Motor congruency and multisensory integration jointly facilitate visual information processing before movement execution.

Attention allows us to select important sensory information and enhances sensory information processing. Attention and our motor system are tightly coupled: attention is shifted to the target location before a goal-directed eye- or hand movement is executed. Congruent eye-hand movements to the same target can boost the effect of this pre-movement shift of attention. Moreover, visual information processing can be enhanced by, for example, auditory input presented in spatial and temporal proximity of visual input via multisensory integration (MSI). In this study, we investigated whether the combination of MSI and motor congruency can synergistically enhance visual information processing beyond what can be observed using motor congruency alone. Participants performed congruent eye- and hand movements during a 2-AFC visual discrimination task. The discrimination target was presented in the planning phase of the movements at the movement target location or a movement irrelevant location. Three conditions were compared: (1) a visual target without sound, (2) a visual target with sound spatially and temporally aligned (MSI) and (3) a visual target with sound temporally misaligned (no MSI). Performance was enhanced at the movement-relevant location when congruent motor actions and MSI coincide compared to the other conditions. Congruence in the motor system and MSI together therefore lead to enhanced sensory information processing beyond the effects of motor congruency alone, before a movement is executed. Such a synergy implies that the boost of attention previously observed for the independent factors is not at ceiling level, but can be increased even further when the right conditions are met.

Visually Induced Inhibition of Return Affects the Integration of Auditory and Visual Information.

Multisensory integration (MSI) and exogenous spatial attention can both speedup responses to perceptual events. Recently, it has been shown that audiovisual integration at exogenously attended locations is reduced relative to unattended locations. This effect was observed at short cue-target intervals (200-250 ms). At longer intervals, however, the initial benefits of exogenous shifts of spatial attention at the cued location are often replaced by response time (RT) costs (also known as Inhibition of Return, IOR). Given these opposing cueing effects at shorter versus longer intervals, we decided to investigate whether MSI would also be affected by IOR. Uninformative exogenous visual spatial cues were presented between 350 and 450 ms prior to the onset of auditory, visual, and audiovisual targets. As expected, IOR was observed for visual targets (invalid cue RT < valid cue RT). For auditory and audiovisual targets, neither IOR nor any spatial cueing effects were observed. The amount of relative multisensory response enhancement and race model inequality violation was larger for uncued as compared with cued locations indicating that IOR reduces MSI. The results are discussed in the context of changes in unisensory signal strength at cued as compared with uncued locations.

Audiovisual integration in near and far space: effects of changes in distance and stimulus effectiveness.

A factor that is often not considered in multisensory research is the distance from which information is presented. Interestingly, various studies have shown that the distance at which information is presented can modulate the strength of multisensory interactions. In addition, our everyday multisensory experience in near and far space is rather asymmetrical in terms of retinal image size and stimulus intensity. This asymmetry is the result of the relation between the stimulus-observer distance and its retinal image size and intensity: an object that is further away is generally smaller on the retina as compared to the same object when it is presented nearer. Similarly, auditory intensity decreases as the distance from the observer increases. We investigated how each of these factors alone, and their combination, affected audiovisual integration. Unimodal and bimodal stimuli were presented in near and far space, with and without controlling for distance-dependent changes in retinal image size and intensity. Audiovisual integration was enhanced for stimuli that were presented in far space as compared to near space, but only when the stimuli were not corrected for visual angle and intensity. The same decrease in intensity and retinal size in near space did not enhance audiovisual integration, indicating that these results cannot be explained by changes in stimulus efficacy or an increase in distance alone, but rather by an interaction between these factors. The results are discussed in the context of multisensory experience and spatial uncertainty, and underline the importance of studying multisensory integration in the depth space.

The influence of vertically and horizontally aligned visual distractors on aurally guided saccadic eye movements.

Eye movements towards a new target can be guided or disrupted by input from multiple modalities. The degree of oculomotor competition evoked by a distractor depends on both distractor and target properties, such as distractor salience or certainty regarding the target location. The ability to localize the target is particularly important when studying saccades made towards auditory targets, since determination of elevation and azimuth of a sound are based on different processes, and these processes may be affected independently by a distractor. We investigated the effects of a visual distractor on saccadic eye movements made to an auditory target in a two-dimensional plane. Results showed that the competition evoked by a vertical visual distractor was stronger compared with a horizontal visual distractor. The eye movements that were not captured by the vertical visual distractor were still influenced by it: a deviation of endpoints was seen in the direction of the visual distractor. Furthermore, the interference evoked by a high-contrast visual distractor was stronger compared with low-contrast visual stimuli, which was reflected by a faster initiation of an eye movement towards the high-contrast visual distractor and a stronger shift of endpoints in the direction of the high-contrast visual distractor. Together, these findings show that the influence of a visual distractor on aurally guided eye movements depends strongly on its location relative to the target, and to a lesser extent, on stimulus contrast.

Non-lateralized auditory input enhances averaged vectors in the oculomotor system.

The decision about which location should be the goal of the next eye movement is known to be determined by the interaction between auditory and visual input. This interaction can be explained by the vector theory that states that each element (either visual or auditory) in a scene evokes a vector in the oculomotor system. These vectors determine the direction in which the eye movement is initiated. Because auditory input is lateralized and localizable in most studies, it is currently unclear how non-lateralized auditory input interacts with the vectors evoked by visual input. In the current study, we investigated the influence of a non-lateralized auditory non-target on saccade accuracy (saccade angle deviation from the target) and latency in a single-target condition in Experiment 1 and a double-target condition in Experiment 2. The visual targets in Experiment 2 were positioned in such a way that saccades on average landed in between the two targets (i.e., a global effect). There was no effect of the auditory input on saccade accuracy in the single-target condition, but auditory input did influence saccade accuracy in the double-target condition. In both experiments, saccade latency increased when auditory input accompanied the visual target(s). Together, these findings show that non-lateralized auditory input enhances all vectors evoked by visual input. The results will be discussed in terms of their possible neural substrates.

Molecular evolution of the human immunoglobulin E response: high incidence of shared mutations and clonal relatedness among epsilon VH5 transcripts from three unrelated patients with atopic dermatitis.

We have analyzed the nucleotide sequences of 19 epsilon VH5 transcripts derived from in vivo isotype switched peripheral blood B cells of three patients with atopic dermatitis. Comparison with the patients' own germline VH5 gene segments revealed that the epsilon transcripts were derived from both functional members of the human VH5 gene family and harbored numerous somatic mutations (range 5-36 per VH5 gene). In two patients, we detected clonally related but diverged transcripts, permitting the construction of a genealogical tree in one patient. We observed a high proportion of shared silent (S) and replacement (R) mutations among epsilon VH5 sequences derived from all three individuals, even among transcripts descending from the two different germline VH5 gene segments. A remarkably high number of these mutations is shared with previously reported VH5 genes encoding antibodies with defined specificities. The shared S mutations, and likely a fraction of the R mutations, appear to mark preferential sites ("hot spots") of somatic hypermutations in human VH5 genes. The distribution of R and S mutations over complementarity determining region and framework regions in the majority of VH regions deviated from that characteristic of antigen-driven immune response. We hypothesize that the V regions of immunoglobulin E-bearing B cells have accumulated "selectively neutral" mutations over extended periods of clonal expansion, resulting in unusual R/S ratios. We propose that the molecular characteristics of the epsilon VH regions in atopic dermatitis may be representative of antigens that recurrently or chronically stimulate the immune system.

Class switching in B cells lacking 3' immunoglobulin heavy chain enhancers.

The 40-kb region downstream of the most 3' immunoglobulin (Ig) heavy chain constant region gene (Calpha) contains a series of transcriptional enhancers speculated to play a role in Ig heavy chain class switch recombination (CSR). To elucidate the function of this putative CSR regulatory region, we generated mice with germline mutations in which one or the other of the two most 5' enhancers in this cluster (respectively referred to as HS3a and HS1,2) were replaced either with a pgk-neor cassette (referred to as HS3aN and HS1,2N mutations) or with a loxP sequence (referred to as HS3aDelta and HS1,2Delta, respectively). B cells homozygous for the HS3aN or HS1,2N mutations had severe defects in CSR to several isotypes. The phenotypic similarity of the two insertion mutations, both of which were cis-acting, suggested that inhibition might result from pgk-neor cassette gene insertion rather than enhancer deletion. Accordingly, CSR returned to normal in B cells homozygous for the HS3aDelta or HS1,2Delta mutations. In addition, induced expression of the specifically targeted pgk-neor genes was regulated similarly to that of germline CH genes. Our findings implicate a 3' CSR regulatory locus that appears remarkably similar in organization and function to the beta-globin gene 5' LCR and which we propose may regulate differential CSR via a promoter competition mechanism.

Assessing a single SNP located at TERT/CLPTM1L multi-cancer risk region as a genetic modifier for risk of pancreatic cancer and melanoma in Dutch CDKN2A mutation carriers.

Carriers of pathogenic variants in CDKN2A have a 70% life-time risk of developing melanoma and 15-20% risk of developing pancreatic cancer (PC). In the Netherlands, a 19-bp deletion in exon 2 of CDKN2A (p16-Leiden mutation) accounts for most hereditary melanoma cases. Clinical experience suggests variability in occurrence of melanoma and PC in p16-Leiden families. Thereby, the risk of developing cancer could be modified by both environmental and genetic contributors, suggesting that identification of genetic modifiers could improve patients' surveillance. In a recent genome-wide association study (GWAS), rs36115365-C was found to significantly modify risk of PC and melanoma in the European population. This SNP is located on chr5p15.33 and has allele-specific regulatory activities on TERT expression. Herein, we investigated the modifying capacities of rs36115365-C on PC and melanoma in a cohort of 283 p16-Leiden carriers including 29 diagnosed with PC, 171 diagnosed with melanoma, 21 diagnosed with both PC and melanoma and 62 with neither PC nor melanoma. In contrast to previously reported findings, we did not find a significant association of PC risk with risk variant presence as determined by Generalized Estimating Equations (GEE) modelling. Interestingly, carrier-ship of the risk variant had a significant protective effect for melanoma (OR - 0.703 [95% CI - 1.201 to - 0.205], p = 0.006); however, the observed association was no longer significant after exclusion of probands to assess possible influence of ascertainment. Collectively, genetic modifiers for the prediction of PC and melanoma risk in p16-Leiden carriers remain to be determined.

On the relative contributions of multisensory integration and crossmodal exogenous spatial attention to multisensory response enhancement.

Two processes that can give rise to multisensory response enhancement (MRE) are multisensory integration (MSI) and crossmodal exogenous spatial attention. It is, however, currently unclear what the relative contribution of each of these is to MRE. We investigated this issue using two tasks that are generally assumed to measure MSI (a redundant target effect task) and crossmodal exogenous spatial attention (a spatial cueing task). One block of trials consisted of unimodal auditory and visual targets designed to provide a unimodal baseline. In two other blocks of trials, the participants were presented with spatially and temporally aligned and misaligned audiovisual (AV) targets (0, 50, 100, and 200ms SOA). In the integration block, the participants were instructed to respond to the onset of the first target stimulus that they detected (A or V). The instruction for the cueing block was to respond only to the onset of the visual targets. The targets could appear at one of three locations: left, center, and right. The participants were instructed to respond only to lateral targets. The results indicated that MRE was caused by MSI at 0ms SOA. At 50ms SOA, both crossmodal exogenous spatial attention and MSI contributed to the observed MRE, whereas the MRE observed at the 100 and 200ms SOAs was attributable to crossmodal exogenous spatial attention, alerting, and temporal preparation. These results therefore suggest that there may be a temporal window in which both MSI and exogenous crossmodal spatial attention can contribute to multisensory response enhancement.

Exogenous spatial attention decreases audiovisual integration.

Multisensory integration (MSI) and spatial attention are both mechanisms through which the processing of sensory information can be facilitated. Studies on the interaction between spatial attention and MSI have mainly focused on the interaction between endogenous spatial attention and MSI. Most of these studies have shown that endogenously attending a multisensory target enhances MSI. It is currently unclear, however, whether and how exogenous spatial attention and MSI interact. In the current study, we investigated the interaction between these two important bottom-up processes in two experiments. In Experiment 1 the target location was task-relevant, and in Experiment 2 the target location was task-irrelevant. Valid or invalid exogenous auditory cues were presented before the onset of unimodal auditory, unimodal visual, and audiovisual targets. We observed reliable cueing effects and multisensory response enhancement in both experiments. To examine whether audiovisual integration was influenced by exogenous spatial attention, the amount of race model violation was compared between exogenously attended and unattended targets. In both Experiment 1 and Experiment 2, a decrease in MSI was observed when audiovisual targets were exogenously attended, compared to when they were not. The interaction between exogenous attention and MSI was less pronounced in Experiment 2. Therefore, our results indicate that exogenous attention diminishes MSI when spatial orienting is relevant. The results are discussed in terms of models of multisensory integration and attention.

Multisensory interactions in the depth plane in front and rear space: a review.

In this review, we evaluate the neurophysiological, neuropsychological, and psychophysical evidence relevant to the claim that multisensory information is processed differently depending on the region of space in which it happens to be presented. We discuss how the majority of studies of multisensory interactions in the depth plane that have been conducted to date have focused on visuotactile and audiotactile interactions in frontal peripersonal space and underline the importance of such multisensory interactions in defining peripersonal space. Based on our review of studies of multisensory interactions in depth, we question the extent to which peri- and extra-personal space (both frontal and rear) are characterized by differences in multisensory interactions (as evidenced by multisensory stimuli producing a different behavioral outcome as compared to unisensory stimulation). In addition to providing an overview of studies of multisensory interactions in different regions of space, our goal in writing this review has been to demonstrate that the various kinds of multisensory interactions that have been documented may follow very similar organizing principles. Multisensory interactions in depth that involve tactile stimuli are constrained by the fact that such stimuli typically need to contact the skin surface. Therefore, depth-related preferences of multisensory interactions involving touch can largely be explained in terms of their spatial alignment in depth and their alignment with the body. As yet, no such depth-related asymmetry has been observed in the case of audiovisual interactions. We therefore suggest that the spatial boundary of peripersonal space and the enhanced audiotactile and visuotactile interactions that occur in peripersonal space can be explained in terms of the particular spatial alignment of stimuli from different modalities with the body and that they likely reflect the result of prior multisensory experience.

Lack of CIITA expression is central to the absence of antigen presentation functions of trophoblast cells and is caused by methylation of the IFN-gamma inducible promoter (PIV) of CIITA.

Lack of MHC-mediated antigen presenting functions of fetal trophoblast cells is an important mechanism to evade maternal immune recognition. In this study we demonstrated that the deficiency in MHC expression and antigen presentation in the trophoblast cell lines JEG-3 and JAR is caused by lack of class II transactivator (CIITA) expression due to hypermethylation of its interferon-gamma (IFN-gamma)-responsive promoter (PIV). Circumvention of this lack of CIITA expression by introduction of exogenous CIITA induced cell surface expression of HLA-DR, -DP, and -DQ, leading to an acquired capacity to present antigen to antigen-specific T cells. Transfection of CIITA in JEG-3 cells also upregulated functional HLA-B and HLA-C expression. Noteworthy, this lack of IFN-gamma-mediated induction of CIITA was also found to exist in normal trophoblast cells expanded from chorionic villus biopsies. Together, these observations demonstrate that lack of CIITA expression is central to the absence of antigen presentation functions of trophoblast cells.

Transcriptional control of MHC genes in fetal trophoblast cells.

Tight control of MHC expression is essential for the outcome of a successful pregnancy. The lack of MHC class II and class I mediated antigen presentation by fetal trophoblast cells is an important mechanism to evade maternal immune recognition. Interestingly, the deficient expression of MHC class II molecules (HLA-DR, -DQ and -DP) and of the classical MHC class I molecules HLA-A and HLA-B is also noted after IFN-gamma treatment in trophoblast-derived cell lines. Our studies show that in trophoblast cell lines the IFN-gamma induced transactivation of HLA-A and HLA-B promoters is repressed. Furthermore, it was found that trophoblast cells lacked IFN-gamma mediated induction of the class II transactivator (CIITA). This lack of CIITA expression in trophoblast cells is due to CIITA promoter hypermethylation. In addition to lack of CIITA expression, trophoblast cells also displayed a repressed expression of RFX5. Together, these observations reveal a silencing of multiple activation pathways that are critical to the transcriptional control of MHC class II and class I antigen presentation functions by trophoblast cells.

In vivo and in vitro IgE isotype switching in human B lymphocytes: evidence for a predominantly direct IgM to IgE class switch program.

Molecular analysis of circular excision products and composite genomic switch regions has demonstrated that in mice, immunoglobulin (Ig) isotype switching from IgM to IgE often proceeds sequentially via IgG1. Based on analysis of Ig production in cell cultures, it has been suggested that human B cells may switch to IgE via IgG4, whereas limited molecular data from in vitro switched B cells suggest a direct IgM to IgE switch program. To obtain a quantitative assessment of direct versus sequential IgE switching in humans, we have analyzed the nucleotide sequences of 29 composite S mu/S epsilon switch regions from freshly isolated human B lymphocytes from patients with atopic dermatitis and from B lymphocytes induced to switch to IgE synthesis in vitro. The data show that in these B cells IgE isotype switching progressed directly from IgM to IgE. We conclude that, in contrast to the murine IgM/IgE switch program, the IgM to IgE switch in B lymphocytes from patients with atopic dermatitis as well as in vitro stimulated B cells from healthy donors preferentially proceeds via direct S mu to S epsilon switch recombination.

Reevaluation of 3'Ekappa function in stage- and lineage-specific rearrangement and somatic hypermutation.

Transgenic studies have led to the conclusion that the 3'Ekappa enhancer functions to suppress kappa variable region gene assembly in T lineage cells and in progenitor B cells and have also implicated 3'Ekappa as a critical element in promoting somatic hypermutation of kappa variable region genes. To assess the role of the endogenous 3'Ekappa, we assayed these processes in mice homozygous for mutations in which the 3'Ekappa sequences were deleted by the loxP/Cre method (3'Ekappa delta/delta mice). In contrast to transgenic findings, we found that deletion of the endogenous 3'Ekappa did not deregulate kappa gene rearrangement in T lineage cells or in pro-B cells. Furthermore, immunization of the 3'Ekappa delta/delta mice led to the generation of specific antibodies with mutation patterns typical of affinity maturation, showing that there is no absolute requirement for the 3'Ekappa with respect to somatic mutation of endogenous kappa genes.

The Ig(kappa) enhancer influences the ratio of Ig(kappa) versus Ig(lambda) B lymphocytes.

We generated mice harboring germline mutations in which the enhancer element located 9 kb 3' of the immunoglobulin kappa light chain gene (3'E kappa) was replaced either by a single loxP site (3'E kappa delta) or by a neomycin resistance gene (3'E kappa N). Mice homozygous for the 3'E(kappa delta) mutation had substantially reduced numbers of kappa-expressing B cells and increased numbers of lambda-expressing B cells accompanied by decreased kappa versus lambda gene rearrangement. In these mutant mice, kappa expression was reduced in resting B cells, but was normal in activated B cells. The homozygous 3'E(kappa)N mutation resulted in a similar but more pronounced phenotype. Both mutations acted in cis. These studies show that the 3'E(kappa) is critical for establishing the normal kappa/lambda ratio, but is not absolutely essential for kappa gene rearrangement or, surprisingly, for normal kappa expression in activated B cells. These studies also imply the existence of additional regulatory elements that have overlapping function with the 3'E(kappa) element.

Analysis of early fetal T-cell receptor delta chain in humans.

In the mouse it has been found that a number of T-cell receptor (Tcr) gd phenotypes are generated during fetal thymic development. To examine whether such "waves" of Tcrgd phenotypes can be found in man, we studied the V-region usage and junctional diversity of the T-cell receptor delta chain in human fetal and post-partum thymocytes and peripheral blood T cells. Using the polymerase chain reaction (PCR)-amplification technique it was found that in fetal thymocytes of 15-17 weeks of gestation the Tcrd-V3 gene segment was mainly employed, whereas in post-partum thymocytes the Tcrd-V1 gene segment was preferentially used. These Tcrd-V3 transcripts contained only a single D element (D delta 3) and a limited random nucleotide insertion. The D delta 3 element was also present in Tcrd-V3-containing transcripts derived from peripheral blood gamma delta Tcr+ clones. These data suggest that a wave of Tcr gamma delta might exist early in human fetal development that preferentially use the Tcrd-V3 gene segment.

T-cell receptor beta-chain gene usage in the T-cell recognition of Mycobacterium leprae antigens in one tuberculoid leprosy patient.

The beta chain of the T-cell antigen receptor present on 20 T-cell clones isolated from a tuberculoid leprosy patient was studied by gene rearrangement and PCR analysis. These T-cell clones all responded to Mycobacterium leprae-encoded protein antigens, and 8 of them specifically recognized peptides of the mycobacterial 65-kDa heat shock polypeptide (65hsp). All T-cell clones studied were HLA-DR-restricted (DR2 or -3). In the DR3-restricted group, 7 of 10 used a beta-chain variable region V beta 5 gene family member, whereas in the DR2-restricted group, 2 of 10 T-cell clones used a V beta 5 gene segment and 5 used the V beta 18 gene segment. The deduced amino acid sequences of the beta chain from 8 T-cell clones have revealed that 3 of 4 DR3-restricted T-cell clones expressed the V beta 5.1 gene segment whereas the fourth DR3-restricted T-cell clone employed a V beta 5 family member not previously described. The V beta 5.1-positive T-cell clones all recognized the same 65hsp peptide from residues 2 to 12. The N-D-N segment (where D is diversity) of the junctional region of these T-cell clones was very similar, despite different beta-chain joining gene segments. Of the 4 DR2-restricted T-cell clones investigated, 3 used the V beta 18 gene segment and recognized the 65hsp peptide from residues 418 to 427. In conclusion, within this panel of M. leprae-reactive T-cell clones, the DR3-restricted T-cell clones mainly used a V beta 5 gene segment, whereas the DR2-restricted clones employed preferentially the V beta 18 gene segment.