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ID PMID Title PublicationDate abstract
18591228 The interleukin-17 receptor plays a gender-dependent role in host protection against Porph 2008 Sep Interleukin-17 (IL-17) is a proinflammatory cytokine secreted by the newly described CD4(+) Th17 subset, which is distinct from classic Th1 and Th2 lineages. IL-17 contributes to bone destruction in rheumatoid arthritis but is essential in host defense against pathogens that are susceptible to neutrophils. Periodontal disease (PD) is a chronic inflammatory condition initiated by anaerobic oral pathogens such as Porphyromonas gingivalis, and it is characterized by host-mediated alveolar bone destruction due primarily to the immune response. The role of IL-17 in PD is controversial. Whereas elevated IL-17 levels have been found in humans with severe PD, we recently reported that female C57BL/6J mice lacking the IL-17 receptor (IL-17RA(KO)) are significantly more susceptible to PD bone loss due to defects in the chemokine-neutrophil axis (J. J. Yu, M. J. Ruddy, G. C. Wong, C. Sfintescu, P. J. Baker, J. B. Smith, R. T. Evans, and S. L. Gaffen, Blood 109:3794-3802, 2007). Since different mouse strains exhibit differences in susceptibility to PD as well as Th1/Th2 cell skewing, we crossed the IL-17RA gene knockout onto the BALB/c background and observed a similar enhancement in alveolar bone loss following P. gingivalis infection. Unexpectedly, in both strains IL-17RA(KO) female mice were much more susceptible to PD bone loss than males. Moreover, female BALB/c-IL-17RA(KO) mice were defective in producing anti-P. gingivalis immunoglobulin G and the chemokines KC/Groalpha and MIP-2. In contrast, male mice produced normal levels of chemokines and anti-P. gingivalis antibodies, but they were defective in granulocyte colony-stimulating factor upregulation. This study demonstrates a gender-dependent effect of IL-17 signaling and indicates that gender differences should be taken into account in the preclinical and clinical safety testing of anti-IL-17 biologic therapies.
18417382 Association between salivary flow rates, oral symptoms, and oral mucosal status. 2008 Aug OBJECTIVE: To investigate the association of salivary flow rates with oral symptoms and oral mucosal status. STUDY DESIGN: The study population included 462 Israeli subjects attending a xerostomia clinic. After patient history and oral mucosal examination, major gland sialometry, and complementary tests, patients were divided into 6 groups: drug-induced salivary gland hypofunction (SGH), Sjögren syndrome (SS), radiation-induced SGH, idiopathic SGH, xerostomia without SGH, and control. RESULTS: Oral mucosal alterations were more prevalent in all SGH groups than in the control group. Oral symptoms (except speech impairment) were more frequent in all SGH groups. The postradiation group showed the highest frequency of oral mucosal alterations and of swallowing and mastication complaints. Individuals complaining of xerostomia (compared with those who did not) displayed lower major salivary gland flow rates and a higher frequency of oral mucosal alterations CONCLUSIONS: Presence of oral mucosal alterations may help but are not enough to identify patients for further evaluation of SGH. Difficulties in mastication and swallowing are most specifically related to advanced SGH.
17720850 Cholinoreceptor autoantibodies in Sjögren syndrome. 2007 Sep Previous studies have demonstrated that antibodies against cholinoreceptors of exocrine glands correlate with dry mouth in persons with primary Sjögren syndrome (pSS). The aim of the present investigation was to establish if serum IgG antibodies (pSS IgG) were able to interact with cholinoreceptors in rat submandibular gland-dependent stimulation of cyclooxygenase 2 (COX-2) mRNA expression and PGE(2) production. Our findings indicated that pSS IgG-stimulating M(3), M(4), and M(1) cholinoreceptors exerted an increase in COX-2 mRNA without affecting COX-1 mRNA expression and increased PGE(2) production. Inhibitors of phospholipase A(2), COX- s, L-type calcium channel currents, and Ca(2+)-ATPase from sarcoplasmic reticulum prevented the pSS IgG effect on PGE(2) production. An ionophore of calcium mimicked pSS IgG action, suggesting a crucial role of calcium homeostasis in the cholinoreceptor-stimulated increase in PGE(2) production. Moreover, the amounts of PGE(2) in saliva and in sera from persons with pSS were significantly higher than in pre- or post-menopausal women. These findings illustrate the importance of autoantibodies to cholinoreceptors in the generation of chronic inflammation of target tissues in SS.
17177966 Analysis of parotid glands of primary Sjögren's syndrome patients using proteomic technol 2007 Jan Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration, destruction of the salivary and lacrimal glands and production of autoantibodies against a variety of cellular proteins. The aberrant immune response against these autoantigens may begin or extend to other proteins that are not yet defined. Several studies have shown that autoantibody production is taking place in the affected salivary glands. In the present study, using proteomic approaches, we aimed to: (a) identify new autoantigens in the salivary glands of primary SS (pSS) patients and (b) evaluate the epigenetic changes of known autoantigens. Total parotid gland extracts of pSS patients were analysed using two-dimensional gel electrophoresis, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot with pSS patients' sera or purified autoantibodies and immunoprecipitation using homologous IgG. Identification of the unknown proteins was performed using mass spectrometry (MS). Immunoblot analysis on two-dimensional gels using purified anti-La/SSB antibodies revealed that pSS salivary glands contain high levels of post-translationally modified La/SSB autoantigen, while the native form of the protein is recognized faintly, in contrast to normal controls. Moreover, salivary glands of pSS patients contain post-translationally modified actin that becomes immunogenic in the microenviroment of the affected tissue. The alteration of the physicochemical properties of self-proteins could thus contribute to the break of immune tolerance against them.
18567580 Ubiquitin ligase Smurf1 mediates tumor necrosis factor-induced systemic bone loss by promo 2008 Aug 22 Chronic inflammatory disorders, such as rheumatoid arthritis, are often accompanied by systemic bone loss, which is thought to occur through inflammatory cytokine-mediated stimulation of osteoclast resorption and inhibition of osteoblast function. However, the mechanisms involved in osteoblast inhibition remain poorly understood. Here we test the hypothesis that increased Smad ubiquitin regulatory factor 1 (Smurf1)-mediated degradation of the bone morphogenetic protein pathway signaling proteins mediates reduced bone formation in inflammatory disorders. Osteoblasts derived from bone marrow or long bone samples of adult tumor necrosis factor (TNF) transgenic (TNF-Tg) mice were used in this study. TNF decreased the steady-state levels of Smad1 and Runx2 protein similarly to those in long bones of TNF-Tg mice. In the presence of the proteasome inhibitor MG132, TNF increased accumulation of ubiquitinated Smad1 protein. TNF administration over calvarial bones caused decreases in Smad1 and Runx2 protein levels and mRNA expression of osteoblast marker genes in wild-type, but not in Smurf1(-/-) mice. Vertebral bone volume and strength of TNF-Tg/Smurf1(-/-) mice were examined by a combination of micro-CT, bone histomorphometry, and biomechanical testing and compared with those from TNF-Tg littermates. TNF-Tg mice had significantly decreased bone volume and biomechanical properties, which were partially rescued in TNF-Tg/Smurf1(-/-) mice. We conclude that in chronic inflammatory disorders where TNF is increased, TNF induces the expression of ubiquitin ligase Smurf1 and promotes ubiquitination and proteasomal degradation of Smad1 and Runx2, leading to systemic bone loss. Inhibition of ubiquitin-mediated Smad1 and Runx2 degradation in osteoblasts could help to treat inflammation-induced osteoporosis.
18467203 Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleu 2008 Jul Pro-inflammatory mediators formed by the kallikrein-kinin system can stimulate bone resorption and synergistically potentiate bone resorption induced by IL-1 and TNF-alpha. We have shown that the effect is associated with synergistically enhanced RANKL expression and enhanced prostaglandin biosynthesis, due to increased cyclooxygenase-2 expression. In the present study, the effects of osteotropic cytokines and different kinins on the expression of receptor subtypes for bradykinin (BK), des-Arg10-Lys-BK (DALBK), IL-1beta and TNF-alpha have been investigated. IL-1beta and TNF-alpha enhanced kinin B1 and B2 receptor binding in the human osteoblastic cell line MG-63 and the mRNA expression of B1 and B2 receptors in MG-63 cells, human gingival fibroblasts and intact mouse calvarial bones. Kinins did not affect mRNA expression of IL-1 or TNF receptors. EMSA showed that IL-1beta and TNF-alpha activated NF-kappaB and AP-1 in MG-63 cells. IL-1beta stimulated NF-kappaB via a non-canonical pathway (p52/p65) and TNF-alpha via the canonical pathway (p50/p65). Activation of AP-1 involved c-Jun in both IL-1beta and TNF-alpha stimulated cells, but c-Fos only in TNF-alpha stimulated cells. Phospho-ELISA and Western blots showed that IL-1beta activated JNK and p38, but not ERK 1/2 MAP kinase. Pharmacological inhibitors showed that NF-kappaB, p38 and JNK were important for IL-1beta induced stimulation of B1 receptors, and NF-kappaB and p38 for B2 receptors. p38 and JNK were important for TNF-alpha induced stimulation of B1 receptors, whereas NF-kappaB, p38 and JNK were involved in TNF-alpha induced expression of B2 receptors. These data show that IL-1beta and TNF-alpha upregulate B1 and B2 receptor expression by mechanisms involving activation of both NF-kappaB and MAP kinase pathways, but that signal transduction pathways are different for IL-1beta and TNF-alpha. The enhanced kinin receptor expression induced by the pro-inflammatory cytokines IL-1beta and TNF-alpha might be one important mechanism involved in the synergistic enhancement of prostaglandin formation caused by co-treatment with kinins and one of the two cytokines. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including periodontitis and rheumatoid arthritis.
17908040 TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: new drug can 2007 Sep As the average ages of North Americans and Europeans continue to rise; similarly the incidence of "old age" associated illnesses likewise increases. Most notably among these ailments are conditions linked to dementia-related neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and stroke. While in the early stages, these conditions are associated with cellular dysfunction in distinctly different brain regions, thus affecting different neuronal cell types; it is most likely that the final stages share similar cellular and molecular processes leading to neuronal death and ultimately overt clinical symptoms. In this regard, different environmental and genetic triggers ranging from head trauma to protein mutations and toxicological exposure may instigate a cascade of intracellular events that ultimately lead to neuronal death. One strong candidate trigger protein, and thus a potential target for therapeutic manipulation is the potent pro-inflammatory / pro-apoptotic cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is secreted by the brain resident marcophage (the microglial cell) in response to various stimuli. It has been demonstrated to play a major role in central nervous system (CNS) neuroinflammation-mediated cell death in AD, PD and amyotrophic lateral sclerosis (ALS) as well as several other CNS complications. Recently, agents that modulate the levels of circulating peripheral TNF-alpha protein have been shown to be worthwhile therapeutic agents with the use of Enbrel (Etanercept) and Remicade (Infliximab), both of which display beneficial properties against rheumatoid arthritis and other peripheral inflammatory diseases. Unfortunately, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in the setting of neuroinflammation in the CNS. However, thalidomide, a small molecule drug, can inhibit TNF-alpha protein synthesis and, unlike larger molecules, is readily capable of crossing the blood-brain barrier. Thus thalidomide and its analogs are excellent candidate agents for use in determining the potential value of anti-TNF-alpha therapies in a variety of diseases underpinned by inflammation within the nervous system. Consequently, we have chosen to discuss the relevance of unregulated TNF-alpha expression in illnesses of the CNS and, to an extent, the peripheral nervous system. Additionally, we consider the utilization of thalidomide-derived agents as anti-TNF-alpha therapeutics in the setting of neuroinflammation.
16818766 Prostaglandin E2 augments IL-10 signaling and function. 2006 Jul 15 In inflamed joints of rheumatoid arthritis, PGE(2) is highly expressed, and IL-10 and IL-6 are also abundant. PGE(2) is a well-known activator of the cAMP signaling pathway, and there is functional cross-talk between cAMP signaling and the Jak-STAT signaling pathway. In this study, we evaluated the modulating effect of PGE(2) on STAT signaling and its biological function induced by IL-10 and IL-6, and elucidated its mechanism in THP-1 cells. STAT phosphorylation was determined by Western blot, and gene expression was analyzed using real-time PCR. Pretreatment with PGE(2) significantly augmented IL-10-induced STAT3 and STAT1 phosphorylation, as well as suppressors of cytokine signaling 3 (SOCS3) and IL-1R antagonist gene expression. In contrast, PGE(2) suppressed IL-6-induced phosphorylation of STAT3 and STAT1. These PGE(2)-induced modulating effects were largely reversed by actinomycin D. Pretreatment with dibutyryl cAMP augmented IL-10-induced, but did not change IL-6-induced STAT3 phosphorylation. Misoprostol, an EP2/3/4 agonist, and butaprost, an EP2 agonist, augmented IL-10-induced STAT3 phosphorylation and SOCS3 gene expression, but sulprostone, an EP1/3 agonist, had no effect. H89, a protein kinase A inhibitor, and LY294002, a PI3K inhibitor, diminished PGE(2)-mediated augmentation of IL-10-induced STAT3 phosphorylation. In this study, we found that PGE(2) selectively regulates cytokine signaling via increased intracellular cAMP levels and de novo gene expression, and these modulating effects may be mediated through EP2 or EP4 receptors. PGE(2) may modulate immune responses by alteration of cytokine signaling in THP-1 cells.
20641316 Pyro-Gly-Pro-Leu-Gly-Leu-Ala-Arg-Lys(BHQ3). 2004 Photodynamic therapy (PDT), also known as photochemotherapy, uses light-activated photosensitizers (PS) in the presence of oxygen to kill cells (1). PDT has become a promising modality to treat skin, esophagus, and lung cancers, as well as other diseases such as atherosclerosis, macular degeneration, and rheumatoid arthritis (2). In PDT, light excites the singlet state of the PS, followed by intersystem transition from the singlet state to the triplet state; then, the energy is transferred from the triplet state of the PS to the triplet ground state of oxygen, (3)O(2)(X(3)Σ(g)(-)) ((3)O(2) triplet state quenching) to generate singlet oxygen, (1)O(2)(a(1)Δ(g)) (3). The produced (1)O(2) is a major cytotoxic agent that has a short life time (<200 ns) and an average diffusion range (~20 nm, which is smaller than the diameter of a cell) (2). Such a short diffusion range requires the delivery of target-specific PS agents into subcellular compartments such as cytoskeletal tubulin, lysosomes, mitochondria, plasma membrane, and the nucleus, where they can generate (1)O(2) efficiently (2). A novel type of PS agent, called a photodynamic molecular beacon (PMB) or killer beacon, has been developed to meet this requirement (2, 4). A typical PMB consists of four modular components: a fluorescent PS, a quencher, a linker, and a delivery vehicle. The target-specific linkers keep the fluorescent PS and the quencher within effective distance of the Föster radius (3–6 nm) (2), which allows efficient fluorescence resonance energy transfer between the fluorescent PS and the quencher. As a result, the fluorescent PS is silent until the PMB meets the target, where the enzyme cleaves the linker and activates the fluorescence of the PS (4). Thus, the PS performs two functions by producing (1)O(2) to kill cells and by illuminating detectable fluorescence to image its own therapeutic outcome (5). Matrix metalloproteinases (MMPs) have been pharmaceutical targets for many years because they play important roles in many diseases such as atherosclerosis, lung pulmonary fibrosis, and cancer (4). MMPs in tumors aid the degradation of extracellular matrix, facilitate neoplastic cell motility, and direct cell invasion (4). Also known as matrilysin, MMP subtype-7 (MMP7) is one of only a few MMPs that are actually secreted by tumor cells (6). Pyro-Gly-Pro-Leu-Gly-Leu-Ala-Arg-Lys(BHQ3) (PP(MMP7)B) is a PMB specific for MMP7, and it is detectable with near-infrared (NIR) fluorescence imaging (4). PP(MMP7)B consists of the infrared fluorescence PS pyropheophorbide α (Pyro), a black hole quencher 3 (BHQ3), and a peptide linker (Gly-Pro-Leu-Gly-Leu-Ala-Arg-Lys (GPLGLARK)) (4). The peptide contains the tripeptide motif Pro-Leu-Gly for MMP7 recognition, and the cleavage site is located between the Gly and Leu residues. Pyro acts as the intracellular delivery vehicle and as the PS (absorption, 665 nm; emission, 675 nm and 720 nm) with good (1)O(2) production (50%). Pyro lacks dark toxicity (toxicity in absence of light) because of its low absorption between 450–600 nm. BHQ3 (absorption, 672 nm) can efficiently quench Pyro fluorescence via fluorescence resonance energy transfer (FRET). The cleavage of Pyro-Gly-Asp-Glu-Val-Asp-Gly-Ser-Gly-Lys(BHQ3) (PPB) by MMP7 separates the PS (Pyro) from the quencher (BHQ3) and restores the Pyro fluorescence for detection.
20641887 (64)Cu-Tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid-quantum dot-c(Arg- 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low fluorescence background, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence (NIRF) imaging is becoming a non-invasive alternative to radionuclide imaging in small animals (4, 5). Fluorescent semiconductor quantum dots (QDs) are nanocrystals made of CdSe/CdTe-ZnS with radii of 1–10 nm (6-8). They can be tuned to emit light in a range of wavelengths by changing their sizes and composition, thus providing broad excitation profiles and high absorption coefficients. They have narrow and symmetric emission spectra with long excited-state lifetimes (20–50 ns) compared with fluorescent dyes (1–10 ns). QDs possess good quantum yields of 40–90% and high extinction coefficients, and they are more photo-stable than conventional organic dyes. They can be coated and capped with hydrophilic materials for additional conjugations with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds, which are tested in vitro and in vivo (8-12). Although many cells have been labeled with QDs in vitro with little cytotoxicity, there are only limited studies of long-term toxicity of QDs in small animals (13-21), and little is known about the toxicity and the mechanisms of clearance and metabolism of QDs in humans. Integrins are a family of heterodimeric, cell-surface glycoproteins that mediate diverse biological events involving cell–cell and cell–matrix interactions (22). Integrins comprise an α and a β subunit, and they are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor class, affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (23-28). The α(v)β(3) integrin is strongly expressed on tumor cells and activated endothelial cells. In contrast, expression of α(v)β(3) integrin is weak on resting endothelial cells and on most normal tissues. The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents, and the agonists are being studied as angiogenic agents for coronary angiogenesis (27, 29, 30). A tripeptide sequence comprising Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins including α(v)β(3). Various radiolabeled cyclic RGD peptides have been introduced for tumor imaging and tumor angiogenesis (31). The multimodality probe (64)Cu-DOTA-QD-c(RGDyK) has been developed for PET and NIRF imaging of tumor vasculature to study in vivo biodistribution of the tracer in tumor-bearing mice (32). (64)Cu-DOTA-QD-c(RGDyK) has been shown to have a high accumulation in the tumor vasculature with little extravasation and a predominant liver and spleen accumulation.
18056643 Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosph 2007 Dec 11 The lymphoid-specific tyrosine phosphatase (Lyp) has generated enormous interest because a single-nucleotide polymorphism in the gene (PTPN22) encoding Lyp produces a gain-of-function mutant phosphatase that is associated with several autoimmune diseases, including type I diabetes, rheumatoid arthritis, Graves disease, and systemic lupus erythematosus. Thus, Lyp represents a potential target for a broad spectrum of autoimmune disorders. Unfortunately, no Lyp inhibitor has been reported. In addition, little is known about the structure and biochemical mechanism that directly regulates Lyp function. Here, we report the identification of a bidentate salicylic acid-based Lyp inhibitor I-C11 with excellent cellular efficacy. Structural and mutational analyses indicate that the inhibitor binds both the active site and a nearby peripheral site unique to Lyp, thereby furnishing a solid foundation upon which inhibitors with therapeutic potency and selectivity can be developed. Moreover, a comparison of the apo- and inhibitor-bound Lyp structures reveals that the Lyp-specific region S(35)TKYKADK(42), which harbors a PKC phosphorylation site, could adopt either a loop or helical conformation. We show that Lyp is phosphorylated exclusively at Ser-35 by PKC both in vitro and in vivo. We provide evidence that the status of Ser-35 phosphorylation may dictate the conformational state of the insert region and thus Lyp substrate recognition. We demonstrate that Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling. Our data establish a mechanism by which PKC could attenuate the cellular function of Lyp, thereby augmenting T cell activation.
17475894 A new population of cells lacking expression of CD27 represents a notable component of the 2007 May 15 Human memory B cells comprise isotype-switched and nonswitched cells with both subsets displaying somatic hypermutation. In addition to somatic hypermutation, CD27 expression has also been considered a universal memory B cell marker. We describe a new population of memory B cells containing isotype-switched (IgG and IgA) and IgM-only cells and lacking expression of CD27 and IgD. These cells are present in peripheral blood and tonsils of healthy subjects and display a degree of hypermutation comparable to CD27+ nonswitched memory cells. As conventional memory cells, they proliferate in response to CpG DNA and fail to extrude rhodamine. In contrast to other recently described CD27-negative (CD27neg) memory B cells, they lack expression of FcRH4 and recirculate in the peripheral blood. Although CD27neg memory cells are relatively scarce in healthy subjects, they are substantially increased in systemic lupus erythematosus (SLE) patients in whom they frequently represent a large fraction of all memory B cells. Yet, their frequency is normal in patients with rheumatoid arthritis or chronic hepatitis C. In SLE, an increased frequency of CD27neg memory cells is significantly associated with higher disease activity index, a history of nephritis, and disease-specific autoantibodies (anti-dsDNA, anti-Smith (Sm), anti-ribonucleoprotein (RNP), and 9G4). These findings enhance our understanding of the B cell diversification pathways and provide mechanistic insight into the immunopathogenesis of SLE.
16682805 Transcription factor Ets-1 regulates fibroblast growth factor-1-mediated angiogenesis in v 2006 We previously demonstrated that a modified secreted form of fibroblast growth factor 1 (FGF-1), a prototypic member of the FGF family, has the ability to stimulate angiogenesis in an in vivo model of angiogenesis, the so-called chick chorioallantoic membrane assay or CAM. We recently defined the importance of the phosphatidylinositol 3-kinase/AKT pathway in FGF-1-mediated angiogenesis in this model using specific pharmacological inhibitors. In our continuing efforts to define the molecular signaling pathway regulating FGF-1-induced angiogenesis in vivo, we utilized a transcription factor activity assay and identified transcription factor Ets-1 as a critical effector of FGF-1-induced angiogenesis. Both activity and mRNA expression levels of the Ets-1 molecule were increased in response to FGF-1 overexpression in CAMs, as documented by electrophoretic mobility shift assay (gel shift) and reverse transcription real-time PCR techniques, respectively. Furthermore, the delivery of Ets-1 antisense (AS) into CAM tissues effectively reduced angiogenesis in the CAM assay. In addition, both Ets-1 AS-treated chicken CAMs and cultured endothelial cells exhibited a reduction in matrix metalloproteinase 1 gene expression levels. The Ets-1 AS-treated endothelial cells also demonstrated a reduction in migration. These data suggest that Ets-1 activation is a requisite for FGF-1-mediated angiogenesis in vivo. Therefore, Ets-1 might be a potential target for the generation of inhibitor drugs for the treatment of FGF-dependent pathological angiogenesis such as metastatic tumors, rheumatoid arthritis and diabetic retinopathy.
17241436 Pilocarpine treatment in a mixed cohort of xerostomic patients. 2007 Jan OBJECTIVE: To compare the effect of a single 5-mg dose of pilocarpine hydrochloride on the salivary flow rate in three groups of xerostomic patients. SUBJECTS AND METHODS: Forty-five patients were divided into three groups according to the etiology of their xerostomia: (i) radiotherapy; (ii) Sjögren's syndrome; and (iii) sialosis and xerogenic medications. Following the oral administration of a 5-mg pilocarpine hydrochloride tablet blood pressure, heart rate, body temperature and saliva secretion rates were monitored hourly for 3 h and adverse events were reported. RESULTS: The most significant and persistent elevation of salivary flow rate was observed in the sialosis/drug-induced group followed by the Sjögren's syndrome group. The radiotherapy group presented a significant elevation of salivary secretion rate after 1 and 2 h, but returned to baseline at 3 h. No significant changes in vital signs were reported, except for low diastolic pressure measured at 1 h in the radiotherapy group. Several adverse events were recorded throughout the trial; however, only one patient withdrew from the study. CONCLUSION: Treatment with pilocarpine hydrochloride tablets may improve saliva secretion in patients taking xerogenic medications and/or suffering from metabolic sialosis expanding the beneficial potential of this sialogogue.
17001167 Diabetic (lymphocytic) mastopathy with exuberant lymphohistiocytic and granulomatous respo 2006 Oct We report a case of a 66-year-old woman who presented with multiple painless masses in both breasts. Prior bilateral biopsies were diagnosed as Rosai-Dorfman disease (Sinus Histiocytosis with Massive Lymphadenopathy). A recent lumpectomy specimen revealed a gray-white smooth cut surface with a discrete masslike lesion. The histopathology demonstrated a fibrotic breast parenchyma with foci of dense fibrosis and scattered inconspicuous breast epithelium surrounded by lymphocytes that formed aggregates and follicles with germinal centers. The inflammation was in a periductal, perilobular, and perivascular distribution. In addition, an exuberant inflammatory response with histiocytes and fibroblasts was present. This inflammatory response focally surrounded areas of fat necrosis and formed noncaseating granulomas with rare multinucleated giant cells. This process had infiltrative, ill-defined edges and involved the subcutaneous tissues. The overlying epidermis was normal. The final diagnosis was diabetic mastopathy with an exuberant lymphohistiocytic response. The differential diagnosis included Rosai-Dorfman disease, inflammatory myofibroblastic tumor, granulomatous mastitis, sclerosing lipogranulomatous response/sclerosing lipogranuloma, lupus panniculitis, and rheumatoid nodules. Immunohistochemical studies and flow cytometry confirmed the polyclonal nature of the lymphoid infiltrate. After the histologic evaluation, we inquired if the patient had a history of diabetes mellitus, and learned that she did have type 2 noninsulin-dependent diabetes mellitus. In conclusion, we report a case of diabetic mastopathy that presents with bilateral tumorlike masses and an unusual exuberant lymphohistiocytic response with granuloma formation. The pathologist may not be provided with a history of diabetes mellitus, but the characteristic fibrosis, lymphocytic ductitis/lobulitis, and sclerosing lobulitis with perilobular and perivascular lymphocytic infiltrates should provide clues for an accurate diagnosis, even when an exuberant and an unusual lymphohistiocytic response is present. A timely accurate diagnosis can help limit repeat surgeries in this vulnerable group of patients.
19091220 [Chronic graft-versus-host disease presenting as bullous lesions]. 2008 Dec Graft-vs-host disease is still the leading cause of morbidity and mortality in patients undergoing bone marrow transplantation. It is important to start treatment early to reduce the severity and consequences of this complication. Cutaneous lesions are often the presenting compliant of graft-vs-host disease and presage visceral involvement. We present the case of a 45-year-old woman with multiple myeloma who underwent autologous and subsequently allogeneic bone marrow transplantation with hematopoietic precursors. She developed bullous lesions with fluid elimination on the abdomen and legs. Biopsy findings were compatible with graft-vs-host disease and immunosuppressive therapy was increased. She subsequently presented oral lichenoid lesions and sicca syndrome. The bullous lesions progressed to painful ulcers that healed leaving highly sclerodermatous skin with substantial hyperpigmentation. Bullous lesions are a rare form of presentation of chronic graft-vs-host disease. In such cases, the diagnosis may not be suspected initially, particularly when the lesions are isolated and internal organs are not involved.
17888211 Anti-GM1 and anti-sulfatide antibodies in patients with systemic lupus erythematosus, Sjö 2007 Jul OBJECTIVES: Over the last two decades, increasing interest has been focused on the association between autoimmune polyneuropathies and anti-neuronal autoantibodies in immune-mediated polyneuropathy. The possible appearance of these autoantibodies in systemic diseases that are not limited to the nervous system has not been fully addressed yet. METHODS: We evaluated 32 patients with systemic lupus erythematosus, 34 patients with hepatitis C virus-associated mixed IgM-k/IgG cryoglobulinemia, 19 with small vessel ANCA-associated vasculitis, and 20 patients with Sjögren's syndrome by means of an immunoenzyme method of anti-neuronal autoantibody detection. RESULTS: As compared to normals, a significant increase (p < 0.001) in plasma titers of both IgM and IgG anti-GM1 ganglioside and IgM and IgG anti-sulfatide was observed in patients with systemic lupus erythematosus, mixed cryoglobulinemia and Sjög-ren's syndrome. Idiopathic systemic vasculitis patients were found to have significantly increased levels of anti-sulfatide IgG autoantibodies (p < 0.001). Clinical and electrophysiologic studies revealed that abnormal titers of anti-neuronal antibodies were associated with evidence of neuropathy in patients with systemic lupus erythematosus and ANCA-related vasculitis (p < 0.05) as well as in patients with mixed cryoglobulinemia and Sjögren's syndrome (p < 0.001). CONCLUSION: Anti-GM1 and anti-sulfatide antibodies are frequently found in patients with small vessel ANCA-associated vasculitis and other multi-organ immune-mediated diseases. Upon detection of these antibodies, accurate neurologic examination should be carried out due to the significant association that can be found between these serologic abnormalities and the involvement of the peripheral nervous system as also detected by electrophysiologic studies. This study supports the unexpected possibility that anti-neuronal reactivity may be a direct trigger of neurologic injury in these systemic disorders.
16729300 Induction of interferon-alpha by immune complexes or liposomes containing systemic lupus e 2006 Jun OBJECTIVE: To investigate the ability of systemic lupus erythematosus (SLE) autoantigen- and Sjögren's syndrome (SS) autoantigen-associated U1 small nuclear RNA (U1 snRNA) and hY1RNA to induce interferon-alpha (IFNalpha) production. METHODS: In vitro-transcribed U1 snRNA or hY1RNA and lipofectin were added to peripheral blood mononuclear cell (PBMC) cultures. Purified U1 snRNP particles and IgG from SLE patients (SLE-IgG) were added to cultures of PBMCs, enriched monocytes, or natural interferon-producing cells (NIPCs); the latter are also known as plasmacytoid dendritic cells (pDC). Cells were double-stained for IFNalpha and either blood dendritic cell antigen 2 (NIPCs/pDC) or CD14 (monocytes) and then analyzed by flow cytometry. In some experiments, RNase or inhibitors of Fc gamma receptor IIa (Fc gammaRIIa) (specific antibodies), endocytosis (chloroquine, bafilomycin A), or Toll-like receptors (TLRs; oligodeoxynucleotide 2088) were used. The produced IFNalpha was measured by immunoassay. RESULTS: Lipofected U1 snRNA and hY1RNA both induced IFNalpha production in monocytes, but not in NIPC/pDC. In contrast, U1 snRNP combined with SLE-IgG induced IFNalpha production only in NIPCs/pDC, and this response was decreased by RNase treatment or inhibition of the Fc gammaRIIa, the endocytosis pathways, or the TLRs. CONCLUSION: Our finding that U1 snRNA and hY1RNA have IFNalpha-inducing capacity indicates that immune complexes containing such RNA, for example U1 snRNP particles, can be at least partly responsible for the ongoing IFNalpha production seen in SLE and SS. These results may help to explain the molecular mechanisms behind the pathogenesis of these and other autoimmune diseases in which autoantibodies to RNA-binding proteins occur.
16385525 Toll-like receptor 9 signaling protects against murine lupus. 2006 Jan OBJECTIVE: Hypomethylated CpG-containing DNA, which is recognized by Toll-like receptor 9 (TLR-9), has been strongly implicated in the pathogenesis of autoantibody-mediated diseases such as systemic lupus erythematosus. This study was undertaken to determine the role of TLR-9 in the MRL/+ and MRL/lpr models of murine lupus. METHODS: TLR-9-deficient MRL mice were generated by backcrossing a TLR-9-deficient allele against the MRL backgrounds by a speed congenic technique. Parameters of murine lupus were examined by routine methods. Regulatory T cell activity was assessed by autologous mixed lymphocyte reaction (AMLR), an in vitro assay for autoreactivity. RESULTS: Surprisingly, TLR-9-deficient animals of both the MRL/+ and the MRL/lpr backgrounds developed more severe lupus, as judged by anti-DNA and rheumatoid factor autoantibodies, total serum Ig isotypes, lymphadenopathy, inflammatory infiltrates in the salivary gland and kidney, proteinuria, and mortality, in comparison with their TLR-9-sufficient littermates. In vitro, regulatory T cells from TLR-9-deficient animals were impaired in their ability to suppress the AMLR. CONCLUSION: In the MRL model of murine lupus, TLR-9 signaling plays a protective role, perhaps by modulating the activity of regulatory T cells. These results contrast with findings of recent studies that implicate TLR-9 in the pathogenesis of anti-DNA responses, based in part on investigations in incompletely backcrossed TLR-9-deficient MRL/lpr mice in vivo or transgenic B cells in vitro. The present results highlight the need for caution in the assessment of disease paradigms based on the study of isolated cell populations in vitro, as well as in vivo studies of knockout animals involving non-ideal genetic models.
17727302 Elderly-onset systemic lupus erythematosus: prevalence, clinical course and treatment. 2007 Systemic lupus erythematosus is an autoimmune multi-system disease of uncertain aetiology with highly variable clinical manifestations. Women of child-bearing age are most often affected; however, approximately 10-20% of cases occur in older patients. Elderly-onset lupus has been defined in various studies as onset of lupus after age 50-65 years. Menopause and changes in cellular immunity with aging may contribute to development of lupus in older adults. Many studies suggest that the clinical and serological features of elderly-onset lupus differ from those of lupus in younger patients. Arthritis, fever, serositis, sicca symptoms, Raynaud's syndrome, lung disease and neuropsychiatric symptoms are more common in patients with elderly-onset lupus, while malar rash, discoid lupus and glomerulonephritis are less common in elderly-onset patients compared with younger lupus patients. Most elderly-onset lupus patients have a positive anti-nuclear antibody test, but the prevalence of anti-double-stranded DNA and hypocomplementaemia is lower in elderly-onset patients than in younger patients. Rheumatoid factor, anti-Ro/Sjögren's syndrome (SS) A and anti-La/SSB are more often positive in elderly-onset patients. The diagnosis of elderly-onset lupus may be delayed for many months: insidious onset, low prevalence and similarity to other more common disorders make the diagnosis of lupus challenging in this population. Treatment of lupus in the elderly may be complicated by co-morbidities and increased risk of toxicities from usual treatments. Optimal management of elderly-onset lupus is empiric because of a lack of randomised controlled studies. However, the approach to treatment is similar regardless of the age of the patient. This article discusses the prevalence, clinical course, serological features, prognosis and treatment of elderly-onset systemic lupus erythematosus.