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PubMed1984

Relapsing polychondritis with segmental necrotizing glomerulonephritis.

Glomerulonephritis is a very unusual feature of relapsing polychondritis. A 16-year-old woman presented with microscopic hematuria and severe renal insufficiency during the course of relapsing polychondritis. A renal biopsy specimen disclosed focal segmental proliferative glomerulonephritis with necrotizing lesions and crescent formation. Immunofluorescent studies suggested immune complex mediated glomerular injury. The renal involvement appeared during high-dose steroid therapy. Subsequently, she was treated by adding plasmapheresis and cyclophosphamide during 6 weeks, with sustained improvement. A regimen of plasmapheresis and immunosuppression warrants consideration for use in cases of relapsing polychondritis with glomerulonephritis.

Adolescent↗
PubMed1988

The relationship of infiltrating renal leucocytes to disease activity in lupus and cryoglobulinaemic glomerulonephritis.

In order to evaluate the contribution of cellular immune mechanisms in the pathogenesis of immune complex-mediated glomerulonephritis, renal biopsies from 18 patients with lupus glomerulonephritis and 26 with cryoglobulinaemic glomerulonephritis were studied. Leucocyte profiles including T cell subsets and 'activated' macrophages within both glomeruli and interstitium were determined, using a panel of monoclonal antibodies as markers, and a sensitive 4-layer peroxidase technique to localize these within tissues. The infiltrating leucocytes were correlated with clinical, histological and immunological parameters of disease activity. Normal glomeruli contained few leucocytes though normal interstitium did (145 +/- 30 mm2), made up predominantly of T lymphocytes and macrophages. There was a significant increase in intraglomerular leucocytes in both systemic lupus erythematosus 4-fold, and essential mixed cryoglobulinaemia 7-fold, as compared to normal. These leucocytes consisted mainly of macrophages, and particularly in cryoglobulinaemia of 'activated' macrophages as demonstrated by their surface expression of the procoagulant tissue factor recognized by the A13 monoclonal antibody. In cryoglobulinaemic glomerulonephritis (GN) there was also a significant increase in T lymphocytes due to a predominance of suppressor-cytotoxic cells (OKT8+). There was a significant increase in interstitial leucocytes in both diseases, lymphocytes (mainly OKT8+ve), and macrophages (mainly 'activated' A13+ve). There were significant positive correlations between disease activity and interstitial leucocyte infiltration including, in lupus nephritis, degree of proteinuria and total leucocytes, hypocomplementaemia and T lymphocytes, increased numbers of monocytes and lymphocytes with a higher histological index of activity, and in cryoglobulinaemic GN of T lymphocytes and proliferative lesions, and T lymphocytes and C1q deposition. This study has demonstrated the importance of the interstitium in the pathogenesis of both diseases, delineated the presence of both T lymphocytes and activated monocytes which make cell-mediated immune mechanisms feasible, and linked the presence of immune mediators to disease activity.

Cell Count↗
PubMed1991

Analysis of ultrastructural immune deposits in passive heymann nephritis by double-staining methods with electron microscopy.

In this study, we located and quantitated the ultrastructural glomerulus-bound immunoglobulins of passive Heymann nephritis from 10 min through 64 days using the double immunogold staining method. At the early stage (10 min to 21 days), rabbit IgG was found predominantly comparing rat IgG. With time (from 21 days to 32 days), rat IgG increased, although rabbit IgG was almost the same as at the early stage. At the late stage (64 days), rat IgG was predominantly found in all of the dense deposits on the glomerular basement membrane, whereas rabbit IgG was decreased. Thus, the double staining method was useful to analyze the composition of the immune complex and also to elucidate the immunopathogenesis of immune complex-mediated glomerulonephritis.

Animals↗
PubMed1979

Neuropsychological dysfunction in acute viral hepatitis.

Neuropsychological dysfunction may precede, occur simultaneously with, or follow the icteric phase of viral hepatitis. Encephalitic and meningitic involvement appears to precede the onset of clinical hepatitis while the tremor syndrome usually follows the onset of illness. The Guillain-Barré syndrome, peripheral nerve disorders, and behavioral abnormalities may occur at any stage of the disease. Neuropsychological alterations noted during the prodrome of viral hepatitis usually clear without sequelae but abnormalities which follow the onset of jaundice may persist during the convalescent phase for prolonged periods. Neither occurrence, type, nor severity of neuropsychological dysfunction appear to be related to specific hepatitis viruses since both type B and non-B infections have been implicated. Furthermore, neuropsychological dysfunction does not appear to be related to the severity of the hepatitis as assessed by clinical or histological features. Although direct viral invasion of nervous tissue and immune complex-mediated damage have been postulated, the mechanism(s) of neuropsychological abnormalities remains to be determined.

Acute Disease↗
PubMed1988

The significance of complement activation in the pathogenesis of hypersensitivity pneumonitis: sequential changes of complement components and chemotactic activities in bronchoalveolar lavage fluids.

Hypersensitivity pneumonitis (HP) is believed to be induced by immunological mechanisms, the details of which remain to be clarified. While a role for cellular immunity is accepted in the pathogenesis of HP, several clinical observations also suggest a role for immune-complex-mediated lung injury. We have previously demonstrated the presence of chemotactic factors for polymorphonuclear cells (PMNs) in bronchoalveolar lavage (BAL) fluids of acutely ill patients with the summer type of HP found in Japan. The present study correlated chemotactic factors for PMNs with the level of C5a des Arg in BAL fluids obtained from patients with summer type HP. Furthermore, this study demonstrated that PMNs were increased in BAL fluids obtained after 2 days of avoidance of exposure to the presumptive causative agent. The percentage of PMNs in the BAL increased in proportion to the activity of the chemotactic factors. Finally, leukotriene B4 was not detected in concentrated BAL or supernatant fluids of cultured macrophages. These results suggest that complement activation in the respiratory tract may occur as the early event in the pathogenesis of HP.

Alveolitis, Extrinsic Allergic↗
PubMed2005

Regulation of chemotaxis by the cytoplasmic domain of tissue factor.

We previously demonstrated that FVIIa bound to tissue factor (TF) induces a hyperchemotactic response towards PDGF-BB. The aim of the present study was to investigate the role of the cytoplasmic domain of TF in cell migration. Porcine aortic endothelial (PAE) cells expressing human PDGF beta-receptors (PAE/PDGFRbeta) were transfected for expression of human wildtype TF (PAE/PDGFRbeta,TF), a construct lacking the cytoplasmic domain (PAE/PDGFRbeta,TFDeltacyto), a construct with alanine replacement of serine 258 (PAE/PDGFRbeta,TFS258A), or a construct with alanine replacement of serine 253, 258 and 263 in the cytoplasmic domain (PAE/PDGFRbeta,TF3SA). All stably transfected cell lines expressed functional TF. Chemotaxis was analyzed in a modified Boyden chamber assay. PAE/PDGFRbeta,TF cells stimulated with FVIIa migrated towards a 100-fold lower concentration of PDGF-BB than in the absence of FVIIa, however, hyperchemotaxis was not seen in PAE/PDGFRbeta,TFDeltacyto cells. PAE/PDGFRbeta/TFS258A and PAE/PDGFRbeta,TF3SA cells responded to low levels of PDGF-BB, but migrated a significantly shorter distance than PAE/PDGFRbeta,TF cells. Thus, hyperchemotaxis towards PDGF-BB is likely to depend in part on phosphorylation of the cytoplasmic domain of TF. We conclude that the cytoplasmic domain of TF plays a pivotal role in modulating cellular migration response. Our results suggest that the FVIIa/TF complex mediates intracellular signaling by alternative signal transduction pathway(s).

Animals↗
PubMed1995

Mapping of G protein coupling sites of the angiotensin II type 1 receptor.

Angiotensin II type 1 (AT1) receptors have been identified in a wide variety of tissues, including the kidney, liver, adrenal gland, cardiovascular system, and brain. AT1 receptors also mediate complex signaling mechanisms that elicit a diversity of specific physiological effects. The rat AT1A receptor has seven transmembrane domains and couples with three distinct G proteins: Gq, Gi, and Go. But it is unknown which domains of AT1A couple with and activate each type of G protein. To identify the domains responsible for the activation of various types of G protein, we studied the effect of five different synthetic peptides representing different domains of cytosolic segments of the rat AT1A receptor on the binding of the 35S-labeled stable analogue of GTP, GTP gamma S. Peptides P-3, which is located in the N-terminal region of the putative third intracellular loop of AT1A (residues 216 through 230), and P-5 (residues 306 through 320), corresponding to the N-terminal region of the C-terminal tail, were found to activate purified Gi1, Gi2, and Go proteins. These results indicate that not only the third cytosolic loop but also the C-terminal cytosolic domain of AT1A is important for Gi1, Gi2, and Go protein coupling and activation.

Amino Acid Sequence↗
PubMed2000

Mammalian bufadienolide is synthesized from cholesterol in the adrenal cortex by a pathway that Is independent of cholesterol side-chain cleavage.

An increasing body of evidence suggests that an endogenous mammalian bufadienolide (BD) may be involved in the regulation of Na(+),K(+)-ATPase activity and the pathogenesis of arterial hypertension. We developed a purification scheme for marinobufagenin (MBG), an amphibian cardiotonic BD, and applied it to purify and characterize material in human plasma, culture medium conditioned by Y-1 adrenocortical cells, and rat adrenal tissue. MBG immunoreactivity purified from plasma and measured by ELISA showed important similarities (chromatography and antibody cross-reactivity) to material secreted into cell culture medium by Y-1 cells. This observation indicates that circulating mammalian BD may have an adrenocortical origin. Release of mammalian BD from adrenocortical cells grown in the absence of exogenous cholesterol was reduced by treatment of cultures with mevastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Supplementation of the serum and cholesterol-free cell culture medium with the LDL fraction of human plasma increased the production of MBG material in the presence of mevastatin, supporting its origin from cholesterol. We used Y-1 cell lines transfected with genes shown to inhibit steroidogenesis through cholesterol side-chain cleavage (Y-1/DAX and Y-1/RIAB) to investigate the dependence of MBG biosynthesis on side-chain cleavage. Our results indicate that the mammalian BD is synthesized in the adrenal cortex from cholesterol and shares important similarities with the amphibian BD MBG, that its biosynthesis is independent of transfer of cholesterol to the side-chain cleavage enzyme complex mediated by steroidogenic acute regulatory protein, and that neither cAMP nor protein kinase A appears to be a critical component of the pathway controlling its biosynthesis.

Adrenal Cortex↗
PubMed2026

Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied. METHODS: To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet. RESULTS: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank. CONCLUSIONS: Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.

LDL lowering↗
PubMed1994

Monoclonal antibody KS1/4-methotrexate immunoconjugate studies in non-small cell lung carcinoma.

The antigen reactive with murine monoclonal antibody (MAb) KS1/4 is expressed on epithelial malignancies and some normal epithelial tissues. Studies were undertaken to evaluate KS1/4-methotrexate (KS1/4-MTX) immunoconjugate in patients with advanced non-small cell carcinoma of the lung. Eleven patients in two different groups received KS1/4-MTX in two different escalating dose infusion schedules with a maximal tolerated dose of 1,750 mg/M2 and a cumulative dose of MTX of 40 mg/M2. Toxicities were similar in both groups and included fever, anorexia, nausea, vomiting, diarrhea, abdominal pain, guaiac positive stool, and hypoalbuminemia. Two patients had an associated aseptic meningitis. One patient had a 50% decrease in two lung nodules without a change in lymphangitic infiltrates. This patient received a second course of treatment and developed an immune complex-mediated arthritis and serum sickness. Four patients mounted a human antimouse antibody response. Post-treatment tumor biopsies documented binding of MAb KS1/4. These studies document the feasibility and potential usefulness of a MAb directed against tumor-associated antigens with the targeting of chemotherapeutic drugs in patients with non-small cell lung carcinoma.

Aged↗
PubMed1986

Palmitate uptake by hepatocyte monolayers. Effect of albumin binding.

The uptake of 14C-palmitate by rat liver cell monolayers is depressed by binding of the fatty acid to albumin. When the uptake flux is divided by the concentration of free palmitate in the bathing medium, however, the resulting clearance is approximately 14 times greater in the presence of albumin than in its absence. These findings are not accounted for by the different diffusion rates of free and bound palmitate across an unstirred fluid layer, nor attributable to nonequilibrium binding. Instead we argue that the most plausible explanation is accelerated dissociation of albumin-palmitate complexes mediated by the cell surface--an interpretation that also explains the uptake kinetics of other albumin-bound organic anions by perfused rat liver.

Adsorption↗
PubMed1990

Phagocytosis of Histoplasma capsulatum yeasts and microconidia by human cultured macrophages and alveolar macrophages. Cellular cytoskeleton requirement for attachment and ingestion.

Phagocytosis of Histoplasma capsulatum (Hc) yeasts and microconidia by human macrophages (M phi) was quantified by a fluorescence quenching technique. Phagocytosis of unopsonized Hc yeasts by monocyte-derived M phi and human alveolar M phi (AM) was rapid. After 60 min, 79% of cultured M phi and 59% of AM had ingested an average of 9.8 and 11 yeasts/M phi, respectively. In contrast, only 26% of monocytes ingested 4.5 yeasts/cell after 60 min. Phagocytosis of unopsonized microconidia by cultured M phi and by AM was equivalent. Monoclonal antibodies specific for the alpha-chains and beta-chain of the CD18 family of adhesion receptors inhibited the binding of Hc yeasts and microconidia to cultured M phi and AM. Thus, the M phi CD18 complex mediates recognition of both phases of this dimorphic fungus. Disruption of actin microfilaments with cytochalasin D inhibited both attachment and ingestion of yeasts by M phi. In contrast, nocodazole, which prevents polymerization of microtubules, did not inhibit binding or ingestion. Both drugs inhibited ingestion, but neither drug inhibited binding of C3b- and C3bi-coated sheep erythrocytes to complement receptors type one (CR1) or type three (CR3), respectively. Therefore, different signal transducing mechanisms for phagocytosis appear to be triggered by the binding of Hc yeasts to CD18, and by the binding of EC3bi to CD11b/CD18, respectively.

Antibodies, Monoclonal↗
PubMed1991

Human eosinophils express functional interleukin 2 receptors.

Because T cell-derived cytokines may affect the functioning of eosinophils, we have investigated the capacity of human eosinophils to respond to IL-2. IL-2 was a potent chemoattractant with ED50 of 10(-12) M with eosinophils from all normal and eosinophilic donors tested. The monoclonal antibodies anti-Tac and TU27 against p55 (Tac/CD25) and p75 receptor subunits, respectively, each inhibited IL-2-dependent eosinophil migration. The molar potency of IL-2 and the inhibitory activity of each of the above antibodies suggest that high affinity heterodimeric IL-2 receptor complexes mediated the migration responses of eosinophils to IL-2. Binding of monoclonal antibody against p75 was not detectable by flow cytometry, and high affinity binding sites for 125I-IL-2 were below the limits of quantitation on eosinophils from individuals with eosinophilia. Expression of p55 (Tac/CD25) by eosinophils, without requirement for in vitro activation, was demonstrable by flow cytometry, radioimmunoprecipitation, and Northern blotting for mRNA. Surface expression of p55 on eosinophils from normal or eosinophilic individuals increased during culture for 24-48 h with a biologic activity purified from stimulated U937 cells and to a lesser extent with granulocyte-macrophage CSF or lymphocyte chemoattractant factor but not with nine other cytokines. These studies indicate that blood eosinophils respond to IL-2 and identify one mechanism whereby activation of T lymphocytes may influence the function of eosinophils.

Cell Movement↗
PubMed2002

Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis.

Leukocyte recruitment in inflammation is critical for host defense, but excessive accumulation of inflammatory cells can lead to tissue damage. Neutrophil-derived serine proteases (cathepsin G [CG], neutrophil elastase [NE], and proteinase 3 [PR3]) are expressed specifically in mature neutrophils and are thought to play an important role in inflammation. To investigate the role of these proteases in inflammation, we generated a mouse deficient in dipeptidyl peptidase I (DPPI) and established that DPPI is required for the full activation of CG, NE, and PR3. Although DPPI(-/-) mice have normal in vitro neutrophil chemotaxis and in vivo neutrophil accumulation during sterile peritonitis, they are protected against acute arthritis induced by passive transfer of monoclonal antibodies against type II collagen. Specifically, there is no accumulation of neutrophils in the joints of DPPI(-/-) mice. This protective effect correlates with the inactivation of neutrophil-derived serine proteases, since NE(-/-) x CG(-/-) mice are equally resistant to arthritis induction by anti-collagen antibodies. In addition, protease-deficient mice have decreased response to zymosan- and immune complex-mediated inflammation in the subcutaneous air pouch. This defect is accompanied by a decrease in local production of TNF-alpha and IL-1 beta. These results implicate DPPI and polymorphonuclear neutrophil-derived serine proteases in the regulation of cytokine production at sites of inflammation.

Animals↗
PubMed2003

Bone marrow transplantation reveals an essential synergy between neuronal and hemopoietic cell neurokinin production in pulmonary inflammation.

Neurogenic inflammation is believed to originate with the antidromic release of substance P, and of other neurokinins encoded by the preprotachykinin A (PPT-A) gene, from unmyelinated nerve fibers (C-fibers) following noxious stimuli. Consistent with this concept, we show here that selective sensory-fiber denervation with capsaicin and targeted deletion of the PPT-A gene protect murine lungs against both immune complex-mediated and stretch-mediated injuries. Reconstitution of PPT-A gene-deleted mice with WT bone marrow does not abrogate this protection, demonstrating a critical role for PPT-A gene expression by sensory neurons in pulmonary inflammation. Surprisingly, reconstitution of WT mice with PPT-A gene-deficient bone marrow also confers protection against pulmonary injury, revealing that PPT-A gene expression in hemopoietic cells has a previously unanticipated essential role in tissue injury. Taken together, these findings demonstrate a critical synergy between capsaicin-sensitive sensory fibers and hemopoietic cells in neurokinin-mediated inflammation and suggest that such synergy may be the basis for a stereotypical mechanism of response to injury in the respiratory tract.

Animals↗
PubMed2003

CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice.

Systemic lupus erythematosus (SLE) is a CD4(+) T cell-dependent, immune complex-mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb's or CTLA4-Ig and anti-CD154 mAb's have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB x NZW F(1) mice given three injections of anti-CD137 (4-1BB) mAb's between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice's lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB x NZW F(1) mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4(+) T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4(+) T cells during priming at the DC interface.

Acute Disease↗
PubMed2004

Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses.

Mice containing a disruption of the Hexb gene have provided a useful model system for the study of the human lysosomal storage disorder known as Sandhoff disease (SD). Hexb(-/-) mice rapidly develop a progressive neurologic disease of ganglioside GM2 and GA2 storage. Our study revealed that the disease states in this model are associated with the appearance of antiganglioside autoantibodies. Both elevation of serum antiganglioside autoantibodies and IgG deposition to CNS neurons were found in the advanced stages of the disease in Hexb(-/-) mice; serum transfer from these mice showed IgG binding to neurons. To determine the role of these autoantibodies, the Fc receptor gamma gene (FcR gamma) was additionally disrupted in Hexb(-/-) mice, as it plays a key role in immune complex-mediated autoimmune diseases. Clinical symptoms were improved and life spans were extended in the Hexb(-/-)FcR gamma(-/-) mice; the number of apoptotic cells was also decreased. The level of ganglioside accumulation, however, did not change. IgG deposition was also confirmed in the brain of an autopsied SD patient. Taken together, these findings suggest that the production of autoantibodies plays an important role in the pathogenesis of neuropathy in SD and therefore provides a target for novel therapies.

Animals↗
PubMed2005

Looking forward in geriatric anxiety and depression: implications of basic science for the future.

Major depression and anxiety are common psychiatric illnesses whose etiology remains incompletely understood. This review highlights progress in understanding the etiology of these illnesses through genetic strategies and looks forward to their impact on geriatric psychiatry. We briefly address three broad domains of progress, namely 1) genetic approaches to etiology, including linkage and association studies, pharmacogenetics ("personalized medicine"), and gene x environment interactions; 2) mechanisms of thyroid and testosterone action via nuclear receptors, given these hormones' status as possible augmenters of antidepressants; and 3) the role of the neuroimmune system as a contributor to the stress response. Genetic strategies offer one path for converting correlational findings into causal pathways while complementing studies of a gene's function at the molecular, cellular, network, and whole-organismal levels. Neuroendocrine supplementation (thyroid and testosterone) has a long history and tradition. A molecular understanding of nuclear receptor pathways and their coactivators, the mediator complex proteins, provides a rationale for improved targeting of hormonal action in a tissue-selective manner, yielding drugs with improved safety and efficacy. Neural-immune interactions in psychiatric illness remain tantalizing topics. Research suggests that cytokine pathways may contribute to the maintenance or susceptibility to stress, anxiety, and depressive disorders. The reciprocal and recursive interactions among basic science, drug discovery, and clinical science will continue to provide hopeful themes for improving the lives of patients with treatment-refractive psychiatric illness.

Aged↗