A number of recent studies show that activation of CR3 on dendritic cells (DCs) suppresses TLR-induced TNF-alpha and IL-12 production and inhibits effective Ag presentation. Although the proposed ...physiologic role for these phenomena is immune suppression due to recognition of iC3b opsonized apoptotic cells by CR3, all of the aforementioned investigations used artificial means of activating CR3. We investigated whether iC3b opsonized apoptotic cells could induce the same changes reported with artificial ligands such as mAbs or iC3b-opsonized RBC. We explored the kinetics of iC3b opsonization in two models of murine cell apoptosis, gamma-irradiated thymocytes and cytokine deprivation of the IL-3 dependent cell line BaF3. Using a relatively homogenous population of early apoptotic cells (IL-3 deprived BaF3 cells), we show that iC3b opsonized apoptotic cells engage CR3, but this interaction is dispensable in mediating the anti-inflammatory effects of apoptotic cells. TLR-induced TNF-alpha and IL-12 production by bone marrow-derived DCs occurs heterogeneously, with apoptotic cells inhibiting only certain populations depending on the TLR agonist. In contrast, although apoptotic cells induced homogeneous IL-10 production by DCs, IL-10 was not necessary for the inhibition of TNF-alpha and IL-12. Furthermore, because the ability of iC3b opsonization to enhance phagocytosis of apoptotic cells has been controversial, we report that iC3b opsonization does not significantly affect apoptotic cell ingestion by DCs. We conclude that the apoptotic cell receptor system on DCs is sufficiently redundant such that the absence of CR3 engagement does not significantly affect the normal anti-inflammatory processing of apoptotic cells.
Abstract
The RAG1/RAG2 (RAG) endonuclease generates lymphocyte antigen receptor gene diversity via V(D)J recombination. The large numbers of V, D, and J segments and inherent imprecision in repair of ...RAG DNA double strand breaks (DSBs) together establish a vast diversity of antigen receptor specificities, including self-reactive receptors. Mechanisms have evolved to negatively select self-reactive cells and inhibit autoimmunity. In humans, deletion of the RAG1 N-terminus causes Omenn Syndrome, a fatal immunodeficiency with ab T cell-based autoimmunity. We discovered impaired negative selection in a spontaneous homozygous Rag1 mutant mouse with loss of the Rag1 N-terminus. This Rag1 region, which is not required for V(D)J recombination, has intrinsic ubiquitin ligase activity and interacts with another ubiquitin ligase and a kinase. We hypothesize the RAG1 N-terminus signals from RAG DSBs induced during TCRa recombination to shape the thymocyte proteome and enhance negative selection. To test our hypothesis, we have made mice whose thymocytes lack RAG DSBs or harbor RAG DSBs induced by wild-type Rag1 or mutant Rag1 lacking the N-terminus or intrinsic ubiquitin ligase activity. Our preliminary data suggest that RAG DSBs and distinct RAG1 N-terminus activities up-regulate expression of Zap70, an intracellular protein that transmits TCR signals, and CD80, a transmembrane protein that co-stimulates T cells engaging antigen. These data are consistent with a model wherein the RAG1 N-terminus facilitates negative selection through stimulating TCR signaling in thymocytes that bind self-antigens presented by thymocytes, dendritic cells, or thymic epithelial cells.
Background Prompt identification and treatment of psoriatic arthritis (PsA) in patients with psoriasis is critical to reducing the risk of joint damage, disability, and comorbidities. Objective We ...sought to estimate PsA prevalence in patients with plaque psoriasis in 34 dermatology centers in 7 European and North American countries. Methods Consecutive patients were evaluated by dermatologists for plaque psoriasis and subsequently by rheumatologists for PsA. PsA prevalence was estimated primarily based on rheumatologists' assessment of medical history, physical examination, and laboratory tests. Results Of 949 patients evaluated, 285 (30%) had PsA (95% confidence interval 27-33) based on rheumatologists' assessment. PsA diagnosis changed in 1.2% of patients when diagnostic laboratory tests were added to medical history and physical examination. Of 285 patients given the diagnosis of PsA, 117 (41%) had not been previously given the diagnosis. Limitations Bias may have been introduced by lack of standardized diagnostic criteria and unbalanced recruitment based on country populations. Conclusions In this study, almost a third of patients with psoriasis seen in dermatology centers had PsA as determined by rheumatologists. More than a third of patients with PsA had not been previously given the diagnosis. Clinical evaluation alone is often sufficient basis for PsA diagnosis, but laboratory test results may be helpful in some patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Whipple's disease (WD) is a rare disorder caused by the gram‐positive actinomycete
Tropheryma whippelii
(1). An oral route of acquisition is presumed (2). WD is a chronic systemic infection ...morphologically characterized by foamy PAS‐positive macrophages. This case report depicts the diagnosis and clinical management of a woman who presented with atypical cardial manifestations of WD and died from severe cardiac impairment by
Tropheryma whippelii
which was confirmed by polymerase chain reaction. Histological assessment of myocardial specimens obtained at autopsy showed PAS‐positive macrophages accumulating within foci of interstitial myocardial fibrosis. Immunohistochemical staining demonstrated myocarditis with lymphocytes and neutrophilic granulocytes, which has not been reported so far in the course of WD.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
We introduce a class of Petri nets, simple logic Petri nets (SLPN), that are based on logical expressions. We show how this type of nets can be efficiently mapped into logic programs with negation: ...the corresponding answer sets describe interleaved executions of the underlying nets (Theorem 1). The absence of an answer set indicates a deadlock situation. We also show how to correctly model and specify AgentSpeak agents and multi-agent systems with SLPN’s (Theorem 2). Both theorems allow us to solve the task of model checkingAgentSpeakmulti-agent systems by computing answer sets of the obtained logic program with any ASP system.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
To assess the role of digitalis in the development of visual symptoms severe enough to warrant ophthalmologic consultation in patients who received digitalis and who had no other clinical or ...laboratory evidence of digitalis toxicity.
Clinical case study.
Neuro-ophthalmology referral practice.
Six elderly patients (aged 66 to 85 years) who received digitalis were referred to ophthalmologists for evaluation of photopsia (five patients) or decreased visual acuity (one patient). No patient had chromatopsia or nonvisual clinical manifestations of digitalis intoxication at the time of examination.
All patients had serum digitalis concentrations within or below the therapeutic range. In most patients, the electroretinographic cone b-wave implicit time was longer than normal.
Discontinuation of digitalis therapy, which was possible in five patients, was followed by resolution of visual symptoms and by shortening of the b-wave implicit time. Characteristic features of digitalis-induced photopsia were its dependence on illumination and its tendency to be localized in peripheral visual fields.
In an elderly patient receiving digitalis, the development of photopsia characterized by innumerable points of light in the peripheral visual fields or a decrease in visual acuity raises the possibility that the patient's visual disturbance may have been digitalis induced. Digitalis-induced visual disturbances other than chromatopsia or disturbances of color vision may occur in elderly patients who have no other clinical manifestations of digitalis intoxication and who have a serum digitalis concentration within or below the therapeutic range.
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