis of systemic autoimmune disease. The effect of polyclonal B-cell activation, brought about by injections of a B-cell activator-lipopolysaccharide from Gram-negative bacteria-is sufficient to cause autoimmune disease in an immunologically normal host. In fact, autoimmune disease can be arrested if excessive polyclonal B-cell activation is suppressed; alternatively, autoimmune disease can be exacerbated if polyclonal B-cell activation is enhanced. We explore the mechanism of tissue injury when autoimmune disease is induced or exacerbated, and we consider the pathogenic roles of autoantibodies, immune complexes, complement, the blood cell carrier system, and the mononuclear phagocyte system. Although polyclonal B-cell activation may be the mechanism whereby various factors can cause or exacerbate systemic autoimmune disease, polyclonal B-cell activation may cause autoimmune disease on its own.


Subject(s)
Autoimmunity , B-Lymphocytes/immunology , Infections/immunology , Animals , Autoimmune Diseases/etiology , Humans , Lipopolysaccharides/immunology , Lupus Erythematosus, Systemic/immunology , Lymphocyte Activation
18.
Clin Exp Immunol ; 85(2): 270-7, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1864008

ABSTRACT

Systemic autoimmune disease is influenced by genetic, immunological, hormonal, and environmental factors. Although environmental factors are major agents that induce or exacerbate autoimmune diseases, the mechanism(s) and the molecular events by which they operate remain poorly understood. Here we used the lupus-prone BXSB mouse as an animal model of systemic autoimmune disease, and we used a bacterial lipopolysaccharide (LPS) as a surrogate infectious agent to gain some insight into the mechanism(s) by which infectious agents exacerbate autoimmune diseases. Our experimental protocol was designed to address three questions: (i) whether spontaneous polyclonal B cell activation (PBA) that occurs in BXSB mice could be further enhanced by bacterial LPS; (ii) whether repeated exposure to LPS would exacerbate autoimmune disease, as reflected by enhanced deposits of immune complexes (ICs) in kidneys and exacerbated nephritis; and (iii) whether the mechanism by which LPS exacerbates nephritis might involve interference with blood cell carrier function, mononuclear phagocyte function, or both. BXSB mice were injected with LPS (25 micrograms) twice a week for 5 weeks; control autoimmune BXSB mice and immunologically normal (C57BL/6) mice were injected with vehicle only. The three groups of mice were then challenged with soluble ICs to assess the kinetics of their disappearance from the circulation, their uptake by the mononuclear phagocyte system (liver, spleen), their distribution in target organ (kidney), and blood cell carrier function. The results indicate that: (i) spontaneous PBA can be enhanced further by LPS; (ii) exposure to LPS results in increased deposits of endogenous ICs in kidneys and exacerbated nephritis; and (iii) defective handling of ICs by the mononuclear phagocyte system and impaired blood cell carrier function are contributory factors to exacerbated nephritis, but that mechanisms in addition to passive localization of ICs may also be operative.


Subject(s)
Antigen-Antibody Complex/metabolism , Lipopolysaccharides/pharmacology , Lupus Nephritis/immunology , Animals , B-Lymphocytes/immunology , Half-Life , Kidney/immunology , Kidney/metabolism , Liver/immunology , Liver/metabolism , Lupus Nephritis/etiology , Lupus Nephritis/pathology , Mice , Mice, Inbred C57BL , Mice, Mutant Strains
19.
Clin Exp Immunol ; 84(1): 134-8, 1991 Apr.
Article in English | MEDLINE | ID: mdl-2015704

ABSTRACT

Polyclonal B cell activation (PBA) and autoimmune disease can be induced in immunologically normal mice, or enhanced in lupus-prone mice, by bacterial lipopolysaccharide (LPS). Because immune defects are common in autoimmune diseases and IgA deficiency is prevalent in patients with systemic lupus erythematosus, we investigated: (i) whether LPS might induce IgA deficiency in normal mice; (ii) whether IgA deficiency might be a feature in lupus-prone mice; (iii) whether, if present in lupus-prone mice, IgA deficiency could be further accentuated by LPS; and (iv) whether the effects of LPS on IgA concentrations of normal and lupus-prone mice might be reversible upon withdrawal of LPS. We injected normal (C57BL/6) and lupus-prone (NZB/W) mice with 50 micrograms of LPS from Salmonella minnesota Re595 twice a week for 5 weeks and then discontinued LPS for 6 weeks. We determined the concentrations of plasma immunoglobulins, DNA antibodies, and circulating immune complexes before, during, and after mice were exposed to LPS. Our results indicate that: (i) LPS induces IgA deficiency in normal mice concurrently with PBA; (ii) IgA deficiency is a feature of lupus-prone mice; (iii) LPS accentuates naturally occurring PBA and IgA deficiency in lupus-prone mice; and (iv) LPS induced, or LPS enhanced, IgA deficiency and PBA in normal and lupus-prone mice persist long after withdrawal of LPS. Thus, LPS triggers or enhances autoimmune disease by a mechanism that involves in part PBA with selective increase (IgG, IgM) and concurrent decrease (IgA) of specific isotypes.


Subject(s)
Autoimmune Diseases/immunology , B-Lymphocytes/immunology , Dysgammaglobulinemia , IgA Deficiency , Lipopolysaccharides/administration & dosage , Lupus Erythematosus, Systemic/immunology , Lymphocyte Activation/immunology , Animals , Antigen-Antibody Complex/immunology , Disease Models, Animal , Immunoglobulins/analysis , Mice , Mice, Inbred C57BL , Mice, Inbred NZB , Radioimmunoassay , Salmonella
20.
J Invest Dermatol ; 96(1): 78-84, 1991 Jan.
Article in English | MEDLINE | ID: mdl-1987299

ABSTRACT

The extent to which alpha melanocyte-stimulating hormone (MSH) is a true in vivo regulator of melanogenesis in mice is unknown. The objective of this study was to determine if MSH-induced eumelanogenesis in hairbulb melanocytes of yellow (Ay/a) mice mimics the natural program of eumelanogenesis occurring in genetically black (a/a) hairbulb melanocytes. We conducted quantitative transmission electron microscopy on melanosome differentiation within MSH-treated regenerating 9-d hairbulbs of Ay/a and a/a mice. Results of exogenous alpha-MSH injections (5 d at 0.15 mM MSH) showed that the striking visual darkening of hair was accompanied by an incomplete transformation of phaeo- to eumelanogenesis. Ontogenetic data on developmental stages I-IV of 3678 melanosomes based on geometric considerations (length, width, shape, and area) showed that MSH did not induce a complete transformation from spherical phaeomelanosomes to elliptical eumelanosomes. Also, observations on the number of vesiculoglobular bodies and matrix organization reveled that MSH-treated Ay/a melanosomes retained distinct features of phaeomelanogenesis even after 5 d of MSH treatment. Thus, MSH induced a partial but incomplete pattern of eumelanogenesis in regenerating hairbulb melanocytes of Ay/a mice. The continued investigation of the dynamics of melanin synthesis in MSH-induced Ay/a mice melanocytes possessing "mosaic" melanosomes could be productive in understanding fundamental relationships between tyrosinase activity, matrix function, matrix structure, and regulation of melanin (phaeo- and/or eumelanin) synthesis.


Subject(s)
Melanocyte-Stimulating Hormones/pharmacology , Melanocytes/cytology , Animals , Genes, Lethal , Golgi Apparatus/drug effects , Golgi Apparatus/ultrastructure , Melanocytes/drug effects , Melanocytes/ultrastructure , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Microscopy, Electron , Regeneration , Skin Physiological Phenomena
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