Self tolerance to T cell receptor V beta sequences.

T cell tolerance to self is achieved by deletion or inactivation of clones recognizing peptides of self proteins presented by major histocompatibility complex molecules. A considerable fraction of self proteins accessible to the immune system is contributed by the system itself, for example, the receptors used for antigen recognition (antibodies and T cell receptors [TCRs]). Thus far, it has remained unclear, whether antigen receptors are subject to self tolerance, or on contrary, engage into network interactions implying immunity rather than tolerance. In this study, we demonstrate self tolerance to synthetic peptides corresponding to the first hypervariable region of the V beta 8.1 and V beta 8.2 TCR proteins. We also show that the tolerogenic synthetic peptide corresponds to a fragment produced by processing of the V beta protein, and conversely, that a V beta peptide not produced by processing is also not subject to self tolerance. Thus, the rules of tolerance seem to apply to antigen receptors, at least to their germline-encoded portions, in a similar fashion as to other self proteins. This finding has important implications for studies of natural and artificially induced immune networks.

Linear differentiation of cytotoxic effectors into memory T lymphocytes.

A central question in immunology is the origin of long-lived T cell memory that confers protection against recurrent infection. The differentiation of naïve T cell receptor transgenic CD8+ cells into effector cytotoxic T lymphocytes (CTLs) and memory CD8+ cells was studied. Memory CD8+ cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effectors and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice. Thus, potential vaccines based on CTL memory will require the differentiation of naïve cells into post-effector memory T cells.

Crystal structure of the V alpha domain of a T cell antigen receptor.

The crystal structure of the V alpha domain of a T cell antigen receptor (TCR) was determined at a resolution of 2.2 angstroms. This structure represents an immunoglobulin topology set different from those previously described. A switch in a polypeptide strand from one beta sheet to the other enables a pair of V alpha homodimers to pack together to form a tetramer, such that the homodimers are parallel to each other and all hypervariable loops face in one direction. On the basis of the observed mode of V alpha association, a model of an (alpha beta)2 TCR tetramer can be positioned relative to the major histocompatibility complex class II (alpha beta)2 tetramer with the third hypervariable loop of V alpha over the amino-terminal portion of the antigenic peptide and the corresponding loop of V beta over its carboxyl-terminal residues. TCR dimerization that is mediated by the alpha chain may contribute to the coupling of antigen recognition to signal transduction during T cell activation.

The stoichiometry and affinity of the interaction of murine Fc fragments with the MHC class I-related receptor, FcRn.

The binding of recombinant wild type and mutant Fc-hinge fragments to soluble, FcRn expressed in insect cells has been analysed. The mutant Fc-hinge fragments are derived from murine IgG1 with mutation of residues located at the CH2-CH3 domain interface (Ile253, His31O, Gln311, His433 and Asn434; EU numbering). These mutant Fc-hinge fragments have previously been shown to be deficient in neonatal transcytosis in suckling mice and also have abnormally short serum half lives. The mutated residues are highly conserved in human and rodent gammaglobulins (IgGs) and are also involved in binding to staphylococcal protein A. This study demonstrates that the Fc mutants have lower binding affinities for recombinant FcRn and mutations in the CH2 domain have a greater effect than those in the CH3 domain. There is an excellent correlation between affinity and transcytosis or the control of catabolism, and this provides further evidence in support of the close overlap of the sites of IgG/Fc involved in these processes. The stoichiometry of the FcRn:Fc interaction has also been investigated and has been found to be 1:1, indicating that binding of FcRn to one CH2-CH3 domain interface site precludes an FcRn:Fc interaction at the second site.

Differences in lateral hemispheric asymmetries of glucose utilization between early- and late-onset Alzheimer-type dementia.

Positron emission tomography with [18F]fluorodeoxyglucose revealed greater right than left hemispheric impairment of cortical glucose metabolism in patients with probable Alzheimer's disease who were younger than 65 but not in those over 65. This asymmetry was related to poor visuospatial performance.

Clinical and neurocognitive aspects of source monitoring errors in schizophrenia.

OBJECTIVE: Source monitoring, an aspect of memory that involves judgments about the origin of information, has been found to be more prone to errors in schizophrenic subjects than in normal persons. To examine the precise nature of such errors and their relationship to clinical and neurocognitive variables, the authors compared schizophrenic and normal subjects. METHOD: Schizophrenic subjects who had been medication free for 1 week (N = 26) and demographically matched normal subjects (N = 21) performed a source monitoring task and were assessed on current psychiatric symptoms, IQ, and frontal lobe functioning. RESULTS: The schizophrenic subjects had normal recognition memory of target words (recognition hits) and a normal generation effect but made more errors than the comparison subjects in identifying the source of target words. Specifically, the schizophrenic subjects made more errors in remembering the source of new and self-generated items, and they tended to attribute items to an external source. In 11 retested subjects, these errors were stable and independent from medication status after a 2-year interval. Secondary analyses suggested that certain source monitoring errors may be associated with hostility and lower IQ. When the effect of IQ was controlled, correlations with frontal dysfunction were not significant. CONCLUSIONS: Schizophrenic subjects make significantly more source monitoring errors than normal subjects, but not because of problems with recognition memory hits or with the generation effect. This tendency may be trait like and may be related to hostility. Lower IQ in schizophrenia plays a partial role in these errors, but frontal dysfunction does not.

Longitudinal studies of regional cerebral metabolism in Alzheimer's disease.

Measurement of cerebral glucose metabolism in six patients with Alzheimer's disease using positron emission tomography demonstrated that hypometabolism remained relatively more severe in parietal cortex than in frontal cortex over time. Lateral metabolic asymmetries were preserved in less severely involved brain regions, but were less stable in parietal cortex.

Memory and regional cerebral blood flow in mildly symptomatic Alzheimer's disease.

We performed SPECT perfusion imaging and memory testing with mildly and moderately demented Alzheimer's disease (AD) patients and with healthy controls. All patients had memory abnormalities, but 5 of the 21 patients had neither temporal nor parietal perfusion abnormalities, indicating that temporoparietal blood flow may be normal at a point when memory is pathologic and the clinical diagnosis of AD is possible.

Regional cerebral glucose transport and utilization in Alzheimer's disease.

We performed dynamic positron emission tomographic (PET) studies of glucose utilization, using (18F) 2-fluoro-2-deoxy-D-glucose (FDG), in patients with probable Alzheimer's disease (AD) and healthy age-matched controls, to evaluate blood-brain-barrier glucose transport and glucose utilization rates in the disease. We found no significant differences in rate constants for glucose transport (k1 and k2) and phosphorylation (k3), nor for the vascular fraction (fv), between the 2 groups, although k3 and fv were relatively depressed in temporal cortex in AD. Absolute rates of glucose use were depressed in temporal and parietal cortex, and relative rCMRglc rates were lower in frontal, temporal, parietal, and occipital cortices. These data suggest that in AD bidirectional glucose transport is intact, and that temporal-parietal hypometabolism is present upon a background of widespread cortical metabolic impairment.

Lexical decision and priming in Alzheimer's disease.

Patients with probable Alzheimer's disease (AD) were no faster at making lexical decisions to targets preceded by a semantic prime than to those preceded by an unrelated prime, in contrast to the facilitatory effect of semantic primes for controls. Fewer errors were made by both subject groups on the targets that followed related items, indicating the preservation of associative relationships in AD. The AD patients and controls showed similar effects on lexical decision of repetition priming, word frequency, and the degree to which nonwords approximated real words. The abnormal priming effect in AD may stem from increased susceptibility to lateral inhibition in the semantic network.

Generation and characterization of recombinant vascular targeting agents from hybridoma cell lines.

Vascular targeting agents (VTAs) can be produced by linking antibodies or antibody fragments directed against endothelial cell markers to effector moieties. So far, it has been necessary to produce the components of VTAs (antibody, antibody fragment, linker, and effector) separately and, subsequently, to conjugate them by biochemical reactions. We devised a cloning and expression system to allow rapid generation of recombinant VTAs from hybridoma cell lines. The VTAs consist of a single chain Fv antibody fragment as a targeting moiety and either truncated Pseudomonas exotoxin (resulting in immunotoxins) or truncated human tissue factor (resulting in coaguligands) as effectors. The system was applied to generate recombinant immunotoxins and coaguligands directed against endoglin, vascular endothelial growth factor (VEGF):VEGF receptor (VEGFR) complex and vascular cell adhesion molecule 1 (VCAM-1). The fusion proteins exhibited similar functional activity to analogous biochemical constructs. This is the first report to describe the generation and characterization of recombinant coaguligands.

Semantic priming of word pronunciation and lexical decision in schizophrenia.

Experimental assessments of semantic memory structure and function in schizophrenic subjects can be a useful approach for delineating some of the information processing deficits in schizophrenia. In this study, a pronunciation and a lexical decision semantic priming experiment were conducted with 19 schizophrenic subjects and 20 normal controls. A short stimulus-onset asynchrony (250 msec) and a relatively low proportion of related prime-target pairs were used in order to examine automatic priming and in order to avoid the contribution of attentional, controlled processes. On the pronunciation task, schizophrenic subjects showed a significant priming effect, equal to the priming shown by normal controls. However, on the lexical decision task, schizophrenics, unlike normal controls, did not show a priming effect which is significantly greater than zero, even though the group difference in priming effect (interaction of priming effect by group) was nonsignificant. The lack of priming on the lexical decision task is consistent with the hypothesis that schizophrenic subjects may show abnormalities in the realm of post-lexical, controlled information processing. The equal-to-normal priming for schizophrenic subjects indicates that the basic structure of the semantic network, including associations among related concepts, is intact in schizophrenia, and that spreading activation also occurs normally.

Slower and more variable reaction times in schizophrenia: what do they signify?

Extensive research has demonstrated that schizophrenic subjects are slower than normal comparison subjects on a range of reaction-time tasks. Some investigators have also observed that schizophrenic patients exhibit larger intraindividual variability in reaction times when performing these tasks than do normal comparison subjects. This study, using a lexical decision choice reaction time (CRT) task, explored the relation of mean CRT and it intra-individual variability (CRT-SD) to psychiatric symptoms and to performance on executive-motor tasks in 26 medication-free schizophrenic out-patients and 17 normal comparison subjects. Schizophrenic subjects had both significantly slower and more variable CRTs which were unrelated to general intellectual abilities (IQ). Among schizophrenic subjects, both CRT and CRT-SD were significantly related to severity of psychotic symptoms, failure to maintain cognitive set, and poorer motor coordination and global functioning. After controlling for mean CRT, CRT-SD showed unique covariation with clinical symptoms (positive, disorganized and tension/hostility). Conversely, mean CRT showed unique covariation with the failure to maintain cognitive set and with stereotypic mannerisms, independent of CRT-SD. These results suggest that slower CRT and increased intra-individual variability in CRT, while not fully independent of one another, may reflect separate aspects of symptomatic and cognitive dysfunction in schizophrenia.

Saccadic intrusions in Alzheimer-type dementia.

Horizontal eye-movement responses of four patients with Alzheimer-type dementia were recorded using the infrared oculographic technique. Abnormally frequent saccadic intrusions occurred during the fixation and slow, smooth pursuit tasks in all four patients. Saccadic intrusions have previously been reported in the literature to occur in normals, in strabismus, in patients with certain neurological disorders, and in schizophrenic patients. This is the first report of a group of Alzheimer-type dements with an eye movement abnormality which cannot be regarded as an ocularmotor reflection of diffuse cerebral dysfunction.

Alzheimer's disease: anterior-posterior and lateral hemispheric alterations in cortical glucose utilization.

We performed dynamic positron emission tomographic studies with [18F]fluorodeoxyglucose in 17 subjects with presumed Alzheimer's disease (AD) and 7 healthy aged subjects. Glucose metabolism was depressed by 27% in temporal-parietal cortex of the AD group, as compared to healthy aged controls. This focal impairment in temporal-parietal glucose use was found in all AD subjects. In addition, the AD group showed a striking lateral asymmetry of cortical metabolism not favoring either hemisphere, which has not been previously reported. Relationships between these focal changes and behavioral features of the illness were demonstrated. These results have important implications for the diagnosis and perhaps the etiology of Alzheimer's disease.

Automatic versus controlled semantic priming in schizophrenia.

Schizophrenic individuals (n = 31), including paranoid and nonparanoid diagnostic subgroups, and normal controls (n = 20) participated in a semantic priming experiment involving a single-choice lexical decision task. For the automatic priming blocks, a 260-ms stimulus onset asynchrony (SOA) was used; for the controlled priming blocks, 1,000-ms SOA was used. The paranoid subgroup showed significantly less priming than did the control group. The nonparanoid subgroup showed a decrease in priming compared with the control group that approached significance. There was an increased priming effect for the controlled compared with the automatic priming condition; this difference was not modulated by participant group. Nonsignificant semantic priming (equal to 0) occurred only for schizophrenic subgroups and only in automatic priming conditions.

Conceptual implicit memory performance in Alzheimer's disease.

Alzheimer's disease (AD) patients often exhibit deficits on conceptual implicit memory tests such as category exemplar generation and word association. However, these tests rely on word production abilities, which are known to be disrupted by AD. The current study assessed conceptual implicit memory performance in AD patients and elderly control participants using a conceptual priming task that did not require word production (i.e., semantic decision). Memory performance was also examined using a category exemplar generation test (i.e., a conceptual priming task that required word production) and a recognition memory test. AD patients exhibited deficits on the semantic decision task, the category exemplar generation task, and the recognition memory task. The results indicate that the conceptual memory deficits observed in AD patients cannot be attributed completely to word production difficulties.

Influence of continuous infusion of interleukin-1 alpha on the core protein and the core protein fragments of the small proteoglycan decorin in cartilage.

Decorin, a collagen-binding small proteoglycan, is considered to have a specific function in the organization or stability of the collagen network. Therefore, alteration of its molecular properties may be of pathophysiological relevance during the development of cartilage damage. It is shown here that normal cartilage from rabbit knee-joint contains glycosaminoglycan chain-bearing core protein fragments of 39, 23, and 18 kDa, each one amounting to approximately 5-6% of the intact decorin core protein. Continuous infusion of human recombinant interleukin-1 alpha for 14 days (200 ng/day) into a knee-joint led in condylar cartilage to a reduction in the amount of intact core protein from 2 micrograms/mg wet tissue to about 1.1 micrograms/mg. The increase in its quantity found after infusion of heat-inactivated interleukin-1 was not statistically significant. The concentration of all three core protein fragments became reduced to a similar extent as the intact core protein under the influence of the cytokine, and additional fragments were not found. Surprisingly, there was a much smaller response to interleukin-1-treatment in patellar cartilage.

Methodological control of semantic priming in Alzheimer's disease.

We conducted a lexical-decision, semantic priming experiment that included 250- and 1000-ms stimulus onset asynchronies (SOAs) with 32 probable Alzheimer's disease (AD) and 40 older normal persons. Attention-based, controlled processes are assumed to occur only at the longer of the 2 SOAs. The AD group showed greater than normal priming in the long-SOA but not the short-SOA condition. We conclude that greater than normal AD priming is a function of controlled processing rather than semantic network degradation.

Naturally occurring and experimentally induced tip-of-the-tongue experiences in three adult age groups.

Tip-of-the-tongue (TOT) experiences were examined in 30 young (ages 18-24 years), 30 young-old (ages 60-74), and 30 old-old (ages 80-92) adults. In Study 1, TOT experiences were experimentally induced with definitions of to-be-retrieved targets. If the target was not retrieved, orthographic or semantic cues were provided. Age-related increases in the occurrence of TOT experiences and in the time needed to resolve TOT experiences were found for young versus young-old and young-old versus old-old groups; all comparisons were significant except for young versus young-old TOT occurrence, which approached significance. In Study 2, the same participants recorded naturally occurring TOT experiences in structured diaries during a 4-week interval. Both the number of TOT experiences and the resolution time for TOT experiences increased with age. However, the percentage of TOT experiences resolved was equal across age groups; given enough time, even the oldest participants resolved virtually all TOT experiences.