Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis or dermatitis and the presence of antinuclear autoantibodies is associated with deficiencies of complement factors of the classical activation pathway. Results accumulated over the past few years with the use of complement gene deficient mice made it possible to update the conventional hypothesis for this association in regard to the etiology of the disease, whereby the early events leading to induction of autoimmunity can be explained by various functions of complement. As a conclusion, a new model for the etiology of the SLE based on the reduced elimination of apoptotic cells, the increased uptake of IgM containing immune complexes into the spleen and the CD21/CD35 dependent B cell toleration in the periphery demonstrates the importance of complement in the prevention of autoimmunity whereas the inflammatory reactions occurring in later stages of the disease are relatively independent from complement. The results obtained with complement deficient mice contribute to a better understanding of tolerance-inducing mechanisms and offers the option to develop new therapeutic procedures for autoimmune diseases.
Cell Mol Biol (Noisy-le-grand) 2002 May
PMID:The association between systemic lupus erythematosus and deficiencies of the complement system. 1203 Apr 27

Detection of clonal T-cell receptor gamma rearrangements by polymerase chain reaction (TCRgamma PCR) followed by high-resolution electrophoresis has now become a valuable tool in the diagnosis of cutaneous T-cell lymphoma (CTCL). The identification of clonal TCRgamma PCR products by fluorescent fragment analysis (FFA) on a capillary DNA sequencer is described here and compared with an established hetero-duplex temperature gradient gel electrophoresis (HD-TGGE). Of 55 CTCL derived lesional skin samples, clonality was obtained in 46 samples by FFA (83.6%) and in 45 samples by HD-TGGE (81.8%). Of 35 control skin specimens from various nonmalignant dermatoses, two samples (pityriasis lichenoides chronica) showed clonality by both methods, one sample (chronic dermatitis) only by FFA. The sensitivity of FFA was established using three clonal T-cell lines and peripheral blood mononuclear cells. The detection limit for clonal material was approximately 1% to 2.5% in mixtures of DNA and 1% to 3% in cell dilutions. For cell dilution series, we confirmed a linear correlation between the clonal/polyclonal peak-size ratios and the portion of clonal cells up to about 10%. Thus, the initial ratio between mono-and polyclonal template is correctly displayed by FFA within that concentration range. In conclusion, FFA on capillary DNA sequencer is a well-suited separation technique in TCRgamma PCR-based clonality analysis also exhibiting quantitative properties.
Diagn Mol Pathol 2002 Jun
PMID:A T-cell receptor gamma polymerase chain reaction assay using capillary electrophoresis for the diagnosis of cutaneous T-cell lymphomas. 1204 8

The skin is an important tissue of the immune system; however, little is known about immune cells in dolphin skin, and very few cetacean-specific immunoreagents are available for investigative purposes. Therefore, in this study immunohistochemistry techniques were used with species-specific and non-species-specific antibodies to characterize immune cells, primarily focusing on Langerhans cells, in skin from the Atlantic bottlenose dolphin (Tursiops truncatus). An antibody to human major histocompatibility complex (MHC) class II molecules labeled cells with a dendritic-like morphology. The immunophenotype, morphology, and distribution of some of these cells are consistent with those of Langerhans cells. The cells were predominantly found in dermal papillae, primarily along the epidermal-dermal junction. Thus, the location of these cells was somewhat different from that in terrestrial mammals. Other MHC II (+) cells of varying morphology were observed deeper in the dermis, with a perivascular concentration, and had characteristics of macrophages and dermal dendritic cells. There was no immunostaining with cetacean-specific CD2 or CD21. In diseased skin, a subjective increase of MHC II (+) cells, most notably in the superficial skin layers, was associated with an ulcerative dermatitis. A few CD2 (+) cells were also present. Differences between dolphins and terrestrial mammals in terms of morphology, mechanisms of response to insult and repair, and environmental challenges may explain the modified distribution of MHC II (+) cells in dolphin skin. An elucidation of the immune cells in cetacean skin will contribute to our understanding of the evolution of functional adaptations to various environments, facilitate diagnosis of skin diseases, and define the potential for intradermal administration of vaccines and other immunotherapeutics.
Anat Rec A Discov Mol Cell Evol Biol 2003 Jul
PMID:Distribution of MHC II (+) cells in skin of the Atlantic bottlenose dolphin (Tursiops truncatus): an initial investigation of dolphin dendritic cells. 1280 48

Selectins are carbohydrate-binding molecules that bind to fucosylated and sialylated glycoprotein ligands, and are found on endothelial cells, leukocytes and platelets. They are involved in trafficking of cells of the innate immune system, T lymphocytes and platelets. An absence of selectins or selectin ligands has serious consequences in mice or humans, leading to recurrent bacterial infections and persistent disease. Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes, including post-ischemic inflammation in muscle, kidney and heart, skin inflammation, atherosclerosis, glomerulonephritis and lupus erythematosus. Selectin-neutralizing monoclonal antibodies, recombinant soluble P-selectin glycoprotein ligand 1 and small-molecule inhibitors of selectins have been tested in clinical trials on patients with multiple trauma, cardiac indications and pediatric asthma, respectively. Anti-selectin antibodies have also been successfully used in preclinical models to deliver imaging contrast agents and therapeutics to sites of inflammation. Further improvements in the efficiency, availability, specificity and pharmacokinetics of selectin inhibitors, and specialized application routes and schedules, hold promise for therapeutic indications.
Trends Mol Med 2003 Jun
PMID:The role of selectins in inflammation and disease. 1282 15

Recent studies have demonstrated important pro-inflammatory roles for two matrix metalloproteinases (MMPs)-MMP-3 (stromelysin-1) and MMP-9 (gelatinase B)-in acute lung injury [Am. J. Respir. Cell Mol. Biol. 24 (2001) 1]. A role for MMP-3 in skin inflammation has also been demonstrated [Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 6885]. While leukocytes (neutrophils and macrophages) are known to elaborate these tissue-destructive enzymes, parenchymal cells are also capable of synthesizing MMPs. In the present study, we examined the production of MMP-3 and MMP-9 by rodent lung fibroblasts, type II epithelial cells, and vascular endothelial cells. Dermal fibroblasts were also examined. Cells were examined under control conditions and in response to agonists that induce acute inflammatory tissue injury (IgG-containing immune complexes and lipopolysaccharide [LPS]). In the absence of stimulation, MMP-3 and MMP-9 were not detected or were present at low level. However, upon stimulation with either of the two pro-inflammatory agonists, production of both enzymes occurred in fibroblasts and epithelial cells (though not in endothelial cells). The observation that resident cells in the tissue parenchyma can elaborate MMPs in direct response to pro-inflammatory stimuli provides insight into possible mechanisms by which tissue damage occurs in acute inflammation.
Exp Mol Pathol 2004 Jun
PMID:Matrix metalloproteinases in acute inflammation: induction of MMP-3 and MMP-9 in fibroblasts and epithelial cells following exposure to pro-inflammatory mediators in vitro. 1512

Presenilin (PS1) and (PS2) are the centers of gamma-secretase that release Abeta from APP in Alzheimer's disease (AD). They cleave signaling proteins like Notch and downregulate beta-catenin to modulate Wnt signaling. Inactivation of PS1 or PS1 and PS2 causes a prenatally lethal 'Notch phenotype,' which has hampered investigation of PS function in adulthood seriously. We have thus turned towards PS1+/-PS2-/- mice which carry the most severe reduction of PS alleles compatible with survival, to analyze the consequences of impaired PS function especially in adulthood. In these 'partial deficient' mice, PS1 protein concentration is considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin downregulation. Their phenotype is normal up to approximately 6 months, when the majority of the mice develop an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis, as seen in human systemic lupus erythematosus. Besides B-cell dominated infiltrates, we observe a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies and an increased CD4+/CD8+ ratio. The mice further develop a benign skin hyperplasia similar to human seborrheic keratosis as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. A partial reduction of PS function in PS1+/-PS2-/- mice causes a novel phenotype in adulthood unrelated to the developmental defects of full knockouts. As PS1+/-PS2+/- mice remain healthy, this points towards a sharply defined minimum of PS function. Skin and immune system appear to be especially sensitive targets of impaired PS function and may need careful monitoring if gamma-secretase inhibitors are envisaged for treating AD.
Hum Mol Genet 2004 Jul 01
PMID:Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice. 1512 3

The nuclear factor-kappaB (NF-kappaB) signaling pathway plays a key role in inflammation, immune response, cell growth control and protection against apoptosis. Recently, it has been associated with several distinct genetic diseases that exhibit a large spectrum of dysfunction, such as skin inflammation, perturbed skin appendage development and immunodeficiencies. In this review, a summary of the pathophysiological consequences of impaired NF-kappaB activation in humans is provided with respect to the functions of the molecules which are mutated.
Cell Mol Life Sci 2005 Aug
PMID:The NF-kappaB signaling pathway in human genetic diseases. 1592 63

Occupational and environmental exposure to polycyclic aromatic hydrocarbons (PAHs) has been suggested to provoke inflammatory and/or allergic disorders, including asthma, rhinitis, and dermatitis. The molecular mechanisms of this PAH-mediated inflammation remain to be clarified. Previous studies implied the involvement of PAHs as irritants and allergens, with the reactive oxygen species generated from the oxygenated PAHs believed to be an exacerbating factor. It is also possible that PAHs contribute to the pathogenesis through activation of aryl-hydrocarbon receptor (AhR)-mediated transcription, since PAHs are potent inducers of the AhR. To address this point, we generated transgenic mouse lines expressing the constitutive active form of the AhR in keratinocytes. In these lines of mice, the AhR activity was constitutively enhanced in the absence of ligands, so that any other direct effects of PAHs and their metabolites could be ignored. At birth, these transgenic mice were normal, but severe skin lesions with itching developed postnatally. The skin lesions were accompanied by inflammation and immunological imbalance and resembled typical atopic dermatitis. We demonstrate that constitutive activation of the AhR pathway causes inflammatory skin lesions and suggests a new mechanism for the exacerbation of inflammatory diseases after exposure to occupational and environmental xenobiotics.
Mol Cell Biol 2005 Nov
PMID:Constitutive expression of aryl hydrocarbon receptor in keratinocytes causes inflammatory skin lesions. 1622 87

Psoriasis is a common inflammatory skin disease and is considered as T cell-mediated immune response. In this study, we analyzed T cell receptor alpha-chain variable region (TCR Valpha) usage in the lesions of psoriasis patients using 5'-RACE. As the results, Valpha1, -2, -7, -8, -10, -11, -12, and -23 were commonly detected in psoriatic lesions and comparison of expressions of these Valpha types between psoriasis patients and healthy individuals showed that Valpha1, -7, -11, and -12 were highly increased in psoriasis patients than in healthy individuals. Compared with atopy dermatitis patients, the expressions of Valpha1 and Valpha7 were increased in psoriasis patients. Then, to identify CDR3alpha of T cells infiltrated in psoriatic lesions, we examined which type of J gene segment was rearranged with Valpha1 or Valpha7, which the expressions was specifically increased in psoriatic lesions. The result showed that the V-J rearrangements between the examined patients were not equivalent and their frequencies were diverse, however, several common rearrangements such as Valpha1-Jalpha13, -23, -27, or -34 and Valpha7-Jalpha12, -33 were detected. The results in this study might provide the clue to define the characteristics of T cells associated with the pathogenesis of psoriasis.
Mol Immunol 2006 Feb
PMID:Analysis of T cell receptor alpha-chain variable region (Valpha) usage and CDR3alpha of T cells infiltrated into lesions of psoriasis patients. 1633 84

NF-kappaB essential modulator (NEMO), the regulatory subunit of the IkappaB kinase, is essential for NF-kappaB activation. Mutations disrupting the X-linked NEMO gene cause incontinentia pigmenti (IP), a human genetic disease characterized by male embryonic lethality and by a complex pathology affecting primarily the skin in heterozygous females. The cellular and molecular mechanisms leading to skin lesion pathogenesis in IP patients remain elusive. Here we used epidermis-specific deletion of NEMO in mice to investigate the mechanisms causing the skin pathology in IP. NEMO deletion completely inhibited NF-kappaB activation and sensitized keratinocytes to tumor necrosis factor (TNF)-induced death but did not affect epidermal development. Keratinocyte-restricted NEMO deletion, either constitutive or induced in adult skin, caused inflammatory skin lesions, identifying the NEMO-deficient keratinocyte as the initiating cell type that triggers the skin pathology in IP. Furthermore, genetic ablation of tumor necrosis factor receptor 1 (TNFRI) rescued the skin phenotype demonstrating that TNF signaling is essential for skin lesion pathogenesis in IP. These results identify the NEMO-deficient keratinocyte as a potent initiator of skin inflammation and provide novel insights into the mechanism leading to the pathogenesis of IP.
Hum Mol Genet 2006 Feb 15
PMID:Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. 1639 96


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