Misophonia is a recently defined disorder in which certain aversive repetitive sounds and associated stimuli elicit distressing and impairing affective, behavioral, and physiological responses. The ...responses in misophonia may be stronger when the sound is produced by close friends and family, suggesting that the context in which a triggering cue occurs may have an important role in misophonia. As such, the goal of this study was to test experimentally whether the context of the sound source influences affective and psychophysiological responses to triggering stimuli in misophonia.
Sixty one adults with misophonia and 45 controls listened to audio recordings (8 s) of human eating, animals eating, and human mouth smacking sounds (without eating). After a break, the same audio recordings were presented embedded within videos of human eating (congruent stimuli), animals eating (congruent stimuli), and, in the mouth smacking condition, with visually incongruent stimuli (hands playing in mud or in a bowl with a watery dough). Psychophysiological responses-skin conductance response (SCR) and heart rate (HR), and self-reported affective responses (valence, arousal, dominance) were gathered during the experiment in a laboratory.
Participants with misophonia assessed all the stimuli as more negative and arousing than the controls, and reported feeling less dominant with respect to the sounds. Animal and mouth smacking sounds were assessed by all the participants as less negative and arousing than human eating sounds, but only in the audio-video conditions. SCR data partially confirmed increased psychophysiological arousal in misophonia participants during an exposure to mouth sounds, but did not reflect the self-report changes in response to different contexts. Misophonia participants had deeper deceleration of HR than controls during human eating sound with congruent video stimuli, while there was no group difference during human mouth smacking with incongruent video stimuli.
Results suggest that the context of mouth sounds influences affective experiences in adults with misophonia, but also in participants without misophonia. Presentation of animal eating sounds with congruent visual stimuli, or human mouth smacking sounds with incongruent stimuli, decreased self-report reaction to common misophonic triggers.
In this study,
Gasterophilus intestinalis and
Gasterophilus nasalis collected from horses in northeastern Poland and southern Italy were genetically compared
. The
cox1 sequences of the Polish and ...Italian
G. nasalis larvae revealed a higher degree of geographic genetic diversity, with an intra-specific variation rate of 1.27%, than the
G. nasalis specimens collected in Poland (intra-specific variation rate: 0.49%) and those collected in Italy (intra-specific variation rate: 0.58%). However, the level of genetic homology of the Polish and Italian
G. intestinalis specimens (intra-specific variation rate: 1.27%) was similar to that of the
G. intestinalis larvae collected in northeastern Poland (intra-specific variation rate: 0.94%) and those collected in southern Italy (intra-specific variation rate: 1.16%). Analysis of the restriction enzyme sites in the
coxI gene of
G. nasalis and
G. intestinalis showed that the nucleotide polymorphism (NP) at position 1050 of this gene determines cleavage by MnlI only in
G. nasalis, making it possible to differentiate the two species using PCR-RFLP. Interestingly, comparison of the nucleotide sequences of the PCR-amplified
coxI gene fragments from the Italian specimens of
G. nasalis with other analyzed
cox1 genes revealed an additional NP at position 1236 of
cox1 gene, recognized by MnlI. The present study shows that
G. nasalis specimens from different geographical areas display a level of genetic diversity which can influence PCR-RFLP analysis.
When the immune system encounters an antigen, the response can result in the mobilization of effector cells or in tolerance. The outcome is largely dependent on immunosuppressive CD4 T cells that ...express the transcription factor Foxp3 (Tregs). Yet, how Tregs control different immune effector cells remains elusive. In this issue of The EMBO Journal, Dhainaut et al report on a novel mechanism used by Tregs to prevent differentiation of naïve CD4 T cells to proinflammatory Th1CD4 (Th1) effectors.
A recent study reveals a new mechanism by which regulatory T cells suppress excessive inflammatory responses.
: To date, many studies have attempted to show a relationship between potentially harmful experiences in childhood and gray matter volume (GMV) in specific brain areas. These studies managed to ...identify several affected regions, yet most of them neglected the influence of sex or the occurrence of mental health problems. Furthermore, little is known about mechanisms linking childhood adversity (CA) and temperamental traits as plausible endophenotypes of psychopathology.
: The present study addresses these two issues by trying to identify sex-specific relationships between CA and brain volumes as well as to show the role of the latter in predicting temperament scores.
: Forty-eight people (23 women) without anxiety or affective disorders participated in this study. CA was measured using the Childhood Questionnaire (CQ) and temperament was measured with the use of the behavioral inhibition system-behavioral activation system (BIS-BAS) Scales. Whole-brain MR imaging was performed to identify GMV differences.
: In women, we identified negative relationships between CA and GMV in the left inferior parietal lobule (IPL), right cerebellum, and right precentral gyrus. In men, we found a negative correlation between CA and GMV in the right fusiform gyrus. We also identified sex-specific relationships between CA and temperament traits.
: The results of our study suggest a sex-specific pattern in the relationship between early adverse experiences and brain structure. The results can also help explain the role that temperament plays in the relationship between CA and the risk of psychopathology.
Abstract
Neural bases of cognitive reappraisal may depend on the direction of regulation (up- or downregulation) and stimulus valence (positive or negative). This study aimed to examine this using a ...cognitive reappraisal task and conjunction analysis on a relatively large sample of 83 individuals. We identified regions in which activations were common for all these types of emotion regulation. We also investigated differences in brain activation between the ‘decrease’ and ‘increase’ emotional response conditions, and between the regulation of negative and positive emotions. The common activation across conditions involved mainly the prefrontal and temporal regions. Decreasing emotions was associated with stronger involvement of the dorsolateral prefrontal cortex, while increasing with activation of the amygdala and hippocampus. Regulation of negative emotions involved stronger activation of the lateral occipital cortex, while regulation of positive emotions involved stronger activation of the anterior cingulate cortex extending to the medial prefrontal cortex. This study adds to previous findings, not only by doing a conjunction analysis on both emotional valences and regulation goals, but also doing this in a bigger sample size. Results suggest that reappraisal is not a uniform process and may have different neural bases depending on regulation goals and stimulus valence.
Background
Blastocystis
is a common gut protistan parasite in humans and animals worldwide, but its interrelationship with the host gut microbiota and mucosal immune responses remains poorly ...understood. Different murine models of
Blastocystis
colonization were used to examine the effect of a common
Blastocystis
subtype (ST4) on host gut microbial community and adaptive immune system.
Results
Blastocystis
ST4-colonized normal healthy mice and
Rag1
−/−
mice asymptomatically and was able to alter the microbial community composition, mainly leading to increases in the proportion of
Clostridia
vadinBB60 group and
Lachnospiraceae
NK4A136 group, respectively.
Blastocystis
ST4 colonization promoted T helper 2 (Th2) response defined by interleukin (IL)-5 and IL-13 cytokine production, and T regulatory (Treg) induction from colonic lamina propria in normal healthy mice. Additionally, we observed that
Blastocystis
ST4 colonization can maintain the stability of bacterial community composition and induce Th2 and Treg immune responses to promote faster recovery from experimentally induced colitis. Furthermore, fecal microbiota transplantation of
Blastocystis
ST4-altered gut microbiome to colitis mice reduced the severity of colitis, which was associated with increased production of short-chain fat acids (SCFAs) and anti-inflammatory cytokine IL-10.
Conclusions
The data confirm our hypothesis that
Blastocystis
ST4 is a beneficial commensal, and the beneficial effects of
Blastocystis
ST4 colonization is mediated through modulating of the host gut bacterial composition, SCFAs production, and Th2 and Treg responses in different murine colonization models.
Lck bound to coreceptor is less active than free Lck Wei, Qianru; Brzostek, Joanna; Sankaran, Shvetha ...
Proceedings of the National Academy of Sciences - PNAS,
07/2020, Letnik:
117, Številka:
27
Journal Article
Recenzirano
Odprti dostop
Src family kinase Lck plays critical roles during T cell development and activation, as it phosphorylates the TCR/CD3 complex to initiate TCR signaling. Lck is present either in coreceptor-bound or ...coreceptorunbound (free) forms, and we here present evidence that the two pools of Lck have different molecular properties. We discovered that the free Lck fraction exhibited higher mobility than CD8α-bound Lck in OT-I T hybridoma cells. The free Lck pool showed more activating Y394 phosphorylation than the coreceptor-bound Lck pool. Consistent with this, free Lck also had higher kinase activity, and free Lck mediated higher T cell activation as compared to coreceptor-bound Lck. Furthermore, the coreceptor-Lck coupling was independent of TCR activation. These findings give insights into the initiation of TCR signaling, suggesting that changes in coreceptor-Lck coupling constitute a mechanism for regulation of T cell sensitivity.
Making sense of TCR–pMHC topology
Most T cells use a T cell receptor (TCR) that recognizes major histocompatibility complex molecules bound to peptides (pMHCs) derived from both self- and foreign ...antigens. Although there is great variability in the interface because of the diversity of both partners, this interaction displays a canonical docking topology for reasons that remain contested. Zareie
et al.
tested an assortment of both canonical and reversed-polarity TCRs that were all specific for the same cognate pMHC-I bearing a peptide derived from influenza A virus (IAV) (see the Perspective by Horkova and Stepanek). The authors determined that docking topology was the primary driver of in vivo T cell activation and recruitment when mice were infected with IAV. The canonical topology was required for the formation of a functional signaling complex, suggesting that T cell signaling constraints dictate how TCR and pMHC meet.
Science
, abe9124, this issue p.
eabe9124
; see also abj2937, p.
1038
The highly conserved nature of T cell antigen receptor recognition is required for the colocalization of key signaling molecules.
INTRODUCTION
T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is one of the most diverse receptor–ligand interactions in biology. Nevertheless, these interactions exhibit a highly conserved, or canonical, TCR–pMHC docking polarity in both mice and humans. Whether this canonical docking polarity is driven by evolutionarily conserved, germline-encoded complementarity between the TCR and MHC or by signaling constraints imposed by coreceptors has been a question of enduring debate. Here, we demonstrate that although reversed-polarity TCR–pMHC recognition is prevalent within a naïve, viral epitope–specific T cell repertoire and may exhibit relatively high pMHCI affinity, such TCRs are unable to support TCR signaling in the presence of CD8 coreceptor because of mislocalization of Lck. These data support a paradigm in which the highly conserved TCR–pMHCI docking polarity is driven by structural constraints on TCR signaling.
RATIONALE
Evidence suggests that the canonical TCR–pMHC docking polarity is driven by evolutionary hardwiring of complementary germline-encoded motifs at the TCR and MHC interface. An alternate model suggests that TCR recognition of pMHC is driven during thymic selection by the need for the CD4 or CD8 coreceptors to bind MHC and deliver coreceptor-associated Lck to the CD3 signaling complex. We previously identified reversed-polarity TRBV17
+
TCRs from the preimmune influenza A virus (IAV)–specific repertoire that bound pMHCI (H-2D
b
NP
366
) with a moderate affinity but were unable to support robust T cell recruitment. Here, using a range of canonical and reversed TCRs specific for the same cognate pMHCI, we tested the hypothesis that the TCR–pMHCI docking polarity precedes binding strength as a key determinant of T cell activation. We hypothesized that the underlying driver of the canonical docking polarity is the colocalization of signaling molecules central to the TCR signal transduction pathway.
RESULTS
In this study, we demonstrate that reversed TCRs are prevalent in a naïve virus–specific repertoire but are poorly represented in the immune response after virus challenge. We identified antigen-specific TCRαβ clonotypes that were either poorly recruited or clonally expanded and found an overriding association between immune prevalence and canonical TCR–pMHCI docking. This was irrespective of pMHCI affinity, catch or slip bond formation, or TCR clustering, demonstrating that a canonical docking polarity is required for T cell activation. This finding was verified after viral challenge of adoptively transferred retrogenic T cells expressing reversed or canonical docking TCRs of varying affinities. The inability of T cells expressing reversed-docking TCRs to be recruited into the antiviral immune response demonstrates that TCR–pMHCI docking topology supersedes TCR–pMHCI affinity as the primary determinant for effective in vivo immune recruitment. Using fluorescence lifetime imaging microscopy (FLIM)–Förster resonance energy transfer (FRET) analyses, we show that canonical TCR–pMHCI docking is essential for the colocalization of CD8–Lck with CD3ζ, which is impaired when the TCR engages pMHCI with reversed polarity. The requirement for canonical TCR–pMHCI docking can be circumvented by the removal of the CD8 coreceptor or by dissociation of Lck from CD8, suggesting that sequestration of Lck by the CD8 coreceptor has a dual role: potentiating signaling arising from canonical TCR–pMHCI interactions and impeding reversed-polarity TCR–pMHCI signaling.
CONCLUSION
The inability of reversed-polarity TCRs to participate in the immune response occurs independently of TCR–pMHCI binding affinity and instead is a direct consequence of reversed TCR–pMHCI engagement. Most TCR–pMHC complexes that have been solved to date, upon which the canonical TCR–pMHCI docking paradigm has been established, were derived from expanded immune repertoires. Thus, we conclude that the highly conserved docking polarity is driven predominantly by the structural constraints imposed on TCR signaling and recruitment into an immune response. In addition to the well-recognized augmentation of signaling resulting from canonical TCR–pMHCI engagement, our findings suggest a role for coreceptor–Lck association in preventing signaling by noncanonical TCR–pMHC recognition. Such negative regulation would serve to limit the extent of functional TCR cross-reactivity and constrain the number of signaling-competent TCR-binding modalities.
The canonical polarity of TCR–pMHC docking is essential for colocalization of CD3 and coreceptor-associated Lck and for productive TCR signaling.
Schematic shows how canonical TCR–pMHC recognition colocalizes Lck and CD3, driving TCR-mediated signaling. By contrast, a reversed TCR–pMHC recognition polarity mislocalizes Lck and CD3, impeding signaling.
T cell receptor (TCR) recognition of peptide–major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using “reversed-docking” TCRβ-variable (TRBV) 17
+
TCRs from the naïve mouse CD8
+
T cell repertoire that recognizes the H-2D
b
–NP
366
epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR–pMHCI binding or clustering characteristics. Canonical TCR–pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR–pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR–pMHC docking topology is mandated by T cell signaling constraints.
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