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Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens (1,2). A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat (3). The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses (4-6). Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients (3,7), retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens., Induction of regulatory intestinal responses to oral antigens prevents the subsequent development of systemic T-helper type-1 ([T.sub.H]1) responses to those antigens, a phenomenon referred to as oral tolerance (2). An [...]

The fluid mosaic membrane model proved to be a very useful hypothesis in explaining many, but certainly not all, phenomena taking place in biological membranes. New experimental data show that the compartmentalization of membrane components can be as important for effective signal transduction as is the fluidity of the membrane. In this work, we pay tribute to the Singer-Nicolson model, which is near its 30th anniversary, honoring its basic features, 'mosaicism' and 'diffusion,' which predict the interspersion of proteins and lipids and their ability to undergo dynamic rearrangement via Brownian motion. At the same time, modifications based on quantitative data are proposed, highlighting the often genetically predestined, yet flexible, multilevel structure implementing a vast complexity of cellular functions. This new 'dynamically structured mosaic model' bears the following characteristics: emphasis is shifted from fluidity to mosaicism, which, in our interpretation, means nonrandom codistribution patterns of specific kinds of membrane proteins forming small-scale clusters at the molecular level and large-scale clusters (groups of clusters, islands) at the submicrometer level. The cohesive forces, which maintain these assemblies as principal elements of the membranes, originate from within a microdomain structure, where lipid-lipid, protein-protein, and protein-lipid interactions, as well as sub- and supramembrane (cytoskeletal, extracellular matrix, other cell) effectors, many of them genetically predestined, play equally important roles. The concept of fluidity in the original model now is interpreted as permissiveness of the architecture to continuous, dynamic restructuring of the molecular- and higher-level clusters according to the needs of the cell and as evoked by the environment.

Distribution and lateral organization of Kv1.3 potassium channels and CD3 molecules were studied by using electron microscopy, confocal laser scanning microscopy, and fluorescence resonance energy transfer. Immunogold labeling and electron microscopy showed that the distribution of FLAG epitope-tagged Kv1.3 channels (Kv1.3/FLAG) significantly differs from the stochastic Poisson distribution in the plasma membrane of human T lymphoma cells. Confocal laser scanning microscopy images showed that Kv1.3/FLAG channels and CD3 molecules accumulated in largely overlapping membrane areas. The numerical analysis of cross-correlation of the spatial intensity distributions yielded a high correlation coefficient (C = 0.64). A different hierarchical level of molecular proximity between Kv1.3/FLAG and CD3 proteins was reported by a high fluorescence resonance energy transfer efficiency (E = 51%). These findings implicate that reciprocal regulation of ion-channel activity, membrane potential, and the function of receptor complexes may contribute to the proper functioning of the immunological synapse.

In patients with malignancies and immune disorders expressing Tac ([Alpha] chain of the interleukin 2 receptor; CD25), physiologic shedding of this receptor may lead to high blood levels of the soluble form (sTac). This system was used to model the interaction of soluble antigen with antibody in therapeutic settings and to develop rational principles to optimize the delivery of antibody to tumor target cells. First, we confirmed that sTac in vivo can block anti-Tac binding sites and diminish antibody binding to Tac+ cells. Second, the bioactivity of antibody in vivo correlated directly with the amount of antibody infused and inversely with the sTac concentration. Third, bindability of antibody declined in the hours and days after anti-Tac infusion in patients. Finally, tumor targeting was achieved even in the presence of excess sTac, demonstrating a partition of antibody between soluble and cell-bound antigen. A role is proposed for the Brambell receptor (FcRB) to delay saturation of human or chimeric antibodies via differential catabolism of antigen-antibody complexes. Principles are developed for predicting activity of administered antibody in the presence of soluble antigen to assist in dose selection in passive, radioimmuno and immunotoxin therapies.

For many years, some researchers have suspected that multiple sclerosis results from infection with an as-yet unidentified virus. This suspicion emerges both from some pathological features of the disease itself and from epidemiological observations on the geographical distribution of MS. It is only reasonable, therefore, that when the laboratory technique known as polymerase chain reaction (PCR) was developed, it would be applied to the search for viruses in patients with multiple sclerosis. The PCR method utilizes repetitive cycles of DNA synthesis to amplify extremely small quantities of DNA to a large enough concentration to use for more conventional laboratory tests. One of the primary difficulties of the method, however, is that its sensitivity is so great that false-positive results may indicate the presence of viral gene sequences when, in fact, only random 'noise' and not the viral genes are present. This problem with PCR is illustrated by reports in recent years linking multiple sclerosis to the human T-cell leukemia virus (HTLV). Since this virus is associated with a neurological disease called tropical spastic paraparesis, it did not seem unreasonable when researchers reported its association with multiple sclerosis. However, concerns about the possibility of false-positive results using the PCR method prompted other researchers to conduct a careful large-scale study to determine if HTLV gene sequences are indeed associated with multiple sclerosis. A total of 202 multiple sclerosis patients were tested, as were 803 control subjects, which included MS family members, patients with other neurological diseases, and random blood donors. Initial testing found indications of HTLV in 19 MS patients and 47 other subjects. On further testing, HTLV could be confirmed in only one MS patient and in none of the control subjects. The results confirm that false positives are likely when using the PCR method, and that most of the positive results will not be confirmed on further testing. Furthermore, the results of the present study provide no reason to believe that HTLV plays an important role in the etiology of multiple sclerosis. (Consumer Summary produced by Reliance Medical Information, Inc.)

This article describes the architecture of the new GREGOR telescope and its instrument control system. A short summary is given on the communication structure between instruments and other devices during observation. Because of its importance to all instruments the main functions of the telescope control system are described in detail (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

Studies the use of the interleukin-2 receptor (IL-2R) for the treatment of HTLV-I-associated disorders. Role of HTLV-I-encoded tax in the early phases of HTLV-I-induced disease; Identification of cytokine IL-T/IL-15 that stimulates T-cell proliferation; Presence of IL-2Rs on abnormal T cells in patients with tropical parasitic paraparesis/HTLV-I-associated myelopathy (TSP/HAM).

Summarizes information on in vivo use of monoclonal antibodies for diagnosis and therapy. Cell surface antigenic targets; Genetically engineered antibodies; Human monoclonal antibodies; Bifunctional antibodies; Monoclonal antibody-cytotoxic agent conjugates; Radiolabeled monoclonal antibodies.