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At least 307 records · Page 17Linked to original sources
PubMed2005

A machine learning evaluation of an artificial immune system.

ARTIS is an artificial immune system framework which contains several adaptive mechanisms. LISYS is a version of ARTIS specialized for the problem of network intrusion detection. The adaptive mechanisms of LISYS are characterized in terms of their machine-learning counterparts, and a series of experiments is described, each of which isolates a different mechanism of LISYS and studies its contribution to the system's overall performance. The experiments were conducted on a new data set, which is more recent and realistic than earlier data sets. The network intrusion detection problem is challenging because it requires one-class learning in an on-line setting with concept drift. The experiments confirm earlier experimental results with LISYS, and they study in detail how LISYS achieves success on the new data set.

Algorithms↗
PubMed1997

Effect of beta 2glycoprotein I and human monoclonal anticardiolipin antibody on the protein S/C4b-binding protein system.

The effect of beta 2glycoprotein I (beta 2GPI) and human monoclonal anticardiolipin antibody (aCL) on the protein S/C4b-binding protein (C4BP) system was evaluated. The binding of C4BP to protein S was assessed by ELISA in the presence of beta 2GPI with/without human monoclonal aCL. beta 2GPI downregulated the binding between S and C4BP significantly. Human monoclonal aCL abolished the beta 2GPI inhibitory effect in a calcium (Ca++) independent fashion. In separate experiments, the reactivity of aCL towards protein S in the presence or absence of beta 2GPI and cardiolipin was investigated. Monoclonal aCL bound to protein S only in the presence of a combination of beta 2GPI and cardiolipin. This binding was Ca++ dependent. These findings suggest that human monoclonal aCL increases the affinity of C4BP for protein S, and that protein S may represent one of the targets for aCL when combined with beta 2GPI and cardiolipin. Both issues may explain acquired free protein S deficiency and the attendant risk of thrombosis in patients with aCL.

Animals↗
PubMed2002

Multiple sclerosis as a by-product of the failure to sustain protective autoimmunity: a paradigm shift.

Autoimmune diseases are traditionally viewed as an outcome of a chaotic situation in which an individual's immune system reacts against the body's own proteins. In multiple sclerosis, a disease of the white matter of the central nervous system (CNS), the immune attack is directed against myelin proteins. In this article, the authors propose a paradigm shift in the perception of autoimmune disease. They suggest that an autoimmune disease may be viewed as a by-product of the malfunctioning of a physiological autoimmune response whose purpose is protective. The proposed view is based on observations by their group suggesting that an autoimmune response is the body's own mechanism for coping with CNS damage. According to this view, all individuals are endowed with the potential ability to evoke an autoimmune response to CNS injuries. However, the inherent ability to control this response so that its beneficial effect will be expressed is limited and is correlated with the individual's inherent ability to resist autoimmune disease induction. The same autoimmune T cells are responsible for neuroprotection and for disease development. In patients with CNS trauma or neurodegenerative disorders, it might be possible to gain maximal autoimmune protection and avoid autoimmune disease induction by boosting the immune response, using myelin-associated peptides that are nonpathogenic or antigens that simulate the activities of such peptides. In patients with multiple sclerosis and other neurodegenerative diseases, where the aim is to block the autoimmune disorder while deriving the potential benefit of the autoimmune response, the effect of treatment should be immunomodulatory rather than immunosuppressive. In this article, the authors present a novel concept of protective autoimmunity and propose that autoimmune disease is a by-product of failure to sustain it. They summarize the basic findings that led them to formulate the new concept and offer an explanation for the commonly observed presence of cells and antibodies directed against self-components in healthy individuals. The therapeutic implications of the new concept and their experimental findings are discussed.

Animals↗
PubMed2006

SVRMHC prediction server for MHC-binding peptides.

BACKGROUND: The binding between antigenic peptides (epitopes) and the MHC molecule is a key step in the cellular immune response. Accurate in silico prediction of epitope-MHC binding affinity can greatly expedite epitope screening by reducing costs and experimental effort. RESULTS: Recently, we demonstrated the appealing performance of SVRMHC, an SVR-based quantitative modeling method for peptide-MHC interactions, when applied to three mouse class I MHC molecules. Subsequently, we have greatly extended the construction of SVRMHC models and have established such models for more than 40 class I and class II MHC molecules. Here we present the SVRMHC web server for predicting peptide-MHC binding affinities using these models. Benchmarked percentile scores are provided for all predictions. The larger number of SVRMHC models available allowed for an updated evaluation of the performance of the SVRMHC method compared to other well- known linear modeling methods. CONCLUSION: SVRMHC is an accurate and easy-to-use prediction server for epitope-MHC binding with significant coverage of MHC molecules. We believe it will prove to be a valuable resource for T cell epitope researchers.

Amino Acid Sequence↗
PubMed2006

It takes nerve to tell T and B cells what to do.

The existence of an association between the brain and immunity has been documented. Data show that the nervous and immune systems communicate with one another to maintain immune homeostasis. Activated immune cells secrete cytokines that influence central nervous system activity, which in turn, activates output through the peripheral nervous system to regulate the level of immune cell activity and the subsequent magnitude of an immune response. In this review, we will focus our presentation and discussion on the findings that indicate a regulatory role for the peripheral sympathetic nervous system in modulating the level of cytokine and antibody produced during an immune response. Data will be discussed from studies involving the stimulation of the beta2 adrenergic receptor expressed on CD4+ T cells and B cells by norepinephrine or selective agonists. We will also discuss how dysregulation of this line of communication between the nervous and immune systems might contribute to disease development and progression.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Developmental immunotoxicology and risk assessment: a workshop summary.

A workshop entitled 'Developmental Immunotoxicology and Risk Assessment' was held on 12-13 June 2001, in Washington, DC. The workshop was organized jointly by the Immunotoxicology Technical Committee (ITC) of the International Life Sciences Institute's (ILSI) Health and Environmental Sciences Institute (HESI) with input from the U.S. Environmental Protection Agency (EPA). Growing public concern that early exposure of the developing immune system to immunotoxic compounds may cause significant or persistent postnatal immunosuppression prompted the workshop. The main goal of the workshop was to examine scientific questions that underlie developmental immunotoxicity tests and the interpretation of the results as they relate to human risk assessment. A second goal was to provide a framework, based on current scientific knowledge, for the development of meaningful testing guidelines. The workshop focused on a series of questions that included how to address critical windows of exposure, how to develop and apply more predictive endpoints, does early chemical exposure cause transient or permanent effects on the immune system, as well as other related questions. On the first day, experts were invited to give scientific presentations relating to comparative developmental immunology, models of immunosuppression, and the regulatory aspects of developmental immunotoxicology. The second day was devoted to a panel discussion that included all the speakers as well as meeting participants, which attempted to answer each of the specific questions raised at the workshop. In general, it was acknowledged that there are a variety of techniques available for assessing immunosuppression in adult animal models, but there is uncertainty about how to apply these to a developing animal, especially if the goal is to have some standard procedure that can be applied for regulatory risk assessment. It was pointed out that although we know a lot about the developing immune system of individual species, we do not know how to relate the significance of drug or chemical effects on these systems in terms of human hazard. Overall, the panel deemed the area of developmental immunotoxicity to be still in its infancy and outlined strategies that could lead to the development of standard practices.

Age Factors↗
PubMed1995

Model based calculation for effective cancer radioimmunotherapy.

The major problem of tumour radioimmunotherapy remains the low tumour antibody uptake and this leads to inadequate tumour irradiation. The antibody characteristics which influence uptake have been identified and quantified previously using a non-linear compartmental model that simulates antibody distribution to tumour and body after intravenous injection. The model has now been extended, in combination with MIRD dosimetry tables, to calculate the integral tumour/body radiation dose for a range of antibody masses (1, 10 and 50 mg), sizes (binding site fragments and whole molecules) and affinities (K = 10(9)-10(13) mol-1). Antibody requirements for delivering 60 Gy to the tumour over 11.6 days were calculated for 131I and 90Y-labelled antibodies and included the effect of widely varying dose rates. The model predicted that intact antibodies of high affinity (10(11)-10(13) mol-1) produced effective tumour radiation doses with acceptable whole body radiation levels. By contrast, antibody fragments gave higher body radiation levels and required larger injected activity because of renal excretion. The model predicted higher therapeutic indices for 90Y-labelled antibody compared with 131I.

Antibody Affinity↗
PubMed1999

Generation of recombinant antibodies.

Recombinant antibody technology is opening new perspectives for the development of novel therapeutic and diagnostic agents. In this review we focus on advances in the generation of both genetically engineered humanized and fully human monoclonal antibodies. Methods for their production in different expression systems are also discussed.

Animals↗
PubMed2002

The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression.

The intermediate conductance Ca2+-activated K+ (IK) channel is distinguished from the functionally related Ca2+-activated K+ channels of smaller and larger unitary conductance by its molecular structure, pharmacology, tissue distribution and physiology. Like many K+ channels, IK is an assembly of four identical subunits each spanning the membrane six times and each contributing equally to the K+ selectivity pore positioned centrally in the complex. The IK channel gains its high sensitivity to intracellular Ca2+ from tightly bound calmodulin, and its activity is independent of the membrane potential. Several toxins including charybdotoxin and the more selective mutant, Glu32-charybdotoxin, maurotoxin and stichodactyla toxin potently block IK channels. Among blockers of the IK channel are also several small organic molecules including the antimycotic clotrimazole and the close analogues TRAM-34 and ICA-17043, as well as the antihypertensive, nitrendipine. The IK channel is distributed in peripheral tissues, including secretory epithelia and blood cells, but it appears absent from neuronal and muscle tissue. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca2+ influx that controls T lymphocyte (T cell) proliferation. In this review, special attention is given to an analysis of the use of IK blockers as potential immunosuppressants for the treatment of autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis.

Animals↗
PubMed2005

Analysis of the interaction between human steroid 21-hydroxylase and various monoclonal antibodies using comparative structural modelling.

OBJECTIVE: To study the interaction between human steroid 21-hydroxylase (21-OH) and monoclonal antibodies (MAbs) to 21-OH directed to 3 different epitopes recognised by 21-OH autoantibodies characteristic of autoimmune Addison's disease. DESIGN: Build comparative structural models of 21-OH, 21-OH MAbs and complexes of 21-OH-21-OH MAbs and study the effects of 21-OH MAbs on 21-OH enzyme activity. Then, analyse the relationship between sites important for binding of 21-OH MAbs and 21-OH autoantibodies and sites important for 21-OH enzyme activity. METHODS: Variable (V) regions of 21-OH MAbs (M21-OH1, M21-OH3, M21-OH5) were sequenced and models of the MAbs built using structures of antibodies in the database as templates. A comparative model of 21-OH was built using the crystal structure of rabbit cytochrome p450 2c5/3LVdH as template. 21-OH enzyme activity was measured in terms of conversion of [3H]progesterone to deoxycorticosterone and the effect of purified MAb IgGs on 21-OH enzyme activity was assessed. RESULTS: M21-OH1, M21-OH3 and control MAb had no effect on 21-OH enzyme activity with 88.8% +/- 24% (n = 6), 86.7% +/- 7.6% (n = 6) and 86.5% +/- 10.6% (n = 6) of activity remaining in the presence of the respective IgGs. This was consistent with the epitopes for M21-OH1 and M21-OH3 being located distant from 21-OH enzyme active sites in our 21-OH model. The epitope for M21-OH5 which inhibited 21-OH enzyme activity (48.5 +/- 8.3% activity remaining; P < 0.001 compared with control MAb IgG) was found close to the redox protein binding site in our 21-OH model. CONCLUSIONS: A comparative model of 21-OH has been produced. Analysis of experimental data in the context of the model suggests that M21-OH5 inhibits 21-OH enzyme activity through interference with redox protein binding.

Animals↗
PubMed2002

Nonsynaptic noradrenaline release in neuro-immune responses.

Evidence has recently been obtained that the branches of the autonomic nervous system, mainly, the sympathetic [25], regulate cytokine production. Not only the primary (thymus, bone marrow) and secondary (spleen, tonsils, and lymph nodes) lymphoid organs, but also many other tissues are involved in immune responses and are heavily influenced by noradrenaline (NA) derived from varicose axon terminals of the sympathetic nervous system [25, 100]. Besides NA released from nonsynaptic varicosities of noradrenergic terminals [92], circulating catecholamines (adrenaline, dopamine, NA) are also able to influence immune responses, the production of pro- and anti-inflammatory cytokines by different immune cells. The sympathetic nervous system (catecholamines) and the hypothalamic-pituitary-adrenal (HPA) axis (cortisol) are the major integrative and regulatory components of different immune responses. In our laboratory convincing evidence has been obtained that NA released non-synaptically [90, 92] from sympathetic axon terminals and enhanced in concentration in the close proximity of immune cells is able to inhibit production of proinflammatory (TNF-alpha, IFN-gamma, IL-12, IL-1) and increase antiinflammatory cytokines (IL-10) in response to LPS [25, 91], indicating a fine-tuning control of the production of TNF-alpha and other cytokines by sympathetic innervation under stressful conditions. This effects are mediated via beta2-adrenoceptors expressed on immune cells and coupled to cAMP levels.

Animals↗
PubMed2006

Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders.

This review focuses on possible causes and the impact of different immune states in schizophrenia and major depression. It discusses the fact that, in schizophrenia, an over-activation of the type 2 immune response may dominate, while the type 1 and the pro-inflammatory immune responses are over-activated in major depression. The consequence of these diverse immune states is the activation and, respectively, inhibition of different enzymes in tryptophan/kynurenine metabolism, which may lead to an overemphasis of N-methyl-D-aspartate (NMDA) receptor antagonism in schizophrenia and of NMDA-receptor agonism in depression, resulting in glutamatergic hypofunction in schizophrenia and glutamatergic hyperfunction in major depression. In addition, the activation of the type 1 and the pro-inflammatory immune responses in major depression result in increased serotonin degradation and a serotonergic deficit. While antipsychotics and antidepressants today mainly act on the dopaminergic-glutamatergic and the noradrenergic-serotonergic neurotransmission, anti-inflammatory and immune-modulating therapies might act more basically at the pathophysiological mechanism. The limitations of this concept, however, are critically discussed.

Animals↗
PubMed2004

Immunotherapy for multiple sclerosis: basic insights for new clinical strategies.

Multiple Sclerosis (MS) is a chronic inflammatory degenerative disease of the central nervous system (CNS), first described over 100 years ago. MS is a clinically heterogeneous disease with an increasing incidence over time, and a population prevalence that increases with distance from the equator. It is postulated that environmental factors such as diet and population-specific genetics, influence the distribution of MS. Diagnosis is based on established clinical criteria, aided by magnetic resonance imaging, evoked potential recordings and cerebrospinal fluid examination. Whichever the type of clinical manifestation, MS is considered an organ-specific autoimmune disease, characterized by T-cell and macrophage infiltrates, triggered by CNS-specific CD4 T-cells. The prominent autoimmune etiology of MS is considered to be the aberrant activation of IFN-gamma-producing Th1 cells that recognize self-peptides of the myelin sheath, such as myelin basic protein (MBP) and proteolipid protein (PLP). Current treatments for MS aim primarily to suppress T-cell-mediated immune responses, albeit non-specifically. Experimental approaches towards the therapeutic management of MS involve the use of peptide analogs of disease-associated myelin epitopes or vaccines, to help shift T helper cell responses from Type-1 (secreting pro-inflammatory cytokines) to Type-2 (secreting anti-inflammatory cytokines) or induce peripheral T-cell tolerance. Animal models of MS have been useful to dissect disease mechanisms and evaluate new therapies. Experimental clinical trials, although few, are valuable to assess new treatment regimens and clarify possible conceptual mistakes about the disease. This review attempts to link the current knowledge of MS pathogenesis with clinical and experimental protocols of immunotherapy for MS.

Animals↗
PubMed2000

The inference of antigen selection on Ig genes.

Analysis of somatic mutations in V regions of Ig genes is important for understanding various biological processes. It is customary to estimate Ag selection on Ig genes by assessment of replacement (R) as opposed to silent (S) mutations in the complementary-determining regions and S as opposed to R mutations in the framework regions. In the past such an evaluation was performed using a binomial distribution model equation, which is inappropriate for Ig genes in which mutations have four different distribution possibilities (R and S mutations in the complementary-determining region and/or framework regions of the gene). In the present work, we propose a multinomial distribution model for assessment of Ag selection. Side-by-side application of multinomial and binomial models on 86 previously established Ig sequences disclosed 8 discrepancies, leading to opposite statistical conclusions about Ag selection. We suggest the use of the multinomial model for all future analysis of Ag selection.

Antigens↗
PubMed2002

Receptor-facilitated antigen presentation requires the recruitment of B cell linker protein to Igalpha.

Ags that cross-link the B cell Ag receptor are preferentially and rapidly delivered to the MHC class II-enriched compartment for processing into peptides and subsequent loading onto MHC class II. Proper sorting of Ag/receptor complexes requires the recruitment of Syk to the phosphorylated immunoreceptor tyrosine-based activation motif tyrosines of the B cell Ag receptor constituent Igalpha. We postulated that the Igalpha nonimmunoreceptor tyrosine-based activation motif tyrosines, Y(176) and Y(204), contributed to receptor trafficking. Igalpha(YDeltaF(176,204))/Igbeta receptors were targeted to late endosomes, but were excluded from the vesicle lumen and could not facilitate the presentation of Ag to T cells. Subsequent analysis demonstrated that phosphorylation of Y(176)/Y(204) recruited the B cell linker protein, Vav, and Grb2. Reconstitution of Igalpha(YDeltaF(176,204))/Igbeta with the B cell linker protein rescued both receptor-facilitated Ag presentation and entry into the MHC class II-enriched compartment. Thus, aggregation accelerates receptor trafficking by recruiting two separate signaling modules required for transit through sequential checkpoints.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Selection of Ig mu heavy chains by complementarity-determining region 3 length and amino acid composition.

Although it is generally accepted that Ig heavy chains (HC) are selected at the pre-B cell receptor (pre-BCR) checkpoint, the characteristics of a functional HC and the role of pre-BCR assembly in their selection have remained elusive. We determined the characteristics of HCs that successfully passed the pre-BCR checkpoint by examining transcripts harboring V(H)81X and J(H)4 gene segments from J(H)(+/-) and lambda5(-/-)mice. V(H)81X-J(H)4-HC transcripts isolated from cells before or in the absence of pre-BCR assembly had no distinguishing complementarity-determining region 3 traits. In contrast, transcripts isolated subsequent to passage through the pre-BCR checkpoint had distinctive complementarity-determining regions 3 of nine amino acids in length (49%) and a histidine at position 1 (73%). Hence, our data define specific structural requirements for a functional HC, which is instrumental in shaping the diverse B cell repertoire.

Amino Acids↗