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Autoimmunity in inflammatory bowel disease: a holobiont perspective
Adaptive immunity towards self-antigens (autoimmunity) and intestinal commensal microbiota is a key feature of inflammatory bowel disease (IBD). Considering mucosal adaptive immunity from a holobiont perspective, where the host and its microbiome form a single physiological unit, emphasises the challenge of avoiding damaging responses to self-antigen and symbiotic microbial communities in the gut while protecting against potential pathogens. Intestinal tolerance mechanisms prevent maladaptive T and B cell responses to microbial, environmental, and self-antigens, which drive inflammation. We discuss the spectrum of antimicrobial and autoantibody responses and highlight mechanisms by which common IBD-associated adaptive immune responses contribute to disease.
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.
Review: The potential role of placental extracellular vesicles in blood-brain barrier disruption and neuroinflammation in preeclampsia.
Preeclampsia is a complex pregnancy disorder characterized by hypertension and multisystem organ damage, notably affecting the liver, kidneys, and brain. Eclampsia, a severe form of preeclampsia, is marked by the sudden onset of generalized tonic-clonic seizures. Brain complications, including eclampsia, are responsible for 60-70 % of preeclampsia-related maternal deaths, particularly in low-income regions. Despite the significant impact of brain complications in preeclampsia, their underlying pathophysiology remains unclear. Evidence suggests that brain edema in preeclampsia and eclampsia results from disruption of the blood-brain barrier (BBB). Although direct analysis of the BBB is challenging, in vitro studies indicate that plasma from women with preeclampsia can compromise the BBB, with the specific circulating factors involved still unidentified. Among the potential culprits, recent findings highlight placental-derived small extracellular vesicles (PDsEVs) as key players in BBB disruption observed in preeclampsia. This review examines the role of PDsEVs in the pathophysiology of brain edema associated with preeclampsia, emphasizing areas for future research, including neuroinflammation and neuron dysfunction. Additionally, we discuss the protective role of magnesium sulfate in these processes.
MSP-tracker: A versatile vesicle tracking software tool used to reveal the spatial control of polarized secretion in Drosophila epithelial cells.
Understanding how specific secretory cargoes are targeted to distinct domains of the plasma membrane in epithelial cells requires analyzing the trafficking of post-Golgi vesicles to their sites of secretion. We used the RUSH (retention using selective hooks) system to synchronously release an apical cargo, Cadherin 99C (Cad99C), and a basolateral cargo, the ECM protein Nidogen, from the endoplasmic reticulum and follow their movements to the plasma membrane. We also developed an interactive vesicle tracking framework, MSP-tracker and viewer, that exploits developments in computer vision and deep learning to determine vesicle trajectories in a noisy environment without the need for extensive training data. MSP-tracker outperformed other tracking software in detecting and tracking post-Golgi vesicles, revealing that Cad99c vesicles predominantly move apically with a mean speed of 1.1µm/sec. This is reduced to 0.85 µm/sec by a dominant slow dynein mutant, demonstrating that dynein transports Cad99C vesicles to the apical cortex. Furthermore, both the dynein mutant and microtubule depolymerization cause lateral Cad99C secretion. Thus, microtubule organization plays a central role in targeting apical secretion, suggesting that Drosophila does not have distinct apical versus basolateral vesicle fusion machinery. Nidogen vesicles undergo planar-polarized transport to the leading edge of follicle cells as they migrate over the ECM, whereas most Collagen is secreted at trailing edges. The follicle cells therefore bias secretion of different ECM components to opposite sides of the cell, revealing that the secretory pathway is more spatially organized than previously thought.
The research relationship: participant perspectives on consent in biobanking.
This paper examines challenges associated with the governance of large-scale biobanks. As the collection and interrogation of population-scale data is increasingly positioned as a route to new understandings of health and disease, large-scale biobanks are becoming essential elements of research infrastructure. However, their longitudinal nature presents challenges for governance, particularly in relation to consent. Typically, participants agree to specific activities at recruitment, but evolving technologies make it difficult to anticipate future research applications at this time. Using a case study from UK Biobank, we demonstrate how trying to reconcile new research activities with old consent risks overlooking critical ethical issues -particularly how the proposed activity aligns with participants' understanding and expectation of biobank research. We conducted focus groups with UK Biobank participants using individual and group exercises to explore their views on consent and different types of research on their samples and data. Our findings show that participants locate responsibility for research decisions with the biobank, rather than seeking control through their consent. They perceive their consent not as a one-off agreement but as the `opening act' for a research relationship with the biobank that can be continued through communication. Focussing on the ongoing research relationship -and the practices that sustain it- is more important than the specific wording on consent forms signed at recruitment. We argue this will be more effective in meeting participant expectation as well as supporting ethical research.
Silaproline-bearing nirmatrelvir derivatives are potent inhibitors of the SARS-CoV-2 main protease highlighting the value of silicon-derivatives in structure-activity-relationship studies.
Nirmatrelvir is a substrate-related inhibitor of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) main protease (Mpro) that is clinically used in combination with ritonavir to treat COVID-19. Derivatives of nirmatrelvir, modified at the substrate P2-equivalent position, have been developed to fine-tune inhibitor properties and are now in clinical use. We report the synthesis of nirmatrelvir derivatives with a (R)-4,4-dimethyl-4-silaproline (silaproline) group at the P2-equivalent position. Mass spectrometry (MS)-based assays demonstrate that silaproline-bearing nirmatrelvir derivatives efficiently inhibit isolated recombinant Mpro, albeit with reduced potency compared to nirmatrelvir. Investigations with SARS-CoV-2 infected VeroE6 cells reveal that the silaproline-bearing inhibitors with a CF3 group at the P4-equivalent position inhibit viral progression, implying that incorporating silicon atoms into Mpro inhibitors can yield in vivo active inhibitors with appropriate optimization. MS and crystallographic studies show that the nucleophilic active site cysteine residue of Mpro (Cys145) reacts with the nitrile group of the silaproline-bearing inhibitors. Substituting the electrophilic nitrile group for a non-activated terminal alkyne shifts the inhibition mode from reversible covalent inhibition to irreversible covalent inhibition. One of the two prochiral silaproline methyl groups occupies space in the S2 pocket that is unoccupied in Mpro:nirmatrelvir complex structures, highlighting the value of sila-derivatives in structure-activity-relationship (SAR) studies. The combined results highlight the potential of silicon-containing molecules for inhibition of Mpro and, by implication, other nucleophilic cysteine enzymes.
A systems biology approach to define SARS-CoV-2 correlates of protection.
Correlates of protection (CoPs) for SARS-CoV-2 have yet to be sufficiently defined. This study uses the machine learning platform, SIMON, to accurately predict the immunological parameters that reduced clinical pathology or viral load following SARS-CoV-2 challenge in a cohort of 90 non-human primates. We found that anti-SARS-CoV-2 spike antibody and neutralising antibody titres were the best predictors of clinical protection and low viral load in the lung. Since antibodies to SARS-CoV-2 spike showed the greatest association with clinical protection and reduced viral load, we next used SIMON to investigate the immunological features that predict high antibody titres. It was found that a pre-immunisation response to seasonal beta-HCoVs and a high frequency of peripheral intermediate and non-classical monocytes predicted low SARS-CoV-2 spike IgG titres. In contrast, an elevated T cell response as measured by IFNγ ELISpot predicted high IgG titres. Additional predictors of clinical protection and low SARS-CoV-2 burden included a high abundance of peripheral T cells. In contrast, increased numbers of intermediate monocytes predicted clinical pathology and high viral burden in the throat. We also conclude that an immunisation strategy that minimises pathology post-challenge did not necessarily mediate viral control. This would be an important finding to take forward into the development of future vaccines aimed at limiting the transmission of SARS-CoV-2. These results contribute to SARS-CoV-2 CoP definition and shed light on the factors influencing the success of SARS-CoV-2 vaccination.
CMV serostatus is associated with improved survival and delayed toxicity onset following anti-PD-1 checkpoint blockade
Abstract Cytomegalovirus (CMV) is a globally endemic latent herpes virus that profoundly impacts T cell immunity. We investigated the oncological consequences of CMV infection across 341 prospectively recruited patients receiving immune checkpoint blockade (ICB) for melanoma. CMV+ patients with metastatic melanoma (MM) have higher lymphocyte counts, reduced neutrophil to lymphocyte ratio and divergent CD8+ T cell gene expression. Combination anti-CTLA-4/anti-PD-1 ICB, but not single-agent anti-PD-1 ICB, induces cytotoxicity and CMV-associated gene expression in CD8+ T cells from CMV− patients. Correspondingly, overall survival was independent of CMV serostatus in combination anti-CTLA-4/anti-PD-1 ICB recipients (CMV+ hazard ratio for death: 1.02, P = 0.92), whereas CMV+ single-agent anti-PD-1 ICB recipients had improved overall survival (CMV+ hazard ratio for death: 0.37, P < 0.01), a finding also seen in CMV+ adjuvant single-agent anti-PD-1 ICB recipients (CMV+ hazard ratio for recurrence: 0.19, P = 0.03). We identify TBX21, encoding T-bet, as a transcriptional driver of CMV-associated CD8+ T cell gene expression, finding that TBX21 expression is predictive of overall survival (hazard ratio: 0.62, P = 0.026). CMV+ patients unexpectedly show reduced cumulative incidence of grade 3+ immune-related adverse events at 6 months (0.30 versus 0.52, P = 2.2 × 10−5), with lower incidence of colitis (P = 7.8 × 10−4) and pneumonitis (P = 0.028), an effect replicated in non-melanoma ICB recipients (n = 58, P = 0.044). Finally, we find reduced CMV seropositivity rates in patients with MM compared with UK Biobank controls (odds ratio: 0.52, P = 1.8 × 10−4), indicating CMV seropositivity may protect against MM. Specifically, patients with BRAF-mutated MM are less likely to be CMV+ (odds ratio = 2.2, P = 0.0054), while CMV− patients present 9 yr earlier with BRAF wild-type MM (P = 1.3 × 10−4). This work reveals an interaction between CMV infection, MM development according to BRAF status and response to ICB, while demonstrating CMV infection is protective against severe ICB immune-related adverse events, highlighting the potential importance of previous infection history and chronic immune activation in MM development and immunotherapy outcomes.
IL-10 from tumoral B cells modulates the diffuse large B-cell lymphoma microenvironment and response to immunotherapy
The contribution of IL-10 secreted by tumoral B cells to the progression and shaping of the microenvironment in diffuse large B-cell lymphoma (DLBCL) with activated B-cell (ABC) phenotype is not yet completely understood. To shed light on this issue, we generated an immunocompetent mouse model of ABC-DLBCL with conditional knock-out of IL-10 specifically in malignant B cells. Paradoxically, these mice had significantly worse overall survival when left untreated, but experienced increased sensitivity to conventional anti-CD20 immunotherapy or regulatory T cell (Treg) depletion. We identified various immunomodulatory mechanisms involved in this behavior. In particular, we show that IL-10-deficient lymphomas acquire a highly immunosuppressed and T-cell exhausted microenvironment with increased angiogenesis that results in a more aggressive phenotype, refractory to PD-1 immune checkpoint blockade (ICB). However, the response of IL-10-deficient mice to anti-CD20 immunotherapy was greatly enhanced by upregulation of calcium channels in B cells. In general, IL-10 autocrine signaling promotes survival of malignant B cells, while the paracrine action of B cell-derived IL-10 maintains an immunoreactive microenvironment that influences the efficacy of emerging immunotherapy strategies aimed at the lymphoma microenvironment (LME). Furthermore, IL-10-associated transcriptional signatures derived from our studies may correctly predict clinical outcomes of DLBCL patients treated with R-CHOP. Thus, our work provides important functional and mechanistic insights into the role of B cell-derived IL-10 in the biology of ABC-DLBCL.
Fecal microbiota transplantation from female donors restores gut permeability and reduces liver injury and inflammation in middle-aged male mice exposed to alcohol
Background: Alcohol misuse, binge drinking pattern, and gender-specific effects in the middle-aged population has been clearly underestimated. In the present study, we focused on understanding gender-specific effects of alcohol exposure on the gut-liver axis and the role of gut microbiota in modulating gender-specific responses to alcohol consumption. Methods: Fifty-two-week-old female and male C57BL/6 mice were fasted for 12 h, and then administered a single oral dose of ethanol (EtOH) (6 g/kg). Controls were given a single dose of PBS. Animals were sacrificed 8 h later. Alternatively, fecal microbiota transplantation (FMT) was performed in 52-week-old male mice from female donors of the same age. Permeability of the large intestine (colon), gut microbiota, liver injury, and inflammation was thoroughly evaluated in all groups. Results: Middle-aged male mice exposed to EtOH showed a significant increase in gut permeability in the large intestine, evaluated by FITC-dextran assay and ZO-1, OCCLUDIN and MUCIN-2 immuno-staining, compared to PBS-treated animals, whilst female mice of the same age also increased their gut permeability, but displayed a partially maintained intestinal barrier integrity. Moreover, there was a significant up-regulation of TLRs and markers of hepatocellular injury, cell death (AST, TUNEL-positive cells) and lipid accumulation (ORO) in male mice after EtOH exposure. Interestingly, FMT from female donors to male mice reduced gut leakiness, modified gut microbiota composition, ameliorated liver injury and inflammation, TLR activation and the senescence phenotype of middle-aged mice. Conclusion: Our findings highlighted the relevance of gender in middle-aged individuals who are exposed to alcohol in the gut-liver axis. Moreover, our study revealed that gender-specific microbiota transplantation might be a plausible therapy in the management of alcohol-related disorders during aging.
Venetoclax improves CD20 immunotherapy in a mouse model of MYC/BCL2 double-expressor diffuse large B-cell lymphoma
BackgroundApproximately one-third of diffuse large B cell lymphoma (DLBCL) patients exhibit co-expression of MYC and BCL2 (double-expressor lymphoma, DEL) and have a dismal prognosis. Targeted inhibition of the anti-apoptotic protein BCL2 with venetoclax (ABT-199) has been approved in multiple B-cell malignancies and is currently being investigated in clinical trials for DLBCL. Whether BCL2 anti-apoptotic function represents a multifaceted vulnerability for DEL-DLBCL, affecting both lymphoma B cells and T cells within the tumor microenvironment, remains to be elucidated.MethodsHere, we present novel genetically engineered mice that preclinically recapitulate DEL-DLBCL lymphomagenesis, and evaluate their sensitivity ex vivo and in vivo to the promising combination of venetoclax with anti-CD20-based standard immunotherapy.ResultsVenetoclax treatment demonstrated specific killing of MYC+/BCL2+lymphoma cells by licensing their intrinsically primed apoptosis, and showed previously unrecognized immunomodulatory activity by specifically enriching antigen-activated effector CD8 T cells infiltrating the tumors. Whereas DEL-DLBCL mice were refractory to venetoclax alone, inhibition of BCL2 significantly extended overall survival of mice that were simultaneously treated with a murine surrogate for anti-CD20 rituximab.ConclusionsThese results suggest that the combination of anti-CD20-based immunotherapy and BCL2 inhibition leads to cooperative immunomodulatory effects and improved preclinical responses, which may offer promising therapeutic opportunities for DEL-DLBCL patients.