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At least 505 records · Page 28Linked to original sources
PubMed2006

Expression of the N-methyl-D-aspartate receptor subunit R1 in the developing human hippocampus.

It has been suggested that the N-methyl-D-aspartate (NMDA) receptor family plays a key role in synaptic plasticity and synaptogenesis that is essential for memory, learning, differentiation, and development. Although gene expression of these receptors has been analyzed in the experimental animal brain and in some diseases of the adult or elderly human brain, it has not been studied in the developing human brain. Using in situ hybridization, we investigated the expression of the NMDAR1 gene in the hippocampi of 16 human neonates who were between 22 and 40 weeks of gestation and had no evidence of critical episodes of brain insult at autopsy. Signals for NMDAR1 were detected ubiquitously at all developmental stages. Dense hybridization signals were uniformly detected in the granular cells of the dentate gyrus in all specimens. Stronger signals were observed in the larger-type pyramidal cells in the CA2 and CA3 regions compared with the pattern seen in the CA1 region in the smaller-type pyramidal cells. These results suggest that the NMDAR1 gene is expressed at 22 weeks and possibly occurs earlier in neuronal cell bodies of the dentate gyrus and all CA fields of Ammon's horn and that the NMDAR plays an important role in constructing neuronal networks in developing human brains.

Age Factors↗
PubMed2002

Differential sensitivity of naive and memory CD8+ T cells to apoptosis in vivo.

Apoptosis is a critical regulator of homeostasis in the immune system. In this study we demonstrate that memory CD8(+) T cells are more resistant to apoptosis than naive cells. After whole body irradiation of mice, both naive and memory CD8(+) T cells decreased in number, but the reduction in the number of naive cells was 8-fold greater than that in memory CD8(+) T cells. In addition to examining radiation-induced apoptosis, we analyzed the expansion and contraction of naive and memory CD8(+) T cells in vivo following exposure to Ag. We found that memory CD8(+) T cells not only responded more quickly than naive cells after viral infection, but that secondary effector cells generated from memory cells underwent much less contraction compared with primary effectors generated from naive cells (3- to 5-fold vs 10- to 20-fold decrease). Increased numbers of secondary memory cells were observed in both lymphoid and non-lymphoid tissues. When naive and memory cells were transferred into the same animal, secondary effectors underwent less contraction than primary effector cells. These experiments analyzing apoptosis of primary and secondary effectors in the same animal show unequivocally that decreased downsizing of the secondary response reflects an intrinsic property of the memory T cells and is not simply due to environmental effects. These findings have implications for designing prime/boost vaccine strategies and also for optimizing immunotherapeutic regimens for treatment of chronic infections.

Adoptive Transfer↗
PubMed2004

T cell clonal conditioning: a phase occurring early after antigen presentation but before clonal expansion is impacted by Toll-like receptor stimulation.

After in vivo immunization, Ag-specific T cells disappear from circulation and become sequestered in lymphoid tissue where they encounter Ag presented by dendritic cells. In the same site and just after Ag presentation, they "disappear" a second time and we investigated this process. Using a mouse model of T cell deletion (without Toll-like receptor (TLR) stimulation) vs survival (with TLR stimulation), Ag-specific T cells indeed became undetectable by flow cytometry, however were readily detected by immunohistochemistry. Thus, whether or not the activated T cells were destined to delete or survive, they were difficult to extract from lymphoid tissue and did not disappear but in fact were abundantly present. Nevertheless, profound differences were observed during this time period when tolerizing conditions were compared with immunizing conditions. TLR stimulation induced an increase in CD25 expression, acquisition of surface MHC class II, and abnormally high increases in forward and side scatter of the peptide-specific T cells. Using a modified adoptive transfer approach, we demonstrated by flow cytometry that in the presence of TLR stimulation the Ag-specific T cells were tightly coupled to dendritic cells, explaining the unusual increases in size and granularity. Ultimately, these events induced the specific T cells to differentiate into memory cells. We postulate that this is a stage where T cells are either conditioned to survive or to delete depending upon the activation status of the innate immune system.

Adoptive Transfer↗
PubMed2006

HS1-associated protein X-1 interacts with membrane-bound IgE: impact on receptor-mediated internalization.

Engagement of the BCR triggers signals that control affinity maturation, memory induction, differentiation, and various other physiological processes in B cells. In previous work, we showed that truncation of the cytoplasmic tail of membrane-bound Ig (mIg)E in vivo resulted in lower serum IgE levels, decreased numbers of IgE-secreting plasma cells, and the abrogation of specific secondary responses correlating with a defect in the selection of high-affinity Abs during the germinal center reaction. We concluded that the Ag receptor is necessary at all times during Ab responses not only for the maturation process, but also for the expansion of Ag-specific B cells. Based on these results, we asked whether the cytoplasmic tail of mIgE, or specific proteins binding the cytoplasmic tail in vivo commit a signal transduction accompanying the B cell along its differentiation process. In this study, we present the identification of HS1-associated protein X-1 as a novel protein interacting with the cytoplasmic tail of mIgE. ELISA, surface plasmon resonance analysis, and coimmunoprecipitation experiments confirmed the specific interaction in vitro. In functional assays, we clearly showed that HS1-associated protein X-1 expression levels influence the efficiency of BCR-mediated Ag internalization.

Amino Acid Sequence↗
PubMed2026

Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function.

The X-linked G-protein coupled receptor GPR174 is highly expressed in T and B lymphocytes and has immunoregulatory roles in mice, but its function in humans is unknown. We describe a cohort of six individuals who have function-disrupting variants in GPR174 and a clinical phenotype of lymphadenopathy and autoimmunity. Histological analysis of two patient lymph nodes revealed necrotizing lymphadenitis and lymphoproliferation resembling Kikuchi-Fujimoto disease. In-depth analysis of three patients and related carriers revealed overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (TEMRA). Patient cells and GPR174-deficient CD8 T cells generated from controls showed less repression of proliferation by the GPR174 ligand lysophosphatidylserine (lysoPS) and an effector-biased gene expression program. GPR174-deficient CD4 T cells were resistant to lysoPS-mediated suppression of IL2 production. In mice, chronic viral infection led to over-accumulation of GPR174-deficient effector CD8 T cells. We describe an inborn error of immunity associated with dysregulated lymphocyte responses that we propose predisposes to exaggerated lymphoproliferation and autoimmunity following viral infection.

Journal Article↗
PubMed1999

Allocation of attention in dichotic listening: effects on the detection and localization of targets within lists.

In each of two dichotic listening experiments, 48 normal right-handed adults were instructed to attend selectively to the left and right ears and to divide attention equally between ears. Participants listened for specified targets and reported the ear of entry when the target was heard. Stimuli consisted of lists of digit names in Experiment I and lists of words in Experiment 2. Shifts of attention altered ear asymmetry for localizing but not for detecting digit names. For words, attention shifts altered both detection asymmetry and localization asymmetry, but the effect of attention on detection seemed to reflect differential retrieval from short-term memory rather than differential perception. In both experiments, shifting attention toward either ear resulted in a reporting bias such that signals were attributed to the attended ear more often than to the unattended ear. The results confirm our previous findings, for single pairs of stimuli, that volitional shifts of attention alter response selection rather than perception.

Adolescent↗
PubMed2003

Activation of human melanoma reactive CD8+ T cells by vaccination with an immunogenic peptide analog derived from Melan-A/melanoma antigen recognized by T cells-1.

PURPOSE: As compared with natural tumor peptide sequences, carefully selected analog peptides may be more immunogenic and thus better suited for vaccination. However, T cells in vivo activated by such altered analog peptides may not necessarily be tumor specific because sequence and structure of peptide analogs differ from corresponding natural peptides. EXPERIMENTAL DESIGN: Three melanoma patients were immunized with a Melan-A peptide analog that binds more strongly to HLA-A*0201 and is more immunogenic than the natural sequence. This peptide was injected together with a saponin-based adjuvant, followed by surgical removal of lymph node(s) draining the site of vaccination. RESULTS: Ex vivo analysis of vaccine site draining lymph nodes revealed antigen-specific CD8+ T cells, which had differentiated to memory cells. In vitro, these cells showed accelerated proliferation upon peptide stimulation. Nearly all (16 of 17) of Melan-A-specific CD8+ T-cell clones generated from these lymph nodes efficiently killed melanoma cells. CONCLUSIONS: Patient immunization with the analog peptide leads to in vivo activation of T cells that were specific for the natural tumor antigen, demonstrating the usefulness of the analog peptide for melanoma immunotherapy.

Amino Acid Sequence↗
PubMed2003

[Pathomechanisms of the elicitation phase of allergic contact dermatitis].

Allergic contact dermatitis (ACD) is a T-cell mediated, antigen-specific inflammatory response to repeated epicutaneous exposure to haptens. Two immunologically distinct sequential steps are required to produce the clinical picture of ACD. In the sensitization phase, naïve antigen-specific T cells are primed and differentiate into memory or effector T cells. In the elicitation phase, reapplication of the same hapten leads to local recruitment of hapten-specific T cells which are cytotoxic, release cytokines and recruit other inflammatory cells. These events lead to clinically visible tissue inflammation characterized by edema, erythema, scaling, and blistering. For the clinician, the effector phase is especially important, because sensitization is generally asymptomatic, whereas elicitation produces the clinical picture of ACD. Detailed knowledge about the mechanisms of the elicitation phase of ACD is needed in order to develop novel therapeutic approaches.

Cytokines↗
PubMed1991

Differential sensitivity of virgin and memory T lymphocytes to calcium ionophores suggests a buoyant density separation method and a model for memory cell hyporesponsiveness to Con A.

Previous work from this laboratory has indicated that murine memory T cells differ from virgin T cells in that the former are more resistant to agents that alter intracellular [Ca]i. We have used this difference to devise a method for separating virgin from memory T cells by centrifugation over an ionomycin-containing Percoll step gradient after brief exposure to 2 microM ionomycin. Under these conditions, those T cells that are most sensitive to ionomycin-induced changes in [Ca]i become more dense and therefore travel further into the Percoll/ionomycin gradient than cells that are more resistant to ionomycin. We show that the ionomycin-resistant cell population is enriched for cells that express high levels of Pgp-1 (CD44), and low levels of CD45RB, and thus appears to consist largely of memory T cells. Both CD4 and CD8 cells can be divided into Pgp-1hi and Pgp-1lo subsets in this way. Cells recovered from such a gradient and washed to remove the ionomycin appear normally functional, i.e., neither more nor less responsive to mitogens and costimuli than untreated cells. Limiting dilution methods show that the ionomycin-sensitive (virgin) subset contains most of the Con A-responsive precursors for cytotoxicity, and most of the cells able to produce IL-2 in responses to Con A or staphylococcal enterotoxin B. Ag-specific helper memory cells are, however, found predominantly in the ionomycin-resistant fraction of the spleen and draining lymph nodes of mice infected with Schistosoma mansoni. Changes in resistance to calcium signal development may represent a fundamental distinction between virgin and memory T cells, and could contribute to differences in activation requirements between these two cell subsets.

Animals↗
PubMed1986

[Neurologic, psychologic and logopedic follow-up of 6 to 8-year-old former premature infants with a birth weight below 1,501 g].

The purpose of the present study was to find out if formerly premature babies (birth weight less than or equal to 1,501 g) show differences in their neurological, psychological and linguistic development of school-age when compared to children without perinatal problems. Discrete neurological dysfunctions (clumsy child syndromes, discrete hemi-syndromes) and left-handedness were found significantly more frequently in the premature group. The test psychological investigation of the intellectual development and the development of language did not reveal significant differences between the two groups. Also with regard to the cognitive partial functions (attention, visual differentiation, serial memory performance and visuomotor coordination) the prematures were significantly behind only in serial memory performance. On the other hand the results of the psychological investigations were significantly worse in children of lower social classes independent of birth weight.

Attention Deficit Disorder with Hyperactivity↗
PubMed1979

[A tapeworm infection with fatal outcome (author's transl)].

Parasitoses of the intestinal tract are rare in Europe. Their diagnosis is difficult since the general symptoms are frequently only little pronounced or completely lacking. On the other hand, the course of the disease may be fatal. Such cases from the literature and our own observations are intended to call to memory the differential diagnosis of intestinal parasitosis.

Aged↗
PubMed1980

Differential activation of primary and memory "B" lymphocytes.

Immunization of certain strains of mice with the tobacco mosaic virus protein (TMVP) elicits antibodies capable of binding with a decapeptide representing residues 103-112 of TMVP. However, immunization of mice with decapeptide conjugated to a variety of carriers failed to elicit antibodies to the decapeptide in spite of the fact that antibodies were induced to the carriers or to nonrelated peptides similarily conjugated to the carriers. In contrast to the conjugates inability to induce a primary anti-decapeptide response, the conjugates were able to elicit a secondary anti-decapeptide response. Thus, when irradiated mice were transplanted with syngeneic TMVP-primed B cells and carrier-primed T cells, secondary challenge with the decapeptide on the carrier elicited an excellent secondary anti-decapeptide response. Furthermore, the titer and specificity of the antibodies so induced were the same as that induced by secondary challenge with TMVP. These results suggest a difference between primary and memory B cells in their requirements for activation.

Animals↗
PubMed1983

Contribution of Lyb 5+ and Lyb 5- B cells to the primary and secondary phosphocholine-specific antibody response.

Due to a mutation on their X-chromosome, CBA/N mice lack the Lyb-5+ subset of B cells. The loss of this B cell subset results in a profound alteration in the immune response of these mice to the hapten phosphocholine (PC). Thus, when these mice are immunized with high doses of PC-KLH (200 micrograms) in CFA, they: 1) fail to produce IgM anti-PC antibodies; 2) produce little or no anti-PC antibody bearing the normally predominant T15-idiotype; and 3) produce IgG anti-PC antibodies only late in the primary response. In order to more fully delineate this defect in responsiveness to PC, the splenic focus assay was used to analyze Lyb-5- B cell precursors from both normal and immune defective mice. Lyb-5- cells were obtained from normal (CBA/N x DBA/2)F1 (CD) female spleens by treatment with anti-Lyb-5 serum and complement. These normal Lyb-5- cells and Lyb-5- cells from immune defective CD male mice were stimulated in vitro with either PC-Hy or TNP-Hy in the presence of Hy-primed T helper cells. The results demonstrate that primary Lyb-5- PC-specific B cells fail to respond in the splenic focus assay, while secondary Lyb-5- PC-specific precursors respond normally, and that both primary and secondary Lyb-5- TNP-specific precursors respond in the splenic focus assay. These data suggest that Lyb-5- PC-specific precursors must differentiate into memory cells before they can be activated to secrete antibody, and they also indicate that the Lyb-5- B cell subset may be composed of two subsets with different activation requirements.

Animals↗
PubMed1981

Control of growth related to pattern specification in chick wing-bud mesenchyme.

The distribution of raised mitotic index, and the co-incidence of this with lowered cell packing density, has been studied across the anteroposterior dimension of the terminal 500 mum of chick wing buds following various numbers of hours signalling from an anteriorly grafted extra Zone of Polarizing Activity (ZPA). The results show propagation of the situation that causes these correlated phenomena, from graft-host interface essentially right across the limb mesenchyme, frequently within 8 h. This contrasts with the much slower and more local succession of changes in position memory, for differentiation of a duplicated limb pattern, that also occurs in mesenchyme relatively close the the graft after this operation. The results are discussed, in relation to current ideas about the control of pattern during limb development.

Animals↗
PubMed1995

Phenotypic characterization of CD4+ T cells that exhibit a transendothelial migratory capacity.

The phenotype of CD4+ T cells capable of transendothelial migration was determined using an in vitro model system, in which cells migrate through a monolayer of endothelial cells (EC) on collagen gels. A specific subset of resting CD4+ memory T cells was found to migrate. T cells within this subset can be defined by the bright expression of CD11a, CD26, CD44, and CD49d. Additionally, the migratory CD4+ T cell population is largely CD58bright, CD31-, CD62L-, and is also enriched in cells that brightly express CD49c, CD49e, and CD49f. Only a minority of the cells are activated, as indicated by expression of CD69. The EC were found to play a central role in facilitating migration of this subset because selective enrichment of CD11abright, CD26bright, CD44bright, CD4+ T cells was not observed when cells migrated in the absence of EC. Activation of the T cells induced a modest degree of migration of an additional subset of CD45RA+, CD31+ naive T cells. In contrast, TNF-alpha activation of the EC increased the transendothelial migration of an additional subset of activated memory T cells that expressed CD69 and CD62L. Neither activation of the T cells, stimulation of the EC, nor the presence of macrophage inflammatory protein-1 alpha (MIP-1 alpha) or RANTES, however, altered the phenotype of the majority of the migratory CD4+ T cell population, which is characteristic of a particular stage of memory cell differentiation. These results suggest that CD4+ T cells acquire the capacity for transendothelial migration at a specific phase of maturation that is only minimally altered by the activation of either the T cell or the EC, or by the presence of specific chemokines in the subendothelial matrix.

Antigens, CD↗
PubMed1996

The B-cell development in tonsillar lymphoid follicles.

The palatine tonsils, and particularly the nasopharyngeal tonsil (adenoid), may be functionally comparable to nasal-associated lymphoid tissue in rodents. Primary follicles occur in human tonsils at 16 weeks' gestation, and formation of germinal centres (GC) takes place shortly after birth. The GC arise in T-cell-dependent B-cell responses and are associated with: i) clonal expansion; ii) somatic hypermutation in immunoglobulin variable (Ig V)-region genes; iii) positive selection of B cells based on affinity for antigen; iv) differentiation to memory B cells and plasma cells; and v) induction of the J-chain gene. The follicular dendritic cells (FDC) of GC retain native antigen which stimulates growth of B-cell blasts and hypermutation of their Ig V genes. The resulting centrocytes die by apoptosis unless they are selected by antigen. Cognate interaction between CD4+ helper T cells and B cells is important to promote downstream switching of the heavy chain constant (CH) genes. In human tonsillar GC this process normally gives rise mainly to IgG (55%-72%) and IgA (13%-18%) immunocytes, both isotypes normally being partially associated with J-chain expression (36% and 29%, respectively). Because J chain is a key peptide in secretory IgA, tonsillar GC may contribute precursor cells to mucosal effector sites. Thus, mucosal immunity can be induced in the airways by nasal immunization, and the level of nasopharyngeal and salivary secretory IgA is decreased after adenotonsillectomy.

Adenoidectomy↗
PubMed1997

Normal and malignant B-cell development with special reference to Hodgkin's disease.

During their development, B lymphocytes are repeatedly selected for the expression of an appropriate surface receptor: the pre-B-cell receptor at the pre-B-cell stage and surface immunoglobulin (Ig) at the transition from a pre-B cell to a mature B cell. Furthermore, stringent selection for B cells expressing high affinity antibodies operates when antigen-activated B cells proliferate within germinal centers (GC). Here, somatic point mutations are introduced into rearranged V region genes at a high rate, and B cells acquiring favorable mutations are selected to differentiate into memory B cells or plasma cells. In the frame of this developmental scheme, extending a recent analysis, we investigated 10 primary cases of Hodgkin's disease (HD) for B-lineage origin and clonality [1]. Single Hodgkin and Reed-Sternberg (H-RS) cells were micromanipulated from frozen tissue sections and analyzed by PCR for rearranged V genes. Clonal VH and/or V kappa/ V delta gene rearrangements were obtained from 9 of the cases. This shows that H-RS cells represent a clonal, B-lineage-derived population of tumor cells. Somatic mutations were found in all clonal VH gene rearrangements. Interestingly, mutations leading to stop codons in in-frame V gene rearrangements were detected in four cases. Since GC B cells acquiring such crippling mutations are usually efficiently eliminated within the GC, the finding of those mutations indicates that H-RS cells are derived from precursors within the GC that escaped apoptosis by a transforming event.

Animals↗
PubMed1997

Induction of germinal center B cell markers in vitro by activated CD4+ T lymphocytes: the role of CD40 ligand, soluble factors, and B cell antigen receptor cross-linking.

Following primary immunization, B cells differentiate to memory cells with help from T cells. The specialized path to B cell memory takes place in lymphoid germinal centers (GC), where mouse B cells up-regulate peanut agglutinin receptor (PNA-R), B7-2 (CD86), and MHC class II expression. Using an in vitro culture system, we have studied how different stimuli can enhance the expression of these markers. We show that PNA-R is up-regulated when splenic B cells are cocultured with anti-CD3-stimulated CD4+, but not CD8+, T cells and that this process requires CD40-CD40 ligand engagement. Increased expression of PNA-R is also inducible with supernatants of activated CD4+, but not CD8+, T cells in combination with mitogenic signals, such as anti-Ig, anti-CD40, or LPS, but not by either supernatants or mitogenic signals alone. Unlike with PNA-R, increased expression of B7-2 and I-A occurs in response to activated T cells of either CD4+ and CD8+ subsets or their supernatants, does not require CD40 costimulation, and is readily induced with mitogenic signals alone. Taken together, these results indicate that PNA-R up-regulation has more restricted signaling requirements than B7-2 or I-A, and that it can be induced/maintained by Ag receptor cross-linking or CD40 engagement, as long as there is an appropriate cytokine milieu.

Animals↗