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PubMed2005

How do follicular dendritic cells interact intimately with B cells in the germinal centre?

The germinal centre is a dynamic microenvironment where antigen-activated B cells rapidly expand and differentiate, generating plasma cells and memory B cells. These cellular events are accompanied by dramatic changes in the antibody molecules that undergo somatic hypermutation and isotype switching. Follicular dendritic cells (FDCs) are the stromal cells located in the germinal centre. Although the capacity of FDCs to present antigen to B cells through antigen-antibody complexes has been recognized for many years, additional critical functions of FDCs have only recently been recognized. FDCs prevent apoptosis of germinal centre B cells and stimulate cellular interaction and proliferation. Here, we review the FDC signalling molecules that have recently been identified, some of which offer potential therapeutic targets for autoimmune diseases and B-cell lymphomas.

B-Lymphocytes↗
PubMed2002

Type 1 immunity provides optimal protection against both mucosal and systemic Trypanosoma cruzi challenges.

Chagas' disease results from infection with Trypanosoma cruzi, a protozoan parasite that establishes systemic intracellular infection after mucosal invasion. We hypothesized that ideal vaccines for mucosally invasive, intracellular pathogens like T. cruzi should induce mucosal type 2 immunity for optimal induction of protective secretory immunoglobulin A (IgA) and systemic type 1 immunity protective against intracellular replication. However, differential mucosal and systemic immune memory could be difficult to induce because of reciprocal inhibitory actions between type 1 and type 2 responses. To test our hypotheses, we investigated the protective effects of type 1 and type 2 biased vaccines against mucosal and systemic T. cruzi challenges. Intranasal vaccinations were given with recombinant interleukin-12 (IL-12)- and IL-4-neutralizing antibody (Ab) for type 1 immune bias, or recombinant IL-4 and gamma interferon-neutralizing Ab for type 2 immune bias. Cytokine RNA and protein studies confirmed that highly polarized memory immune responses were induced by our vaccination protocols. Survival after virulent subcutaneous T. cruzi challenge was used to assess systemic protection. Mucosal protection was assessed by measuring the relative inhibition of parasite replication in mucosal tissues early after oral T. cruzi challenge, using both PCR and quantitative culture techniques. As expected, only type 1 responses protected against systemic challenges (P < 0.01). However, contrary to our original hypothesis, type 1 responses optimally protected against mucosal challenges as well (P < 0.05). Type 1 and type 2 biased vaccines induced similar secretory IgA responses. We conclude that future vaccines for T. cruzi and possibly other mucosally invasive, intracellular pathogens should induce both mucosal and systemic type 1 immunity.

Administration, Intranasal↗
PubMed2006

Leukemia-specific T-cell reactivity induced by leukemic dendritic cells is augmented by 4-1BB targeting.

PURPOSE: Acute myelogenous leukemia (AML) blasts are able to differentiate into leukemia-derived dendritic cells (AML-DC), thereby enabling efficient presentation of known and unknown leukemic antigens. Advances in culture techniques and AML-DC characterization justify clinical application. However, additional measures are likely needed to potentiate vaccines and overcome the intrinsic tolerant state of the patients' immune system. Engagement of the costimulatory molecule 4-1BB can break immunologic tolerance and increase CTL responses. In this study, we examined the role of the 4-1BB ligand (4-1BBL) on T-cell responses induced by AML-DC. EXPERIMENTAL DESIGN: In allogeneic and autologous cocultures of T cells and AML-DC, the effect of the addition of 4-1BBL on T-cell proliferation, T-cell subpopulations, and T-cell function was determined. RESULTS: Addition of 4-1BBL to cocultures of AML-DC and T cells induced a preferential increase in the proliferation of CD8(+) T cells. Increased differentiation into effector and central memory populations was observed in both CD4(+) and CD8(+) T cells in the presence of 4-1BBL. AML-DC induce a T helper 1 response, characterized by high IFN-gamma production, which is significantly increased by targeting 4-1BB. T cells primed in the presence of 4-1BBL show specificity for the leukemia-associated antigen Wilms' tumor 1, whereas cytotoxicity assays with leukemic blast targets showed the cytolytic potential of T cells primed in the presence of 4-1BBL. CONCLUSION: We conclude that 4-1BBL is an effective adjuvant to enhance T-cell responses elicited by AML-DC.

CD8-Positive T-Lymphocytes↗
PubMed1994

Neuropsychological differences between college students with learning disabilities and those with mild head injury.

College students with learning disabilities (LD) and those with a history of mild head injury (MHI) are two groups whose learning problems are not adequately addressed. We administered a comprehensive battery of neuropsychological, psychological, and academic achievement tests to college students with learning problems (LD, n = 35; MHI, n = 25) and a control group (n = 22), and completed a series of discriminant function analyses. A combination of six neuropsychological and psychoeducational test variables produced statistically significant differences among the three groups. The instruments were sensitive to LD, MHI, and the differences between them. The students with LD performed poorly on linguistically oriented psychoeducational tests, whereas the students with MHI showed cognitive deficits in visual-spatial skills and in the areas of attention, memory, and novel problem solving. Differential interventions addressing these deficits appear to be indicated.

Adolescent↗
PubMed2026

CSNK1E sustains stemlike drug persistence in diffuse large B-cell lymphoma.

Relapsed or refractory (R/R) disease occurs in up to 40% of patients with diffuse large B-cell lymphoma (DLBCL) following first-line immunochemotherapy. However, the molecular mechanisms underlying drug persistence remain incompletely defined. In this study, we performed single-cell RNA and B-cell receptor sequencing on paired diagnostic and R/R samples from 8 patients who were either treatment-refractory or relapsed after remission, and validated our findings in 3 independent patient cohorts. We found that drug-persistent cells exhibited a transcriptional profile indicative of a less-differentiated state and adopted a memory B-cell-like program with enhanced stemlike properties, which correlated with unfavorable clinical outcomes across multiple DLBCL cohorts. Functionally, drug-persistent cells showed significantly increased in vitro clonogenicity and in vivo tumor-initiating capacity. Mechanistically, the WNT signaling regulator casein kinase 1&#x25b; (CSNK1E) was upregulated in these stemlike drug-persistent cells, in part through the activation of the A proliferation-inducing ligand (APRIL)-TNFRSF13B axis. Notably, CSNK1E inhibition impaired the growth and tumor-initiating capacity of drug-persistent cells and potentiated the efficacy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-based treatment, both in vitro and in vivo. Together, our study reveals the stemlike transcriptional and functional properties of drug-persistent cells, and identifies CSNK1E as a critical mediator and therapeutic vulnerability that may improve the efficacy of standard immunochemotherapy in DLBCL.

Lymphoma, Large B-Cell, Diffuse↗
PubMed1999

Sensitization components of post-traumatic stress disorder: implications for therapeutics.

Behavioral sensitization to psychomotor stimulants and stressors involves increasing reactivity to repetition of the same dose (or intensity) of the stimulus over time. In cocaine-induced behavioral sensitization, conditioned components are prominent and the underlying pharmacological and neuroanatomical substrates differ as a function of stage of its evolution. Since there is cross-sensitization between cocaine-induced behavioral sensitization and stress-induced behavioral sensitization and, as well, a high comorbidity of stimulant abuse with post-traumatic stress disorder, many of the mechanisms and principles of cocaine-induced behavioral sensitization may be pertinent to post-traumatic stress disorder. The extent and duration of cocaine-induced behavioral sensitization/stress-induced behavioral sensitization are a function of age, genetic strain, and gender of the organism, as well as magnitude, frequency, duration, quality, and environmental contingencies of the inducing stimuli. These effect a spatiotemporal evolution of cascades of alterations in gene expression involving a host of immediate early and late effector genes, including neurotrophic and apoptotic factors. They may change the physiology, biochemistry, and neuroanatomy of the developing brain and, in adults, substrates critical for learning and memory. Suggestions are made for differential strategies of therapeutic intervention as primary prevention, in the immediate post-traumatic period, and in the late phases of post-traumatic stress disorder evolution.

Animals↗
PubMed1995

The effects of interaction with the device described by procedural text on recall, true/false, and task performance.

In two experiments, subjects interacted to different extents with relevant devices while reading two complex multistep procedural texts and were then tested with task performance time, true/false, and recall measures. While reading, subjects performed the task (read and do), saw the experimenter perform the task (read and see experimenter do), imagined doing the task (read and imagine), looked at the device while reading (read and see), or only read (read only). Van Dijk and Kintsch's (1983) text representation theory led to the prediction that exposure to the task device (in the read-and-do, read-and-see, and read-and-see-experimenter-do conditions) would lead to the development of a stronger situation model and therefore faster task performance, whereas the read-only and read-and-see conditions would lead to a better textbase, and therefore better performance on the true/false and recall tasks. Paivio's (1991) dual coding theory led to the opposite prediction for recall. The results supported the text representation theory with task performance and recall. The read-and-see condition produced consistently good performance on the true/false measure. Amount of text study time contributed to recall performance. These findings support the notion that information available while reading leads to differential development of representations in memory, which, in turn, causes differences in performance on various measures.

Adult↗
PubMed2001

Role of CD28 for the generation and expansion of antigen-specific CD8(+) T lymphocytes during infection with Listeria monocytogenes.

Infection of mice with the intracellular bacterium Listeria monocytogenes results in a strong CD8(+) T cell response that is critical for efficient control of infection. We used CD28-deficient mice to characterize the function of CD28 during Listeria infection, with a main emphasis on Listeria-specific CD8(+) T cells. Frequencies and effector functions of these T cells were determined using MHC class I tetramers, single cell IFN-gamma production and Listeria-specific cytotoxicity. During primary Listeria infection of CD28(-/-) mice we observed significantly reduced numbers of Listeria-specific CD8(+) T cells and only marginal levels of specific IFN-gamma production and cytotoxicity. Although frequencies were also reduced in CD28(-/-) mice during secondary response, we detected a considerable population of Listeria-specific CD8(+) T cells in these mice. In parallel, IFN-gamma production and cytotoxicity were observed, revealing that Listeria-specific CD8(+) T cells in CD28(-/-) mice expressed normal effector functions. Consistent with their impaired CD8(+) T cell activation, CD28(-/-) mice suffered from exacerbated listeriosis both after primary and secondary infection. These results demonstrate participation of CD28 signaling in the generation and expansion of Ag-specific CD8(+) T cells in listeriosis. However, Ag-specific CD8(+) T cells generated in the absence of CD28 differentiated into normal effector and memory T cells.

Animals↗
PubMed1999

Cholinergic septal afferent terminals preferentially contact neuropeptide Y-containing interneurons compared to parvalbumin-containing interneurons in the rat dentate gyrus.

Septal cholinergic neurons may affect hippocampal memory encoding and retrieval by differentially targeting parvalbumin (PARV)-containing basket cells and neuropeptide Y (NPY) interneurons. Thus, the cellular associations of cholinergic efferents, identified by the low-affinity, p75 neurotrophin receptor (p75(NTR)), with interneurons containing either PARV or NPY in the hilus of the rat dentate gyrus were examined in single sections using dual labeling immunoelectron microscopy. Most profiles immunoreactive (IR) for PARV and NPY were perikaryal and dendritic and found within the infragranular and central hilar regions, respectively, whereas most profiles with p75(NTR)-labeling were unmyelinated axons and axon terminals. Although PARV-labeled profiles were more numerous, p75(NTR)-labeled axons and terminals contacted few PARV-IR profiles compared to NPY-labeled profiles (2% of 561 for PARV vs 12% of 433 for NPY). Moreover, structures targeted by p75(NTR)-IR axon terminals varied depending on the presence of PARV or NPY immunoreactivity. p75(NTR)-IR terminals primarily contacted PARV-IR dendrites (87%) compared to somata (13%); however, they contacted more NPY-IR somata (57%) than dendrites (43%). p75(NTR)-labeled terminals formed exclusively symmetric (inhibitory-type) synapses with PARV-IR somata and dendrites; however, they formed mostly symmetric but also asymmetric (excitatory-type) synapses with NPY-IR somata and dendrites. These results suggest that septal cholinergic efferents in the dentate gyrus: (1) preferentially innervate NPY-containing interneurons compared to PARV-containing basket cells; and (2) may provide a more powerful (i.e., somatic contacts), yet functionally diverse (i.e., asymmetric and symmetric synapses), modulation of NPY-containing interneurons. Moreover, they provide evidence that neurochemical subsets of hippocampal interneurons can be distinguished by afferent input.

Afferent Pathways↗
PubMedDate not supplied

[Concerning a conflict nature of the "spatial delayed response" test].

Neuropsychological analysis of rats' performance of the spatial delayed response (SDR) in different testing conditions revealed a conflict nature of the indirect variation of the SDR task. It was found that the execution of the response based on the image short-term memory interferes with the response differentiation acquired during learning the rule of indirect SDR performance, i.e., during acquisition of the spatial discrimination. It is evident that the maximization of conditions, which promote the acquisition of response differentiation (additional training of animals for spatial discrimination), makes it difficult to perform the indirect variation of the SDR task, while the minimization of these conditions facilitates the correct task performance.

Animals↗
PubMed1992

[Demonstration of dissociation between frontal and temporal lesions in man on two versions of delayed non-matching recognition tests used in monkeys].

11 patients with frontal lobe lesions (F group), 9 patients with temporal lobe lesions (T group) and 18 normal control subjects (C group) were tested on two versions of the delayed non matching-to-sample task using either different pairs (DNMTS) or the same pairs of objects (RECURRENT) on successive test trials. The results revealed that the DNMTS task was sensitive to memory impairment but did not differentiate the two experimental groups. In contrast, the recurrent version of the task showed a dissociation between the two pathologies. Thus, whereas patients of group T exhibited an accelerated rate of forgetting as a function of the retention interval, patients of group F were impaired whatever the retention interval.

Adult↗
PubMed1995

[Follicular dendritic cells: phenotype, origin and functions].

Follicular dendritic cells (FDC) are only located in lymph node follicles and particularly developed in the light zones of the germinal centers. FDC differ on important points from the classical dendritic cells presenting antigens to T cells. They are long-lived and derived from local mesenchymal cells. Their complex cytoplasmic extensions, covered with dendrites, are intermingled in a network which surrounds germinal B and T cells. On their surface, receptors fix immune complexes without endocytosis and adhesion molecules ensure close contacts to the lymphoid cells. FDC influence the migration, activation, proliferation, survival and differentiation of B cells into memory cells and probably act also on the germinal center T cells.

Acquired Immunodeficiency Syndrome↗
PubMed1999

[Correlations between brain SPECT and neuropsychology assessments in mild and moderate stages of Alzheimer's disease].

UNLABELLED: Thirty-four patients with a probable Alzheimer's Disease (AD) (mild AD = 16; moderate AD = 18) and 12 matched controls were evaluated using semiquantitative SPECT-99mTc-HMPAO and neuropsychological tests (CERAD). RESULTS: Both temporal hypoperfusion (p < 0.01) and memory tests (p < 0.001) made it possible to differentiate the controls from mild AD patients. In these patients, significant correlations (p < 0.05) were also found between: 1) delayed recall test/temporal hypoperfusion, 2) learning memory test/temporoparietal and frontal hypoperfusion and 3) visual constructive praxis/posterior temporal hypoperfusion. In contrast to mild AD, moderate AD patients showed higher temporal (p < 0.01) parietal and frontal (p < 0.05) hypoperfusion along with worsening of praxis (p < 0.001) and memory tests (p < 0.05). CONCLUSIONS: SPECT imaging and neuropsychology evaluation can distinguish controls from AD patients with mild an moderate grades of dementia, showing a strong correlation from the early stages of AD.

Aged↗
PubMed2003

Lorazepam and scopolamine: A single-dose comparison of effects on human memory and attentional processes.

This placebo-controlled, double-blind, double-dummy, independent groups study directly compared effects of the benzodiazepine, lorazepam (2.0 mg/70 kg orally administered), and the anticholinergic scopolamine (0.6 mg/70 kg subcutaneously administered) on memory and attentional measures hypothesized to differentiate the drugs. At the studied doses, lorazepam and scopolamine produced similar decrements in psychomotor performance, free recall, and overall sensitivity in distinguishing between studied and nonstudied items on a recognition memory test. However, the drugs differed with respect to effects on working memory, response bias, metacognition, subjective awareness, and selective attention. In addition to providing information about the cognitive psychopharmacological profiles of drugs with distinct neurochemical and pharmacological mechanisms of action, this study also informs the understanding of memory and attentional processes.

Adult↗
PubMed1993

Memory effectors: a potent, IL-4-secreting helper T cell population that develops in vivo after restimulation with antigen.

Resting CD4+ memory T cells from the spleens of mice primed more than 6 wk earlier with KLH in adjuvant produce IL-2 and IL-3, but only low levels of IL-4 and IFN-gamma, and undetectable IL-5 after specific restimulation in vitro. In contrast, when previously primed mice are boosted by i.v. injection of soluble KLH, a CD4+ T cell population develops in the spleen that can produce greatly increased levels of IL-4, and variably increased IL-2, IFN-gamma, and/or IL-3. The ability of these memory effector Th cells to be restimulated to secrete cytokines is maximal by 3 days after in vivo boosting with Ag, and declines rapidly thereafter. Memory effector Th are induced in the spleens of KLH-primed mice that have been depleted of precursor T cells by thymectomy more than 25 wk previously, suggesting that they are derived from a memory T cell population. Cell separation on the basis of CD45RB or MEL-14, surface markers that are down-regulated on memory CD4+ cells, indicates that memory effector Th are in the CD45RBlo and MEL-14- subsets of CD4+ T cells. The frequency of KLH-specific splenic CD4+ T cells with the capacity to secrete cytokines in limiting dilution cultures is very low in unprimed mice (1/3 x 10(4) to 1/9 x 10(4)), but increases as much as 50-fold after priming. IL-2, but not IL-4, can be detected in the supernatants of stimulated unprimed CD4+ T cells. Both IL-2- and IL-4-producing cells are readily detected after priming, and frequencies of IL-2-secreting cells (1/250 to 1/4000) are up to ninefold greater than those for IL-4 secreting cells. Boosting elicits variable (two to eightfold) increases in the frequencies of both IL-2- and IL-4-producing CD4+ T cells. However, high IL-4 titers associated with memory effector Th function can be obtained when significant frequency changes are not detected after boosting. The data suggest that reactivation of resting memory Th in vivo induces their differentiation into effector Th with the capacity to secrete much higher levels of IL-4. Although the capacity to produce high levels of IL-4 is associated with both primary and memory CD4+ effector populations, memory effector Th are the higher producers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Vasopressin and memory. II. Lesions to the hippocampus block the memory enhancing effects of AVP4-9 in the radial maze.

Previous work has shown that the arginine vasopressin fragment AVP4-9 enhanced overall performance in the radial arm maze. This enhancement effect was due to improved working memory as well as to improved reference memory. The present study uses a behavioral approach to investigate whether these effects of vasopressin on memory are mediated by the hippocampus. Animals received either NMDA lesions to the hippocampus or sham operations and were then treated with AVP4-9 or saline. The testing was performed in an eight-arm radial maze for 60 sessions, and all injections were given s.c. 30 min prior to testing. The hippocampal lesioned animals showed a marked deficit in working memory that was not ameliorated by AVP4-9; however, the improvement in reference memory produced by the compound was as large as in healthy animals. Since the AVP treatment did not differentiate between the two hippocampal groups, the memory enhancing effects of AVP4-9 were blocked by hippocampal lesions. It is concluded that vasopressin has a more general effect on memory and that its site of action includes but is not limited to the hippocampus.

Animals↗
PubMedDate not supplied

[Interdisciplinary research strategies in geriatric psychiatry--studies and results in dementia and depressed patients].

Eighty-one patients (mean age: 66 +/- 9 years) who had been in gerontopsychiatric in-patient care were included in the study. As well as physical, psychiatric and neurological examinations, EEG, brain CT scanning and the determination of the Ischemic Scale were performed, in order to confirm the clinical diagnosis of dementia of Alzheimer type (DAT), dementia of vascular type (DVT) or multi-infarct dementia (MID), and depression in old age, as based on the DSM III criteria. A comprehensive psychological test battery was administered, to one section of the subjects. Our results indicate that EEG and Ischemic Score can differentiate patients with DAT and DVT to a satisfactory degree, whereas CT findings and psychometric assessment were apt to confirm the overall diagnosis of dementia (DAT/DVT) and depression. Patients with dementia showed memory impairment to a greater extent than depressive patients, as could be proved by a memory test (Syndrom-Kurztest). However, a dementia screening test (Information-Memory-Concentration Test) could more accurately differentiate dementia and depression. The application of a comprehensive psychometric testing procedure did not prove to be an effective diagnostic tool in the assessment of various stages of dementia. Short dementia tests and rating scales seem to be appropriate to distinguish depression from dementia, especially in cases of mild to moderate dementia. In patients with very mild and insignificant organic brain disturbances these screening methods fall short of diagnostic validity. Beyond this, there is a current need for assessment instruments in the evaluation of alterations in personality and affectivity, such as are seen in depression.

Aged↗
PubMed2006

Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease.

Individuals with X-linked lymphoproliferative disease (XLP) display defects in B cell differentiation in vivo. Specifically, XLP patients do not generate a normal number of CD27 memory B cells, and those few that are present are IgM. Recent studies have suggested that IgMCD27 B cells are not true memory cells, but rather B cells that guard against T cell-independent pathogens. Here we show that human XLP IgMCD27 B cells resemble normal memory B cells both morphologically and phenotypically. Additionally, IgMCD27 B cells exhibited functional characteristics of normal memory B cells, including the ability to secrete more Ig than naive B cells in response to both T cell-dependent and -independent stimuli. Analysis of spleens from XLP patients revealed a paucity of germinal centers (GCs), and the rare GCs detected were poorly formed. Despite this, Ig variable region genes expressed by XLP IgMCD27 B cells had undergone somatic hypermutation to an extent comparable to that of normal memory B cells. These findings reveal a differential requirement for the generation of IgM and Ig isotype-switched memory B cells, with the latter only being generated by fully formed GCs. Production of affinity-matured IgM by IgMCD27 B cells may protect against pathogens to which a normal immune response is elicited in XLP patients.

Adolescent↗