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PubMed2006

Modelling two possible mechanisms for the regulation of the germinal center dynamics.

Research on the germinal center has tried to unravel the mechanisms that control its dynamics. In this study we focus on the termination of the germinal center reaction, which is still an open problem. We propose two hypothetical biological mechanisms that may be responsible for the control of germinal center dynamics and analyze them through mathematical models. The first one is based on the differentiation of follicular dendritic cells and/or T cells. Interaction of these cells in the differentiated state with germinal center B cells would promote B cell differentiation into memory B cells and Ab-forming cells, ending the germinal center reaction. The second mechanism applies only to a scenario without recycling and consists of the decay of a hypothetical proliferation signal for centroblasts that limits the number of cell divisions. Each of the models makes predictions that can be experimentally tested.

Animals↗
PubMed2007

Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK.

Foreign CpG-DNA from viruses and bacteria can activate memory B cells through binding to toll-like receptor 9, and this pathway has been hypothesized to be involved in the continuous activation of memory B cells ensuring life-long humoral immunity. In this study, we demonstrate that retinoic acid (RA) is a potent coactivator of this pathway in human B cells. RA enhanced the CpG-mediated proliferation of CD27(+) memory B cells, and the proliferative response was accompanied by increased immunoglobulin (Ig) secretion indicative of plasma-cell formation. The RA-induced proliferation was preceded by enhanced expression of cyclin D3, and both the expression of cyclin D3 and the induced Ig secretion were found to be dependent on IL-10. Of importance, RA increased the CpG-induced phosphorylation of ERK1/2, p38MAPK, and IkappaB as early as 30 minutes after stimulation. By using specific inhibitors, all the RA-mediated events, including proliferation, cyclin D3 expression, IL-10 secretion, and Ig secretion, were shown to be dependent on p38MAPK. Hence, we propose that RA can strengthen humoral immunity by promoting CpG-mediated stimulation of CD27(+) B cells via activation of p38MAPK resulting in increased proliferation and differentiation to Ig-secreting plasma cells.

Adjuvants, Immunologic↗
PubMed2004

Differential analysis of CD4+ Th memory clones with identical T-cell receptor (TCR)-alphabeta rearrangement (non-transgenic), but distinct lymphokine phenotype, reveals diverse and novel gene expression.

This study describes a subtractive hybridization analysis to identify differences in gene expression between sibling Th memory clones, elicited by virus infection and expressing identical T-cell receptor (TCR)-alphabeta rearrangements but distinct lymphokine phenotype: clone Bpp9 secretes interleukin (IL)-4, IL-5 and IL-10; clone Bpp19 secretes interferon (IFN)-gamma, low levels of IL-4, and IL-5 on TCR ligation. cDNA sequencing of difference products (DP) identified both novel and known regulatory (DNA: RNA-binding) or signalling proteins (kinases: phosphatases). Of the 10 novel genes identified, three were putative membrane proteins, one a predicted nuclear protein containing a PEST sequence motif, one a predicted transporter fragment and one contained a zinc-finger motif. One of the membrane proteins was found only in RNA from the activated IFN-gamma-producing clone, i.e. not in other tissues. In addition, a high frequency of granzyme A, B, C and G transcripts (for clone Bpp9) or transcripts for CD94 and NKG2A (for clone Bpp19) were expressed differentially, together with transcripts that mapped to, so far, unassigned regions of the mouse genome that may be further novel genes. The transcriptional profiles presented here may therefore include candidate regulators of Th diversity and effector function.

Animals↗
PubMed2003

Extensive MHC class I-restricted CD8 T lymphocyte responses against various yeast genera in humans.

The human cellular immune response against 14 distantly related yeast species was analyzed by intracellular cytokine staining of lymphocytes after ex vivo stimulation of whole blood. While the CD4 T cell response was marginal, extensive MHC class I-restricted CD8 T cell responses were detected against a number of species including spoiling, environmental and human pathogenic yeasts. The yeast-specific CD8 T cells expressed interferon-gamma but lacked expression of CD27 and CCR7, indicating that they were end-differentiated effector memory cells. Mainly intact yeast cells rather than spheroplasts were able to induce cytokine expression in T cells demonstrating that the dominant immunogens were located in the yeast cell wall. Together these data underline the importance of the cellular immune response in protecting humans against yeast and fungal infections. And, from another perspective, recombinant yeast suggests itself as a potential vaccine candidate to efficiently induce antigen-specific CD8 T cell responses.

Adult↗
PubMed1999

CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha.

CC-chemokine receptor (CCR) 6 is the only known receptor for macrophage inflammatory protein (MIP)-3alpha, a CC chemokine chemotactic for lymphocytes and dendritic cells. Using anti-serum that we raised against the N-terminal residues of CCR6, we have characterized the surface expression of CCR6 on peripheral blood leukocytes and we have correlated CCR6 expression with responses to MIP-3alpha. We found that CCR6 was expressed only on memory T cells, including most alpha4beta7 memory cells and cutaneous lymphocyte-associated Ag-expressing cells, and on B cells. Accordingly, chemotaxis of T cells to MIP-3alpha was limited to memory cells. Moreover, calcium signals on T cells in response to MIP-3a were confined to CCR6-expressing cells, consistent with CCR6 being the only MIP-3alpha receptor on peripheral blood T cells. Unlike many CC chemokines, MIP-3alpha produced a calcium signal on freshly isolated T cells, and CCR6 expression was not increased by up to 5 days of treatment with IL-2 or by cross-linking CD3. Despite their surface expression of CCR6, freshly isolated B cells did not respond to MIP-3alpha. In addition to staining peripheral blood leukocytes, our anti-serum detected CCR6 on CD34+ bone marrow cell-derived dendritic cells. Our data are the first to analyze surface expression of CCR6, demonstrating receptor expression on differentiated, resting memory T cells, indicating differences in receptor signaling on T cells and B cells and suggesting that CCR6 and MIP-3alpha may play a role in the physiology of resting memory T cells and in the interactions of memory T cells, B cells, and dendritic cells.

Cell Line↗
PubMed2006

Persistent cytomegalovirus-specific memory responses in the lung allograft and blood following primary infection in lung transplant recipients.

Primary CMV infection in lung transplant recipients (LTRs) is associated with increased mortality. We studied 22 donor CMV-positive, recipient-negative (D(+)R(-)) LTRs for the development of posttransplant CMV-specific immunity. We found that 13 of 22 D(+)R(-) LTRs (59.1%) seroconverted (CMV IgG Ab(+)). Using pooled peptides of the immunodominant CMV Ags pp65 and IE1, we detected CMV-specific CD8(+)IFN-gamma(+) T cells in the PBMC of 90% of seroconverted individuals following primary infection by intracellular cytokine staining. In contrast, few seroconverters had detectable CMV-specific CD4(+)IFN-gamma(+) T cells during viral latency. However, the majority of IgG(+) LTRs demonstrated CMV-specific CD4(+) and CD8(+) T cell proliferative responses from PBMC, with CD4(+)IFN-gamma(+) T cells detectable upon re-expansion. Examination of lung allograft mononuclear cells obtained by bronchoalveolar lavage revealed both CMV-specific CD4(+) and CD8(+)IFN-gamma(+) T cells, including patients from whom CD4(+)IFN-gamma(+) T cells were simultaneously undetectable in the PBMC, suggesting differential effector memory populations between these compartments. Moreover, both responses in the PBMC and lung allograft were found to persist, despite substantial immunosuppression, long after primary infection. Clinical correlation in this cohort demonstrated that the acquisition of CMV immunity was associated with freedom from CMV disease (p < or = 0.009) and preservation of allograft function (p < or = 0.02) compared with those who failed to develop CMV immunity. Together, our data reveal immunologic heterogeneity in D(+)R(-) LTRs, with the development and persistence of primary CMV responses that may provide clinical benefit.

Adolescent↗
PubMed2003

Alterations in the phenotype of CMV-specific and total CD8+ T-cell populations in Wegener's granulomatosis.

Wegener's granulomatosis (WG) is an autoimmune disease of as yet unknown etiology. To date it has remained obscure what causes WG or determines disease progression. Case reports suggest that viral infections such as cytomegalovirus (CMV) reactivation may contribute to disease flares. In this study we found a skewing of the phenotype of CMV-specific CD8+tet(ramer)+ T-cells in WG. A marked proportion of these cells displayed a late differentiated "effector memory" T-cell phenotype with decreased expression of CD28 and CD62L, and heterogeneous CD27 expression, features which were also seen in CD8+tet- T-cells in WG, but not in controls. Our results might reflect profound generalized changes in the CD8+ T-cell compartment also affecting virus-specific T-cell responses in WG.

ADP-ribosyl Cyclase↗
PubMed1998

Mutation, selection, and memory in B lymphocytes of exothermic vertebrates.

Unlike mammals, cold-blooded vertebrates produce antibodies of low heterogeneity that show little increase in binding affinity with time after immunization. In secondary responses, antibody titers and affinities are often little, if any, higher than in primary responses. That is, specificity, diversity, and memory--the hallmarks of the immune system--are rather meager in the humoral immune responses of exothermic vertebrates. As the genetic components of the immunoglobulin (Ig) gene systems in fishes, amphibians or reptiles are not deficient in number or diversity, their responses probably do not stem from restrictions in the primary antibody repertoire. Somatic hypermutation at the Ig locus, which generates diversity and higher affinity antibodies in mammals, is not lacking in the South African frog Xenopus or in the shark. However, the Ig mutants recovered are strongly biased toward alterations at GC pairs, an indication that they have not undergone effective selection. While cells resembling follicular dendritic cells are present in cold-blooded vertebrates, germinal centers do not form. It is suggested that this absence of germinal centers, the site of selection for the mutants with higher affinity receptors and of differentiation into memory B cells in mammals, may explain the principal differences between cold and warm-blooded vertebrates.

Alleles↗
PubMed2005

Modulation of interleukin-7 receptor expression characterizes differentiation of CD8 T cells specific for HIV, EBV and CMV.

OBJECTIVES: To further understand differentiation and homeostasis of CD8 T cells specific for HIV, Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) during HIV infection, we investigated interleukin-7 receptor alpha (IL-7Ralpha) expression on those virus-specific T cells. METHODS: Microarrays and cytometry analyses were performed on peripheral blood mononuclear cells (PBMC), total and tetramer-binding virus-specific CD8 T cells from 66 HIV-infected patients. RESULTS: Microarray analysis revealed reduced levels of IL-7Ralpha and increased levels of perforin with disease progression in total PBMC. This loss of IL-7Ralpha expression was observed on CD8 T cells and was inversely related to perforin expression. The relative expression of both molecules defined three new subsets: IL-7Ralpha(pos)Perforin(neg); IL-7Ralpha(loneg)Perforin(lo); and IL-7Ralpha(loneg)Perforin(hi) corresponding to naive and effector-memory CD8 differentiation, as assessed by CD45RA/CD11a. The IL-7Ralpha expression decreased along the CD8 differentiation pathway defined by CD27 and CD28. In contrast, IL-7Ralpha expression was down-modulated on all the CD8 T cells specific for HIV, EBV and CMV that were almost exclusively IL-7Ralpha(lo/neg)Perforin(lo) and was parallel with the CD27 expression. In addition, this low IL-7Ralpha expression on HIV-specific CD8 T cells was independent of virus load and T-cell activation and remained stable during the first 6 months of antiretroviral therapy despite successful control of HIV replication. CONCLUSION: The relative expression of IL-7Ralpha, perforin reveals new aspects of virus-specific CD8 T cell differentiation, independently of T-cell activation and virus load. This opens new perspectives for understanding homeostasis of those cells and immune-based therapeutic strategies.

Antiretroviral Therapy, Highly Active↗
PubMed2005

The clinical utility of structural neuroimaging with MRI for diagnosis and differential diagnosis of dementia: a memory clinic study.

OBJECTIVES: The individual contribution to the final comprehensive clinical diagnosis of neuropsychology (NP) and magnetic resonance imaging (MRI), respectively, was quantified in a specialized tertiary care setting to investigate the added clinical value of routine MRI. METHODS: In 106 patients referred to a university memory clinic for the work-up of cognitive disturbances the primary care diagnosis, the initial clinical neuropsychiatric diagnosis, the neuropsychological and MRI diagnoses, and the final comprehensive clinical diagnosis were documented. The neuropsychological investigation was performed using the CERAD test battery. MRI was performed using T1, double echo and FLAIR sequences without contrast medium. The change of the final comprehensive clinical diagnosis in relation to the initial neuropsychiatric diagnosis was used to determine the diagnostic contribution of both, MRI and NP. RESULTS: NP and MRI led to a significant change of the final comprehensive diagnosis in 26% of patients (CI: 0.26 +/- 0.09; p < 0.05). In addition, three cases of secondary dementias, and six cases of vascular encephalopathy without dementia were recognized by MRI. Sensitivity, specificity, and the positive predictive value were higher for NP and MRI, respectively, than for the initial clinical diagnosis alone. CONCLUSION: MRI as well as neuropsychological testing improves early detection and differential diagnosis of dementia and additionally supplies clinically relevant findings. MRI carries added clinical value in the investigation of dementias.

Aged↗
PubMed1976

Immunoglobulin M receptors on memory cells of immunoglobulin G antibody-forming cell clones.

The memory cells of two antibody-forming cell clones had receptors of the IgM class, even though the clones had been producing IgG1 or IgG2a anti-2,4-dinitrophenyl antibodies for 9-15 months previously (on exposure to antigen). Thus a phenotypic switch in heavy chain constant region evidently occurred after re-exposure of these memory cells to antigen. To show that, we first removed the clonal cells' surface immunoglobins by "capping" and "stripping", with class- or subclass-specific antisera. Then, to assay their remaining receptor activity, the cells were incubated with antigen in vitro, washed and transferred (together with carrier primed cells) to irradiated recipients, and their antibody responses to this in vitro boost were assayed by iselectric focusing. Pretreatment with anti-mu serum, as well as with anti-Fab(kappa), prevented the responses of the IgG1 and IgG2a clones to an in vitro boost, while anti-gamma1 and anti-gamma2a antisera had no effect. An antiserum to the putative mouse IgD also had no effect. The anti-mu serum failed to react with the IgG1 and IgG2A clonal serum antibodies in the test tube. Some other contaminating clones were suppressed completely only by the anti-Fab serum. This result strongly suggests that switching in class commitment may occur during the differentiation of memory cells to antibody producers, and may therefore be antigen-dependent. It also implies that some apparently naive cells with surface IgM may, in reality, be B memory cells.

Animals↗
PubMed2006

Differential sensitivity of naïve and memory subsets of human CD8+ T cells to TNF-alpha-induced apoptosis.

In this investigation, we have examined the relative sensitivity of human naïve, central memory (T(CM)), and two types of effector memory CD8+ T cells (T(EM) and T(EMRA)) to TNF-alpha-induced apoptosis. Our data show that naïve and T(CM) CD8+ T cells were sensitive, whereas T(EM) and T(EMRA) CD8+ T cells were relatively resistant to TNF-alpha-induced apoptosis. The apoptosis profile correlated with the activation of caspase-8 and caspase-3. However, no correlation was observed between relative sensitivity of four CD8+ T cell subsets to apoptosis and the expression of TNFR-I or TNFR-II. T(EM) and T(EMRA) CD8+ T cells displayed increased phosphorylation of IKKalpha/beta and IkappaB and increased NF-kappaB activity as compared to naïve and T(CM) CD8+ T cells. Bcl-2, Bcl-x(L) and FLIP(L) expression was higher and Bax expression was lower in T(EM) and T(EMRA) CD8+ T cells as compared to naïve and T(CM) CD8+ T cells. These data suggest that signaling molecules downstream of TNFRs may be responsible for differential sensitivity among subsets of CD8+ T cells to TNF-alpha-induced apoptosis.

Adult↗
PubMed2006

Cognitive dysfunction in patients with relapsing-remitting multiple sclerosis.

Cognitive dysfunction is considered one of the clinical markers of multiple sclerosis (MS). However, in the literature there are inconsistent reports on the prevalence of cognitive dysfunction, and separate data for the relapsing-remitting (RR) type of the disease are not always presented. In this study, we submitted 461 RRMS patients to a battery of neuropsychological tests to investigate their impairment in various cognitive domains. As a consequence of the exclusion criteria, the sample is not fully representative of the entire population of RRMS patients. In this selected sample, when only the eight scores of a core battery (Mental Deterioration Battery) were considered (with respective cutoffs), it emerged that 31% of the patients were affected by some degree of cognitive deficit. In particular, 15% had mild, 11.2% moderate and 4.8% had severe impairment. Information processing speed was the most frequently impaired area, followed by memory. When two other tests (SDMT and MCST) were added and cognitive domains were considered, it emerged that 39.3% of the patients were impaired in two or more domains. When four subgroups were obtained by means of cluster analysis and then compared, it emerged that information processing speed and memory deficits differentiated the still cognitively unimpaired from the mildly impaired MS patients. Significant associations were found between cognitive and clinical characteristics. However, due to the large sample size, clinically irrelevant relationships may also have emerged. Even with the limitations imposed by the sample selection and the possible underestimation of the prevalence and severity of cognitive dysfunction, these results seem to provide further evidence that information processing speed deficit may be an early and important marker of cognitive impairment in MS patients.

Adult↗
PubMed1998

Regulation of adhesion and migration in the germinal center microenvironment.

T cell dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell homing to the GC and interaction with FDC critically depend on integrin-mediated adhesion. We have recently indentified the c-met-encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signalling pathway regulating B cell adhesion (van der Voort et al., 1997, J. Exp. Med. 185, 2121-2131). The c-Met protein is expressed on B cells localized in the dark zone of the GC (centroblasts) and is induced by CD40 plus BCR ligation. Stimulation of c-Met with HGF/SF, which is produced at high levels by tonsillar stromal cells and FDC, leads to receptor phosphorylation and to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Interestingly, these responses to HGF/SF are promoted by heparan-sulfate proteoglycan forms of CD44 (CD44-HS). Like c-Met, CD44-HS is induced on B cells by CD40 ligation. It efficiently binds HGF/SF and strongly promotes signalling through c-Met. We conclude that integrin regulation during antigen specific B cell differentiation involves cross-talk between the HGF/SF-c-Met pathway and CD44-HS.

Animals↗
PubMed2002

Molecular pharmacological dissection of short- and long-term memory.

1. It has been discussed for over 100 years whether short-term memory (STM) is separate from, or just an early phase of, long-term memory (LTM). The only way to solve this dilemma is to find out at least one treatment that blocks STM while keeping LTM intact for the same task in the same animal. 2. The effect of a large number of treatments infused into the hippocampus, amygdala, and entorhinal, posterior parietal or prefrontal cortex on STM and LTM of a one-trial step-down inhibitory avoidance task was studied. The animals were tested at 1.5 h for STM, and again at 24 h for LTM. The treatments were given after training. 3. Eleven different treatments blocked STM without affecting LTM. Eighteen treatments affected the two memory types differentially, either blocking or enhancing LTM alone. Thus, STM is separate from, and parallel to the first hours of processing of, LTM of that task. 4. The mechanisms of STM are different from those of LTM. The former do not include gene expression or protein synthesis; the latter include a double peak of cAMP-dependent protein kinase activity, accompanied by the phosphorylation of CREB, and both gene expression and protein synthesis. 5. Possible cellular and molecular events that do not require mRNA or protein synthesis should account for STM. These might include a hyperactivation of glutamate AMPA receptors, ribosome changes, or the exocytosis of glycoproteins that participate in cell addition.

Animals↗
PubMed1988

Automatic and effortful processing in attention deficit/hyperactivity disorder.

Twenty-five boys with Attention Deficit/Hyperactivity Disorder and 23 age-matched controls were compared on verbal memory tasks differentiating automatic versus effortful information processing. Automatic processing tasks included the recognition of new or old words in a list and the recognition of frequency of occurrence of words in a list. Effortful tasks included free recall of lists of both related and unrelated words. Hyperactive boys did not differ from controls in automatic processing capabilities but demonstrated significantly poorer effortful processing. Intercorrelations of the variables revealed high correlations between scores on effortful measures and also raise questions about the purity of automaticity in some tasks employed. Stepwise discriminant analysis demonstrated that free recall of related words (an effortful task) best discriminated between groups. Effort-related processing in hyperactive and normal children is discussed in relation to variables of motivation, affect, arousal, and other higher-order cognitive processes.

Arousal↗
PubMed1995

[Functional memory disorders. A study of 25 patients].

Twenty-five patients without relevant organic disease were examined who complained of long-standing memory disturbance, but were free of relevant organic disease and exhibited a test performance that was normal, or reduced by not more than two standard deviations. Cases of amnesia in the context of dissociative reactions were not considered. Symptoms attributed to memory disturbance were differentiated into deficits of new learning, retrograde memory and attention. Typical complaints were forgetting plans on the way to executing them and temporary blockage of material that had been committed to memory. While sex and age were evenly distributed, there was a clear predominance of professionals compared to manual workers. Relevant psychiatric findings or psychiatric diagnoses were present in all cases. The most frequent diagnoses were chronic stress disorder and depressive syndromes. Accompanying psychosomatic symptoms were present in about half of the cases. Wordlist learning scores were in the normal range in the majority of cases, and psychomotor speed scores were in the normal range in nearly all cases. The discussion addresses symptoms, diagnosis, etiology and therapy of functional memory disturbances and examines the relationship to the syndrome of pseudodementia.

Adult↗
PubMed2007

The germinal center response is impaired in the absence of T cell-expressed CXCR5.

Germinal centers support the differentiation of memory B cells and long-lived antibody-secreting cells during infection or upon vaccination. Here, we constructed mice with T cells that selectively lack the chemokine receptor CXCR5 to determine if expression of this receptor by T cells is mandatory for germinal center formation and function. In these animals, germinal centers that are properly localized in B cell follicles and contain T cells do form after immunization with a thymus-dependent antigen. However, fewer and smaller germinal centers form, resulting in a significant reduction in the frequency of germinal center B cells. The defect in germinal center formation is paralleled by decreased frequencies of isotype-switched antibody-secreting cells in the spleen and bone marrow and reduced serum concentrations of total and high-affinity hapten-specific IgG1. The results demonstrate that although CXCR5-dependent T cell positioning is important for maximal induction and expansion of germinal centers, stimulation of isotype class switching, and development of antibody-secreting cells that seed the spleen and bone marrow, it is not absolutely required for the formation and function of follicular germinal centers.

Animals↗