Determinant analysis of IgE and IgG4 antibodies and T cells specific for bovine alpha(s)1-casein from the same patients allergic to cow's milk: existence of alpha(s)1-casein-specific B cells and T cells characteristic in cow's-milk allergy

In an effort to clarify the etiology of milk allergy from the standpoint of allergen-specific immune reactions, we investigated the determinants of IgE, IgG4, and T cells specific for bovine alpha(s)1-casein from the same individual patients by using its synthetic peptides and cyanogen bromide-digested fragments. Alpha(s)1-casein is a major allergen in cow's milk, and its unique conformation enabled us to investigate the determinants of antibodies without consideration about missing the reactivities because of conformational changes. Nine patients were selected as subjects from among 129 milk-sensitive infants screened by ELISA to assess the anti-alpha(s)1-casein IgE levels in their sera. By using ELISA for epitope mapping, a C-terminal region of alpha(s)1-casein was identified as a common binding site for IgE from all of these patients, whereas those for anti-alpha(s)1-casein IgG4 were located in multiple regions of alpha(s)1-casein. We determined the specificities of seven alpha(s)1-casein-specific T-cell lines established from peripheral blood mononuclear cells of two of the patients. These T cells have been shown to secrete IL-4. All of the T-cell lines had different specificities to alpha(s)1-casein. However, a common amino acid residue use was found among the determinants of various T-cell lines from each patient. The results suggest that patients allergic to cow's milk have characteristic B cells recognizing a limited region of alpha(s)1-casein and secreting alpha(s)1-casein-specific IgE. These B cells may interact particularly with T cells recognizing determinants with a common structure.     

Comparison of skin-prick test and specific serum IgE determination for the diagnosis of latex allergy

The synthesis and anticonvulsant activity of novel 7,8-methylenedioxy-4H-2,3-benzodiazepin-4-ones 3a-e, structurally-related to GYKI 52466 1, a well-known noncompetitive AMPA-receptor antagonist, are reported. The new compounds possess marked anticonvulsant properties and, in analogy to 1, antagonize seizures induced by AMPA. In addition, when compared to the model compound 1, compounds 3 show a longer-lasting anticonvulsant activity and a lower toxicity.     

Mast cells: a possible link between psychological stress, enteric infection, food allergy and gut hypersensitivity in the irritable bowel syndrome

Intestinal mast cell activation (degranulation), which results from previous enteric infection and/or intestinal allergy, may play a central role in the gut hypersensitivity in both motor response and visceral perception in the Irritable Bowel syndrome. This occurs through various mediators acting on enteric neurons and smooth muscle cells. Psychological stress may trigger this sensitive alarm system via the brain-gut axis.     

Glucocorticoids inhibit human antigen-specific and enhance total IgE and IgG4 production due to differential effects on T and B cells in vitro

Although anti-inflammatory properties of glucocorticoids (GC) are well documented, their activity in allergic diseases is still controversial. Recently, it has been reported that GC can increase, both in vivo and in vitro, the polyclonal production of total IgE. In this study we investigated the effects of GC on the antigen (Ag)-specific IgE response in a human in vitro system with peripheral blood mononuclear cells or B cells of bee venom-sensitized individuals that allows the production of bee venom phospholipase A2 (PLA)-specific IgE and IgG4 antibodies (Ab). PLA-specific Ab were induced by simultaneously activating T cells and B cells specifically with allergen and polyclonally with anti-CD2 and soluble CD40 ligand (sCD40L) in the presence of interleukin (IL)-4. Indeed, dexamethasone and prednisolone enhanced the formation of total IgE and IgG4 in PBMC, while the production of PLA-specific IgE and IgG4 Ab was selectively inhibited in a dose-dependent manner. The suppressive effect of GC was mediated during Ag-specific stimulation and T cell-B cell interaction. This was due to GC suppressing specific T cell proliferation and cytokine production, whereas neither allergen-specific nor total IgE and IgG4 production by sCD40L/IL-4-stimulated pure B cells was affected. In contrast to GC, cyclosporine A inhibited both total and PLA-specific IgE and IgG4 secretion in peripheral blood mononuclear cells and B cell cultures. Further experiments showed that increase in nonspecific total isotype response resulted from inhibition of IL-4 uptake by cells other than B cells and sufficient availability of IL-4 to B cells for isotype switch and synthesis. Furthermore, demonstration of opposite regulatory effects of GC on specific and total isotype formation in vitro, including the inhibition of allergy-relevant Ag-specific IgE response, may contribute to a better understanding of apparently controversial observations, and explain why most allergic patients benefit from GC therapy.     

Chemical respiratory allergy, IgE and the relevance of predictive test methods: a commentary

Polycystic ovary syndrome is a diagnosis made in 5%-10% of women between late adolescence and the menopause. Patients may present with oligomenorrhoea or amenorrhoea, anovulation or infertility, hirsutism or acne. Women with the syndrome have at least seven times the risk of myocardial infarction and ischaemic heart disease of other women, and by the age of 40 years up to 40% will have type 2 diabetes or impaired glucose tolerance. Polycystic ovary syndrome is associated with insulin resistance, with consequent hyperinsulinaemia and (frequently) hyperlipidaemia and obesity. Recent research has shown that the application of diabetes management techniques aimed at reducing insulin resistance and hyperinsulinaemia (such as weight reduction and the administration of oral hypoglycaemic agents) can not only reverse testosterone and luteinising hormone abnormalities and infertility, but can also improve glucose, insulin and lipid profiles. The management of polycystic ovary syndrome should now include patient education and attention to diabetes and cardiovascular risk factors such as hyperlipidaemia, obesity, physical exercise, glucose intolerance, hypertension and cigarette smoking.     

Autoimmune diabetes: the role of T cells, MHC molecules and autoantigens

Type 1 diabetes (IDDM) is a T cell mediated autoimmune disease which in part is determined genetically by its association with major histocompatibility complex (MHC) class II alleles. The major role of MHC molecules is the regulation of immune responses through the presentation of peptide epitopes of processed protein antigens to the immune system. Recently it has been demonstrated that MHC molecules associated with autoimmune diseases preferentially present peptides of other endogenous MHC proteins, that often mimic autoantigen-derived peptides. Hence, these MHC-derived peptides might represent potential targets for autoreactive T cells. It has consistently been shown that humoral autoimmunity to insulin predominantly occurs in early childhood. The cellular immune response to insulin is relatively low in the peripheral blood of patients with IDDM. Studies in NOD mice however have shown, that lymphocytes isolated from pancreatic islet infiltrates display a high reactivity to insulin and in particular to an insulin peptide B 9-23. Furthermore we have evidence that cellular autoimmunity to insulin is higher in young pre-diabetic individuals, whereas cellular reactivity to other autoantigens is equally distributed in younger and older subjects. This implicates that insulin, in human childhood IDDM and animal autoimmune diabetes, acts as an important early antigen which may target the autoimmune response to pancreatic beta cells. Moreover, we observed that in the vast majority of newly diagnosed diabetic patients or individuals at risk for IDDM, T cell reactivity to various autoantigens occurs simultaneously. In contrast, cellular reactivity to a single autoantigen is found with equal frequency in (pre)-type 1 diabetic individuals as well as in control subjects. Therefore the autoimmune response in the inductive phase of IDDM may be targeted to pancreatic islets by the cellular and humoral reactivity to one beta-cell specific autoantigen, but spreading to a set of different antigens may be a prerequisite for progression to destructive insulitis and clinical disease. Due to mimic epitopes shared by autoantigen(s), autologous MHC molecules and environmental antigens autoimmunity may spread, intramolecularly and intermolecularly and amplify upon repeated reexposure to mimic epitopes of environmental triggers.     

Production of a mouse/human chimeric IgE monoclonal antibody to the house dust mite allergen Der p 2 and its use for the absolute quantification of allergen-specific IgE

1. We evaluated the antianginal effects of YM430 in several experimental models in vitro and in vivo. 2. In isolated dog coronary artery, YM430 (10(-8)-10(-6) M) inhibited 3,4-diaminopyridine-induced rhythmic contractions with an IC50 value of 59.2 nM. 3. In anesthetized rats, YM430 (10-100 mg/kg PO) inhibited arginine vasopressin-induced ST-segment depression with an IC50 value of 36.6 mg/kg PO. 4. In anesthetized dogs, YM430 (0.3 mg/kg IV) significantly inhibited ST-segment elevation induced by coronary artery occlusion. 5. These findings suggest that YM430 may be of value in the treatment of various types of angina pectoris such as variant and stable angina.     

Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents

BACKGROUND: The double-blind, placebo-controlled food challenge (DBPCFC) is the "gold standard" for diagnosis of food hypersensitivity. Skin prick tests and RASTs are sensitive indicators of food-specific IgE antibodies but poor predictors of clinical reactivity. Previous studies suggested that high concentrations of food-specific IgE antibody were predictive of food-induced clinical symptoms. Because the CAP System FEIA (Pharmacia Diagnostics, Uppsala, Sweden) provides a quantitative assessment of allergen-specific IgE antibody, this study was undertaken to determine the potential utility of the CAP System FEIA in diagnosis of IgE-mediated food hypersensitivity. METHODS: Sera from 196 patients with food allergy were analyzed for specific IgE antibodies to egg, milk, peanut, soy, wheat, and fish by CAP System FEIA. Sera were randomly selected from 300 stored samples of children and adolescents who had been evaluated by history, skin prick tests, and DBPCFCs. The study population was highly atopic; all patients had atopic dermatitis, and approximately 50% had asthma and allergic rhinitis at the time of initial evaluation. The performance characteristics of the CAP System FEIA were compared with those of skin prick tests and the outcome of DBPCFCs or "convincing" histories of anaphylactic reactions. RESULTS: The prevalence of specific food allergies in the study population varied from 22% for wheat to 73% for egg. Allergy to egg, milk, peanut, and soy accounted for 87% of confirmed reactions. The performance characteristics of skin prick tests and CAP System FEIA (egg, milk, peanut, fish) were comparable, with excellent sensitivity and negative predictive accuracy but poor specificity and positive predictive accuracy. The performance characteristics of the CAP System FEIA for soy and wheat were poor. For egg, milk, peanut, and fish allergy, diagnostic levels of IgE, which could predict clinical reactivity in this population with greater than 95% certainty, were identified: egg, 6 kilounits of allergen-specific IgE per liter (kU[A]/L); milk, 32 kU(A)/L; peanut, 15 kU(A)/L; and fish, 20 kU(A)/L. CONCLUSIONS: When compared with the outcome of DBPCFCs, results of CAP System FEIA are generally comparable to those of skin prick tests in predicting symptomatic food hypersensitivity. Furthermore, by measuring the concentrations of food-specific IgE antibodies with the CAP System FEIA, it is possible to identify a subset of patients who are highly likely (>95%) to experience clinical reactions to egg, milk, peanut, or fish. This could eliminate the need to perform DBPCFCs in a significant number of patients suspected of having IgE-mediated food allergy.     

A role for BDNF in early postnatal rat vestibular epithelia maturation: implication of supporting cells

The early development of the inner ear is largely determined by two members of the neurotrophic family: brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3). Little information is available on the role of these neurotrophins during the late stages of vestibular development in the rat which take place during the first postnatal weeks. At this period where terminal synaptogenesis and maturation occur, we have investigated the expression and the activity of BDNF, the most important neurotrophin in the vestibular system. Using different experimental approaches, we show that BDNF is released by vestibular epithelia on postnatal day 3 (P3) and continues to have a trophic effect on vestibular neurones in vitro. Immunocytochemistry coupled to confocal microscopy revealed a remarkable evolution in BDNF localization during later stages of development. Whereas BDNF is present in both supporting cells and hair cells at P3, its distribution gradually changed and is highly compartmentalized within the upper part of supporting cells at P8 and P15. In parallel, we observed the presence of a truncated form of the BDNF receptor in sensory hair cells. These results suggest an original role for supporting cells, which could be involved in the release of BDNF during the late stages of synaptogenesis in mammalian vestibular epithelia. In particular, BDNF could participate to the set up of the calyx, a specific nerve structure surrounding type I vestibular hair cells.     

Contagious depression: Existence, specificity to depressed symptoms, and the role of reassurance seeking.

This study prospectively examined the phenomenon of contagious depression in 96 pairs of college roommates during 2 assessment sessions separated by 3 wks. Depression, anxiety, negative and positive affect, negative life stress, and reassurance seeking were assessed. Consistent with prediction, roommates of depressed target students became more depressed themselves over the course of the 3-wk study. The effect persisted when baseline levels of roommate depression and roommate negative life events were controlled. Furthermore, these findings were specific to depressed symptoms. Finally, as predicted, reassurance seeking served as a vulnerability factor for the contagion effect: High- but not low-reassurance-seeking roommates of depressed target students became more depressed themselves. However, the moderating effects of reassurance seeking were not specific to depressed symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Complexity, communication between cells, and identifying the functional components of living systems: some observations

The concept of 'complexity' has become very important in theoretical biology. It is a many faceted concept and too new and ill defined to have a universally accepted meaning. This review examines the development of this concept from the point of view of its usefulness as a criteria for the study of living systems to see what it has to offer as a new approach. In particular, one definition of complexity has been put forth which has the necessary precision and rigor to be considered as a useful categorization of systems, especially as it pertains to those we call 'living'. This definition, due to Robert Rosen, has been developed in a number of works and involves some deep new concepts about the way we view systems. In particular, it focuses on the way we view the world and actually practice science through the use of the modelling relation. This mathematical object models the process by which we assign meaning to the world we perceive. By using the modelling relation, it is possible to identify the subjective nature of our practices and deal with this issue explicitly. By so doing, it becomes clear that our notion of complexity and especially its most popular manifestations, is in large part a product of the historical processes which lead to the present state of scientific epistemology. In particular, it is a reaction to the reductionist/mechanistic view of nature which can be termed the 'Newtonian Paradigm'. This approach to epistemology has dominated for so that its use as a model has become implicit in most of what we do in and out of science. The alternative to this approach is examined and related to the special definition of complexity given by Rosen. Some historical examples are used to emphasize the dependence of our view of what is complex in a popular sense on the ever changing state of our knowledge. The role of some popular concepts such as chaotic dynamics are examined in this context. The fields of artificial life and related areas are also viewed from the perspective of this rigorous view of complexity and found lacking. The notion that in some way life exists 'at the edge of chaos' is examined from the perspective of the second law of thermodynamics given by Schneider and Kay. Finally, the casual elements in complex systems are explored in relation to complexity. Rosen has shown that a clear difference in causal relations exists between complex and simple systems and that this difference leads to a uniquely useful definition of what we mean by 'living'. Rosen makes it very clear that the class of systems which are complex is a much larger class than those which we call living. For that reason, the focus of this review will be on complexity as a stepping stone towards the deeper question of what makes a system alive.     

The role of microglia and tumor-primed lymphocytes in the interaction between T lymphocytes and brain endothelial cells

We investigated the role of IFN-gamma activated microglia in the passage of T lymphocytes across a monolayer of brain endothelial cells (EC) in vitro. Microglia isolated from Fisher 344 (F344) newborn rats were stimulated with IFN-gamma (100 U/ml) for 48 h. T lymphocytes primed with glioma cells were 51Cr-labeled, and added to the monolayer of F344 brain EC. In the adhesion assay, when EC were cultured in medium containing the supernatant of reactive microglia before the assay was carried out, the number of T lymphocytes adhering was increased. In addition, this adhesion was blocked by the addition of anti-ICAM-1 mAb to the EC. In the migration assay, performed using the double chamber system, when reactive microglia adhered to the other side of EC, the number of T lymphocytes migrating to the underwell was also increased. When T lymphocytes were primed to tumor cells in vivo, both their adhesion and migration were enhanced. These results suggest that some soluble factors from reactive microglia are capable of enhancing the expression of ICAM-1 on the brain EC. As a consequence, large numbers of tumor-primed T lymphocytes can adhere to EC and migrate across the EC monolayer.     

Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells

Activation of the high affinity IgE receptor (Fc epsilon RI) of mast cells, a member of the antigen receptor family, leads to the release of allergic mediators, a critical event in the onset of immediate hypersensitivity. Stimulation of Fc epsilon RI results in the rapid association and activation of the Syk tyrosine kinase. Using Syk-deficient mast cells we show that they fail to degranulate, synthesize leukotrienes and secrete cytokines when stimulated through Fc epsilon RI, conclusively demonstrating an essential role for Syk in Fc epsilon RI signalling. Furthermore, our data strongly supports a model of Fc epsilon RI engagement leading to the sequential activation of the tyrosine kinases Lyn and then Syk. A similar mechanism is likely to apply to signal transduction through all members of the antigen receptor family.     

Expression of the Fc receptor for IgG (Fc gamma RII/CDw32) by human circulating T and B lymphocytes

Tissue-specific isoforms of the human FcR for IgG Fc gamma RII (CDw32) have previously been described by using mAb. These mAb were shown to exhibit different patterns of reactivity with lymphocytes. Among human PBL, Fc gamma RII has been detected on B cells but not T cells when assessed by flow cytometry and microscopy with the use of mAb KB61 and 41H16. Although KB61 and 41H16 were found to react with B cells, the mAb IV.3, CIKM5, and 2E1 did not react with any PBL subset. In this study, we show that KB61 and 41H16 react strongly with the majority (93-96%) of B cells (CD20+), and weakly with a proportion (18-42%) of T cells (CD3+), including 10 to 14% of CD4+ and 27 to 69% of CD8+ cells. In addition, mRNA for Fc gamma RII was detected in purified CD3+CD8high+ lymphocytes by polymerase chain reaction. KB61 and 41H16 also reacted with a majority of CD3-CD16/CD56+ cells, and CD3-CD20- cells. These findings indicate that a subset of T cells and non-T/non-B cells express Fc gamma RII, and are of interest in the light of previous studies which postulate that human Fc gamma R+ cells and Fc gamma RII+ murine T cells suppress the B cell immune response.     

Mercury-induced autoimmunity in Brown Norway rats: kinetics of changes in RT6+ T lymphocytes correlated with IgG isotypes of circulating autoantibodies to laminin 1

Repeated exposure to mercury causes various autoimmune effects in rats of the Brown Norway (BN) strain. Previous studies from our laboratory have shown that on day 15 of HgCl2 treatment BN rats exhibit a relative decrease in RT6.2+ T cells. At the same time, they produce high levels of autoantibodies to renal antigens and experience a membranous glomerulonephropathy. In contrast, Lewis (LEW) rats are resistant to autoimmunity caused by mercury and do not demonstrate a decrease in RT6+ cells after administration of HgCl2. In the present paper we provide novel information on the correlation between changes in RT6.2+ lymph node T cells and the production of autoantibodies to laminin 1, obtained by detailed kinetic studies of HgCl2-treated BN rats. We have confirmed a decrease in the percentage of RT6.2+ lymphocytes on day 15 of mercury treatment, despite a significant increase in the number of peripheral lymphocytes. No such changes were observed in LEW rats. We have determined that on day 15 the percentage decrease in RT6+ cells is evident in both RT6.2+CD4+ and RT6.2+CD8+ T cell subsets. Kinetic studies demonstrated that significant changes in the percentage of RT6.2+ cells are first observed by day 8 and continue through days 11 and 15. We have also observed a significant percent decrease in CD4+ T lymphocytes as well as an increase in CD4-CD8- cells. The dramatic increase in the percentage of these double negative cells at the level of peripheral lymphoid tissues does not appear to be due to higher thymic output, since there was a decrease in the percentage of TCR+Thy1+ cells, a phenotype that is associated with recent thymic emigrants. Finally, we have demonstrated that 100% of HgCl2-treated BN rats had circulating antibodies that reacted with both mouse and rat laminin 1, i.e. are autoantibodies to laminin 1. These autoantibodies were predominantly of the IgG1 and IgG2a isotype, possibly as the result of a polarized autoimmune response driven by Type 2 cytokines. A kinetic investigation showed that significant levels of IgG1 and IgG2a autoantibodies to laminin 1 were first presentin the circulation by day 11. The inverse correlation between levels of RT6.2+ T lymphocytes and autoantibodies to laminin 1 suggests that mercury may induce autoimmune responses in BN rats by its effects on these immunoregulatory cells.     

Human IgE, IgG subclass, and IgM responses to worm and egg antigens in schistosomiasis haematobium: a 12-month study of reinfection in Cameroonian children

Methylglyoxal (MG), a dicarbonyl compound produced by the fragmentation of triose phosphates, forms advanced glycation endproducts (AGEs) in vitro. Glyoxalase-I catalyzes the conversion of MG to S-D-lactoylglutathione, which in turn is converted to D-lactate by glyoxalase-II. To evaluate directly the effect of glyoxalase-I activity on intracellular AGE formation, GM7373 endothelial cells that stably express human glyoxalase-I were generated. Glyoxalase-I activity in these cells was increased 28-fold compared to neo-transfected control cells (21.80+/-0.1 vs. 0. 76+/-0.02 micromol/min/mg protein, n = 3, P < 0.001). In neo-transfected cells, 30 mM glucose incubation increased MG and D-lactate concentration approximately twofold above 5 MM (35.5+/-5.8 vs. 19.6+/-1.6, P < 0.02, n = 3, and 21.0+/-1.3 vs. 10.0+/-1.2 pmol/ 10(6) cells, n = 3, P < 0.001, respectively). In contrast, in glyoxalase-I-transfected cells, 30 mM glucose incubation did not increase MG concentration at all, while increasing the enzymatic product D-lactate by > 10-fold (18.9+/-3.2 vs. 18.4+/- 5.8, n = 3, P = NS, and 107.1+/-9.0 vs. 9.4+/-0 pmol/10(6) cells, n = 3, P < 0.001, respectively). After exposure to 30 mM glucose, intracellular AGE formation in neo cells was increased 13.6-fold (2.58+/-0.15 vs. 0.19+/-0.03 total absorbance units, n = 3, P < 0.001). Concomitant with increased intracellular AGEs, macromolecular endocytosis by these cells was increased 2.2-fold. Overexpression of glyoxalase-I completely prevented both hyperglycemia-induced AGE formation and increased macromolecular endocytosis.     

Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity

In the present report, cytotoxic T lymphocyte (CTL) clones are described that display dual specificity for one of two common human leukocyte antigens (HLA B14 or B35) as alloantigens, and an immunodominant epitope (FLRGRAYGL) from Epstein-Barr virus (EBV) that binds to HLA B8. These T cell clonotypes were isolated from several unrelated HLA B8+, EBV-exposed individuals, and each distinct cross-reactivity pattern was associated with a common, public T cell receptor (TCR). In some individuals, CTL cross-reactive with these alloantigens completely dominated the memory response to this EBV epitope. Moreover, these memory T cells to EBV could be reactivated as a significant component of the repertoire of CTL responding to allogeneic stimulator cells expressing either HLA B14 or B35. These data illustrate how a history of infection with an immunogenic virus such as EBV can augment responsiveness to particular alloantigens; such influences may underlie the observed clinical association between herpesvirus infection and both allograft rejection and graft-versus-host disease. We have also explored the molecular basis for T cell cross-reactivity with alloantigens using the HLA B35 allo-reactive CTL clonotype. To elucidate the structural features of peptides that may be cross-recognized by these T cells, mono-substituted analogs of the viral epitope were screened for recognition, revealing broad specificity for major histocompatibility complex (MHC)-bound peptide. Based on the particular amino acid changes tolerated by the CTL at each peptide position, the human protein sequence database was searched for possible sequences that were recognized in association with HLA B35. Four peptides were identified (MPEATVYGL, IPIAPVYGM, KPSPPYFGL, and KPIVVLHGY) that were powerful activating ligands for the CTL when presented on HLA B35 but not B8. Thus, equivalent epitopes, capable of fully activating a single TCR, were formed by peptides with minimal obvious sequence homology bound to either HLA B8 or B35. These data indicate that degenerate peptide recognition by TCR may play an important role in the vigorous response of self-MHC-restricted T cells to alloantigens.     

Phenotype, and migration properties of three major subsets of tissue homing T cells in sheep

T cells show a bias in their migration pathways: some T cells preferentially migrate to peripheral lymph nodes (LN), some to mucosal tissues, and some to peripheral tissues such as skin. These recirculation pathways were examined in sheep by collecting lymph draining into and out of peripheral and intestinal LN, and using fluorescent dyes to trace the recirculation of the lymph cells. Monoclonal antibodies (mAb) to alpha 4, beta 1, and beta 7 integrins, and L-selectin, were used to define three major populations of recirculating T cells. Naive-type T cells (L-selectin+, alpha 4 beta 1lo beta 7lo) migrated preferentially through peripheral LN. Two memory populations could be defined: alpha 4 beta 1hi beta 7- and alpha 4 beta 7hi beta 1lo. alpha 4 beta 1hi beta 7- T cells were present in lymph draining from the skin. T cells migrating preferentially through intestinal LN were alpha 4 beta 7hi beta 1lo. Consistent with this migration pattern, the endothelial receptor for alpha 4 beta 7, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) was detected on high endothelial venules within intestinal LN and Peyer's patches, but only weakly on high endothelial venules within peripheral LN. Thus, there are at least three easily definable subsets of T cells, based on integrin expression, which show distinct migration preferences.     

Inflammation in high-grade carotid stenosis: a possible role for macrophages and T cells in plaque destabilization

BACKGROUND AND PURPOSE: Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. In this study, we investigated whether the extent of inflammatory infiltration in high-grade stenoses of the internal carotid artery (ICA) correlates to clinical features of plaque destabilization. METHODS: Endarterectomy specimens from 37 consecutive patients undergoing surgery for high-grade ICA stenosis were stained immunocytochemically for macrophages (CD68) and T cells (CD3). The staining was quantified by planimetry of immunostained areas (CD68) or counting individual cells (CD3). Clinical evidence of plaque instability was provided by the preoperative assessment of recent ischemic symptoms attributable to the stenosis and of the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. RESULTS: The percentage of macrophage-rich areas and number of T cells per mm2 section area were larger in recently symptomatic patients than in asymptomatic patients (macrophages: 18+/-10% versus 11+/-4%, P=0.005; T cells: 71.2+/-34.4 versus 40.5+/-31.4 mm2, P=0.005). The presence of microembolism was associated with an increase in macrophage-rich areas (P=0.011). Macrophage (19+/-10% versus 9+/-3%, P=0.0009) and T cell (71.5+/-39.0 versus 46.4+/-22 mm2, P=0.045) infiltration were more pronounced in predominantly atheromatous than in fibrous plaques, but did not correlate significantly to the presence of surface ulceration or luminal thrombosis. CONCLUSIONS: Our data suggest a role of plaque-infiltrating macrophages and T cells in the clinical destabilization of high-grade ICA stenoses. Inflammatory mechanisms may be a therapeutic target in patients with symptomatic ICA disease.