Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decay-accelerating factor (DAF, CD55) is a glycosylphosphatidylinositol-anchored membrane protein that restricts complement activation on autologous cells. It is also a ligand for CD97, an activation-associated lymphocyte antigen with seven transmembrane domains. It is widely expressed on cells of both the hematopoietic and nonhematopoietic lineages. Although deficiency of DAF on human erythrocytes is associated with the hemolytic anemia syndrome paroxysmal nocturnal hemoglobinuria, the in vivo biology of DAF is still poorly understood. We addressed the in vivo function of DAF in a knockout mouse model and describe here that deletion of DAF exacerbates autoimmune disease development in MRL/lpr mice, a model for human systemic lupus erythematosus. Compared to DAF-sufficient littermate controls, DAF-deficient female MRL/lpr mice developed exacerbated lymphadenopathy and splenomegaly, higher serum anti-chromatin autoantibody levels, and aggravated dermatitis. Consistent with the phenotype of aggravated dermatitis in DAF-deficient mice, Northern and Western blots and immunofluorescence studies showed DAF to be expressed abundantly in the mouse skin, suggesting that it may play a particularly important role in this tissue. Histology and immunostaining demonstrated inflammatory infiltrate and focal C3 deposition in early skin lesions, mostly along the dermal-epidermal junction. These results reveal a protective function of DAF in the development of a systemic autoimmune syndrome and suggest that dysfunction or down-regulation of DAF may contribute to autoimmune disease pathogenesis and manifestation.
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PMID:Deletion of decay-accelerating factor (CD55) exacerbates autoimmune disease development in MRL/lpr mice. 1221 36

Idiopathic ulcerative dermatitis is a well-recognized disease in C57BL mice and related strains. This disease manifests as a pruritic dermatitis with resulting self-mutilation, dermal ulceration, necrosis, and fibrosis. Ulcerative dermatitis has the ability to confound ongoing research by causing systemic pathologic changes, such as lymphadenopathy and splenomegaly. Although various treatments have been described, none has been curative consistently; therefore, minimizing negative effects on research through prevention of disease is ideal. To identify etiologic factors, we conducted a 2-y retrospective study of 1352 mice with a C57BL/6 genetic background; these mice demonstrated an overall prevalence of 4.1% and a seasonal effect with a peak incidence during midsummer. Corroborating previous studies, our study revealed a disease predilection for female mice. In contrast to prior reports, the disease prevalence was greatest in 10- to 16-mo-old mice. In addition, mice with a C57BL/6 background that were deficient in the gene for inducible nitric oxide synthase had a 50% disease incidence, suggesting a potential animal model for further characterizing the pathogenesis, prevention, and treatment of ulcerative dermatitis.
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PMID:A retrospective study of idiopathic ulcerative dermatitis in mice with a C57BL/6 background. 1708 84

The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3-4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome-transgenic mice termed "depletion of regulatory T cell" (DEREG) mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo.
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PMID:Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. 1720 Apr 12

Decay-accelerating factor (DAF) is a glycosylphosphatidylinositol-anchored membrane protein that restricts complement activation on autologous cells. Previous studies have established a significant protective activity of DAF in the MRL/lpr murine model of human systemic lupus erythematosus. To dissect the mechanism of protection by DAF in this disease model, we evaluated the effect of C3 gene ablation on disease development in MRL/lpr-Daf-1(-/-) mice. We found no significant difference in lymphadenopathy, splenomegaly, or anti-chromatin autoantibody titer between complement-sufficient and complement-deficient MRL/lpr-Daf-1(-/-) mice. On the other hand, complement deficiency strikingly reduced the incidence and severity of dermatitis in MRL/lpr-Daf-1(-/-) mice. To assess the contribution of DAF expression on lymphocytes versus local tissues in suppressing dermatitis, we generated BM chimeric mice between MRL/lpr-Daf-1(-/-) and MRL/lpr-Daf-1(+/+) mice. Compared with MRL/lpr-Daf-1(-/-) --> MRL/lpr-Daf-1(-/-) controls, MRL/lpr-Daf-1(-/-) --> MRL/lpr-Daf-1(+/+) chimeras developed significantly attenuated dermatitis, suggesting that the protective effect of DAF in suppressing dermatitis is primarily attributable to its local expression. We conclude that DAF works as a complement regulator in the skin to protect MRL/lpr mice from skin inflammation, whereas its inhibitory role in the induction phase of MRL/lpr autoimmunity is complement-independent. Together, these results reveal multiple mechanisms of action for DAF in ameliorating systemic autoimmunity.
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PMID:Decay-accelerating factor ameliorates systemic autoimmune disease in MRL/lpr mice via both complement-dependent and -independent mechanisms. 1739 65

Dietary pulverized konjac glucomannan (PKGM) suppresses the development of eczema in NC/Nga mice, a model of atopic dermatitis (AD). Although NC/Nga mice were originally recognized as an autoimmune disease model, recent studies on their autoimmunity are still poorly performed. Here, we show that cervical lymphadenopathy, splenomegaly, and increases in plasma levels of anti-dsDNA, rheumatoid factor IgG autoantibodies, and B cell-activating factor of the TNF family (BAFF) were co-elicited in eczematous NC/Nga mice; however, these symptoms were all prevented in PKGM-fed mice. Our results imply the possible involvement of autoimmunity on the pathogenesis of dermatitis and hyper-IgE syndrome in NC/Nga mice. PKGM might be effective in preventing autoimmune responses in AD.
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PMID:Development of autoantibody responses in NC/Nga mice: its prevention by pulverized konjac glucomannan feeding. 1793 42

In 2006 an outbreak of canine distemper affected 14 young domestic ferrets in Barcelona, Spain. Their clinical signs included a reduced appetite, lethargy, dyspnoea, coughing, sneezing, mucopurulent ocular and nasal discharges, facial and perineal dermatitis, diarrhoea, splenomegaly and fever. Late in the course of the disease, general desquamation and pruritus, and hyperkeratotic/crusting dermatitis of the lips, eyes, nose, footpads, and perineal area were observed. None of the ferrets developed neurological signs. Non-regenerative anaemia and high serum concentrations of alpha- and beta-globulins were the most common laboratory findings. Most of the animals died or were euthanased because of respiratory complications. Postmortem there were no signs of lung collapse. Distemper was diagnosed by direct immunofluorescence of conjunctival swabs or pcr of several organs, and histology revealed the characteristic eosinophilic intracytoplasmic and intranuclear inclusion bodies of canine distemper virus in several organs. The minimum incubation periods calculated for six of the ferrets were 11 to 56 days, and in 13 of the ferrets the signs of disease lasted 14 to 34 days. Inclusion bodies compatible with infection by herpesvirus were found in the lungs of one of the ferrets.
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PMID:Outbreak of canine distemper in domestic ferrets (Mustela putorius furo). 1872 66

Delta-6 desaturase (D6D) catalyzes the first step in the synthesis of highly unsaturated fatty acids (HUFA) such as arachidonic (AA), docosapentaenoic (DPAn-6), and docosahexaenoic (DHA) acids, as well as the last desaturation of DPAn-6 and DHA. We created D6D-null mice (-/-), which enabled us to study HUFA deficiency without depleting their precursors. In -/-, no in vivo AA synthesis was detected after administration of [U-(13)C]linoleic acid (LA), indicating absence of D6D isozyme. Unexpectedly, all of the -/- developed ulcerative dermatitis when fed a purified diet lacking D6D products but containing ample LA. The -/- also exhibited splenomegaly and ulceration in duodenum and ileocecal junction. Male -/- lacked normal spermatozoa with a severe impairment of spermiogenesis. Tissue HUFAs in -/- declined differentially: liver AA and DHA by 95%, and a smaller decrease in brain and testes. Dietary AA completely prevented dermatitis and intestinal ulcers in -/-. DPAn-6 was absent in -/- brain under AA supplementation, indicating absence of D6D isozyme for DPAn-6 synthesis from AA. This study demonstrated a distinct advantage of the D6D-null mice (-/-) to elucidate (1) AA function without complication of LA deprivation and (2) DHA function in the nervous system without AA depletion or DPAn-6 replacement seen in traditional models.
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PMID:Disruption of FADS2 gene in mice impairs male reproduction and causes dermal and intestinal ulceration. 1935 70

PLA2 (phospholipase A2) group III is an atypical sPLA2 (secretory PLA2) that is homologous with bee venom PLA2 rather than with other mammalian sPLA2s. In the present paper, we show that endogenous group III sPLA2 (PLA2G3) is expressed in mouse skin and that Tg (transgenic) mice overexpressing human PLA2G3 spontaneously develop skin inflammation. Pla2g3-Tg mice over 9 months of age frequently developed dermatitis with hyperkeratosis, acanthosis, parakeratosis, erosion, ulcer and sebaceous gland hyperplasia. The dermatitis was accompanied by infiltration of neutrophils and macrophages and by elevated levels of pro-inflammatory cytokines, chemokines and prostaglandin E2. In addition, Pla2g3-Tg mice had increased lymph aggregates and mucus in the airway, lymphocytic sialadenitis, hepatic extramedullary haemopoiesis, splenomegaly with increased populations of granulocytes and monocytes/macrophages, and increased serum IgG1. Collectively, these observations provide the first demonstration of spontaneous development of inflammation in mice with Tg overexpression of mammalian sPLA2.
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PMID:Group III secreted phospholipase A2 transgenic mice spontaneously develop inflammation. 1937 Dec 33

Acute schistosomiasis is a systemic hypersensitivity reaction against the migrating schistosomula and eggs. A variety of clinical manifestations appear during the migration of schistosomes in humans: cercarial dermatitis, fever, pneumonia, diarrhoea, hepatomegaly, splenomegaly, skin lesions, liver abscesses, brain tumours and myeloradiculopathy. Hypereosinophilia is common and aids diagnosis. The disease has been overlooked, misdiagnosed, underestimated and underreported in endemic areas, but risk groups are well known, including military recruits, some religious congregations, rural tourists and people practicing recreational water sports. Serology may help in diagnosis, but the finding of necrotic-exudative granulomata in a liver biopsy specimen is pathognomonic. Differentials include malaria, tuberculosis, typhoid fever, kala-azar, prolonged Salmonella bacteraemia, lymphoma, toxocariasis, liver abscesses and fever of undetermined origin. For symptomatic hospitalised patients, treatment with steroids and schistosomicides is recommended. Treatment is curative in those timely diagnosed.
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PMID:Acute schistosomiasis mansoni: revisited and reconsidered. 2072 85

Mice overexpressing the proallergic cytokine thymic stromal lymphopoietin (TSLP) in the skin develop a pathology resembling atopic dermatitis. RabGEF1, a guanine nucleotide exchange factor for Rab5 GTPase, is a negative regulator of IgE-dependent mast cell activation, and Rabgef1-/- and TSLP transgenic mice share many similar phenotypic characteristics, including elevated serum IgE levels and severe skin inflammation, with infiltrates of both lymphocytes and eosinophils. We report here that Rabgef1-/- mice also develop splenomegaly, lymphadenopathy, myeloid hyperplasia, and high levels of TSLP. Rabgef1-/-TSLPR-/- mice, which lack TSLP/TSLP receptor (TSLPR) signaling, had levels of blood neutrophils, spleen myeloid cells, and serum IL-4, IgG1, and IgE levels that were significantly reduced compared with those in Rabgef1-/-TSLPR+/+ mice. However, Rabgef1-/-TSLPR-/- mice, like Rag1- or eosinophil-deficient Rabgef1-/- mice, developed cutaneous inflammation and epidermal hyperplasia. Therefore, in Rabgef1-/- mice, TSLP/TSLPR interactions are not required for the development of epidermal hyperplasia but contribute to the striking myeloid hyperplasia and overproduction of immunoglobulins observed in these animals. Our study shows that RabGEF1 can negatively regulate TSLP production in vivo and that excessive production of TSLP contributes to many of the phenotypic abnormalities in Rabgef1-/- mice. However, the marked epidermal hyperplasia, cutaneous inflammation, and increased numbers of dermal mast cells associated with RabGEF1 deficiency can develop via a TSLPR-independent pathway, as well as in the absence of Rag1 or eosinophils.
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PMID:Thymic stromal lymphopoietin contributes to myeloid hyperplasia and increased immunoglobulins, but not epidermal hyperplasia, in RabGEF1-deficient mice. 2082 37


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