CD40 Ligand and Autoantigen Are Involved in the Pathogenesis of Low-Grade B-Cell Lymphomas of Mucosa-Associated Lymphoid Tissue

Low-grade MALT-type lymphomas are malignancies of mucosal marginal-zone B cells and preceded by reactive inflammatory lymphoid tissue. Experimental observations suggest that antigen and CD40 Ligand act during cognate T/B cell interaction and are crucial for germinal center B-cell maturation generating marginal-zone B cells. To investigate the mechanisms underlying the development of extranodal MALT-type lymphomas, the immunoglobulin receptor was sequenced and analyzed for antigen specificity using heterohybridoma technology. Furthermore, CD40 ligand expression was evaluated by immunohistochemistry and by semiquantitative RT-PCR, and ligand binding to the CD40 of tumor B cells was studied using the CD40 system. Hypermutations were found in low-grade lymphomas throughout CDR1- CDR3 suggestive of positive selection through their antigen receptor. Different VH families were used and more than 69% of tumor immunoglobulins bound different mucosal antigens. CD40L expression was found in the tumor marginal zone in substantial amounts. The in vitro proliferation response of all low-grade MALT-type lymphomas was dependent on anti-CD40- mediated signals and cytokines. Our data provide evidence that autoantigen as well as the CD40L expressed by activated nonneoplastic T cells may drive the evolution of low-grade MALT-type lymphomas either directly or by paracrine mechanisms and that antigen may contribute to lymphoma pathogenesis

Local T/B cooperation in inflamed tissues is supported by T follicular helper-like cells

Autoimmune diseases and other inflammatory conditions are characterized by large lymphocytic tissue infiltrates in which T and B cells can be found in close contact. Here, using a murine airway inflammation model, we compare antigen-specific T and B cells in lung tissue versus lung-draining lymph node. In the lung we identify a B-cell population exhibiting a classical germinal centre phenotype without being organized into ectopic lymphoid tissue. By contrast, classical CXCR5+ Bcl-6+ T follicular helper cells are not present. Nevertheless, lung-infiltrating T cells exhibit follicular helper-like properties including the potential to provide help to naive B cells. The lung tissue is also a survival niche for memory T and B cells remaining in residual peribronchial infiltrates after resolution of inflammation. Collectively, this study shows the importance of T/B cooperation not only in lymph nodes but also in inflamed peripheral tissues for local antibody responses to infection and autoimmunity

Widespread Recommendations Can Change Our Habits of Hand-Washing and Physical Distance During the COVID-19 Pandemic

[Background] Habits and behaviors in everyday life currently need to be modified as quickly as possible due to the COVID-19 pandemic. Two of the most effective tools to prevent infection seem to be regular and thorough hand-washing and physical distancing during interpersonal interactions. [Method] Two hundred and eighty-four participants completed a short survey to investigate how previous habits regarding hand-washing and physical distancing have changed in the general population as a function of the current pandemic and the thereby increased information and constant recommendations regarding these behaviors. [Results] Participants aged 51 and older reported a greater change in everyday hand-washing behavior than younger participants. In addition, participants aged 31 and older selected significantly greater distances to have a conversation than younger participants. However, that was not the case if participants had to actively stop their conversational partner from approaching. [Conclusion] Participants aged 51 years and older seem to be well aware of their at-risk status during the current pandemic and might therefore be willing to change their behavior more strongly than younger survey participants. Nevertheless, they seem to struggle with enforcing the current rules towards others. The group aged between 31 and 50 years, however, reports a comparable level of fear, but no corresponding change in hand-washing behavior. Future surveys should try to provide more insight into why this might be the case

Contributions of left frontal and temporal cortex to sentence comprehension: Evidence from simultaneous TMS-EEG

Sentence comprehension requires the rapid analysis of semantic and syntactic information. These processes are supported by a left hemispheric dominant fronto-temporal network, including left posterior inferior frontal gyrus (pIFG) and posterior superior temporal gyrus/sulcus (pSTG/STS). Previous electroencephalography (EEG) studies have associated semantic expectancy within a sentence with a modulation of the N400 and syntactic gender violations with increases in the LAN and P600. Here, we combined focal perturbations of neural activity by means of short bursts of transcranial magnetic stimulation (TMS) with simultaneous EEG recordings to probe the functional relevance of pIFG and pSTG/STS for sentence comprehension. We applied 10 Hz TMS bursts of three pulses at verb onset during auditory presentation of short sentences. Verb-based semantic expectancy and article-based syntactic gender requirement were manipulated for the sentence final noun. We did not find any TMS effect at the noun. However, TMS had a short-lasting impact at the mid-sentence verb that differed for the two stimulation sites. Specifically, TMS over pIFG elicited a frontal positivity in the first 200 msec post verb onset whereas TMS over pSTG/STS was limited to a parietal negativity at 200-400 msec post verb onset. This indicates that during verb processing in sentential context, frontal brain areas play an earlier role than temporal areas in predicting the upcoming noun. The short-living perturbation effects at the mid-sentence verb suggest a high degree of online compensation within the language system since the sentence final noun processing was unaffected. (C) 2019 Elsevier Ltd. All rights reserved

Batf3-Dependent Dendritic Cells in the Renal Lymph Node Induce Tolerance against Circulating Antigens

Although the spleen is a major site where immune tolerance to circulating innocuous antigens occurs, the kidney also contributes. Circulating antigens smaller than albumin are constitutively filtered and concentrated in the kidney and reach the renal lymph node by lymphatic drainage, where resident dendritic cells (DCs) capture them and induce tolerance of specific cytotoxic T cells through unknown mechanisms. Here, we found that the coinhibitory cell surface receptor programmed death 1 (PD-1) on cytotoxic T cells mediates to their tolerance. Renal lymph node DCs of the CD8(+) XCR1(+) subset, which depend on the transcription factor Batf3, expressed the PD-1 cognate ligand PD-L1. Batf3-dependent DCs in the renal lymph node presented antigen that had been concentrated in the kidney and used PD-L1 to induce apoptosis of cytotoxic T cells. In contrast, T cell tolerance in the spleen was independent of PD-1, PD-L1, and Batf3. In summary, these results clarify how the kidney/renal lymph node system tolerizes the immune system against circulating innocuous antigens

Functional co-activation within the prefrontal cortex supports the maintenance of behavioural performance in fear-relevant situations before an iTBS modulated virtual reality challenge in participants with spider phobia

A number of studies/meta-analyses reported moderate antidepressant effects of activating repetitive transcranial magnetic stimulation (rTMS) over the prefrontal cortex (PFC). Regarding the treatment of anxiety, study outcomes are inconsistent, probably because of the heterogenity of anxiety disorders/study designs. To specifically evaluate the impact of rTMS on emotion regulation in fear-relevant situations we applied a sham-controlled activating protocol (intermittent Theta Burst Stimulation/iTBS) over the left PFC (F3) succeeded by a virtual reality (VR) challenge in n=41 participants with spider phobia and n=42 controls. Prior to/after iTBS and following VR prefrontal activation was assessed by functional near infrared spectroscopy during an emotional Stroop paradigm. Performance (reaction times/error rates) was evaluated. Stimuli were rated regarding valence/arousal at both measurements. We found diminished activation in the left inferior frontal gyrus (IFG) of participants with spider phobia compared to controls, particularly elicited by emotionally-irrelevant words. Simultaneously, a functional connectivity analysis showed increased co-activation between the left IFG and the contra-lateral hemisphere. Behavioural performance was unimpaired. After iTBS/VR no significant differences in cortical activation between the phobic and control group remained. However, verum-iTBS did not cause an additional augmentation. We interpreted our results in terms of a prefrontal network which gets activated by emotionally-relevant stimuli and supports the maintenance of adequate behavioural reactions. The missing add-on effects of iTBS might be due to a ceiling effect of VR, thereby supporting its potential during exposure therapy. Concurrently, it implies that the efficient application of iTBS in the context of emotion regulation still needs to be studied further. (C) 2016 Elsevier B.V. All rights reserved