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We are delighted to announce that Pernille Søgaard, a 2nd year DPhil student at the Kennedy Institute, NDORMS has received an award for best presentation at the 32nd Winter School on Proteinases and Their Inhibitors held in Tiers an Rosengarten, Italy earlier this month.
Role of Gynecologic Findings in Interstitial Cystitis/Bladder Pain Syndrome: A Consensus.
ObjectiveTo evaluate the role of gynecologic findings in Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) by reviewing current international guidelines and identifying relevant gynecologic co-morbidities.MethodsThis consensus statement was developed through a systematic four-phase process: (1) comprehensive literature review across PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science databases (inception-January 2025) using predefined search terms related to IC/BPS and gynecologic conditions; (2) assembly of a 6-member multidisciplinary expert panel including urologists, urogynecologists, gynecologists and pain specialists; (3) consensus development via modified Delphi technique comprising several electronic rating rounds and a face-to-face meeting, with consensus defined as ≥ 80% agreement; and (4) manuscript preparation with iterative review.ResultsA number of associated gynecologic disorders may overlap with IC/BPS, our consensus committee identified five main co-morbid disorders: Endometriosis/Adenomyosis, Genito-Pelvic Pain Penetration Disorder/Sexual Dysfunction, Overactive Pelvic Floor Muscles, Hormone- Associated Genitourinary Changes, Vulvodynia/Vestibulodynia.ConclusionWhile not exhaustive, this consensus highlights the most prevalent gynecologic co-morbidities supported by current literature. Clinical evaluation should prioritize a detailed medical history and pelvic examination to identify these overlapping conditions. Future directions include developing a multidisciplinary diagnostic and treatment algorithm to guide clinicians-including urologists, gynecologists, urogynecologists, physical therapists-in comprehensive IC/BPS care.
Mucosal signatures of pathogenic T cells in HLA-B*27+ anterior uveitis and axial spondyloarthritis.
HLA-B*27 was one of the first HLA alleles associated with an autoimmune disease, i.e., axial spondyloarthritis (axSpA) and acute anterior uveitis (B27AAU), which cause joint and eye inflammation, respectively. Gastrointestinal inflammation has been suggested as a trigger of axSpA. We recently identified a bacterial peptide (YeiH) that can be presented by HLA-B*27 to expanded public T cell receptors in the joint in axSpA and the eye in B27AAU. While YeiH is present in enteric microbiota and pathogens, additional evidence that pathogenic T cells in HLA-B*27-associated autoimmunity may have had a prior antigenic encounter within the gastrointestinal tract remains lacking. Here, we analyzed ocular, synovial, and blood T cells in B27AAU and axSpA, showing that YeiH-specific CD8+ T cells express a mucosal gene set and surface proteins consistent with intestinal differentiation, including CD161, integrin α4β7, and CCR6. In addition, we found an expansion of YeiH-specific CD8+ T cells in axSpA and B27AAU blood compared with that from individuals acting as healthy controls, whereas influenza-specific CD8+ T cells were equivalent across groups. Finally, we demonstrated the dispensability of TRBV9 for antigen recognition. Collectively, our data suggest that, in HLA-B27-associated autoimmunity, early antigen exposure and differentiation of pathogenic CD8+ T cells may occur in enteric organs.
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.
Effects of temporarily suspending low-dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study)
This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1136/bmjopen-2022-062599 Introduction It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions. Methods and analysis An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status. Ethics and dissemination This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers. Trial registration number ISRCTN11442263. Funding This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] DOI https://doi.org/10.1136/bmjopen-2022-062599
Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial
This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/S2665-9913(23)00298-9 Summary Background Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Method We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Finding Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. Interpretation 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. Funding National Institute for Health and Care Research. Funding This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] DOI https://doi.org/10.1016/S2665-9913(23)00298-9
Exploring nutritional supplement use for countering respiratory tract infections through an X (formerly Twitter)-based survey
Background: Respiratory tract infections are a common health issue, driving interest in preventive strategies like nutritional supplements, while evidence on their usage and effectiveness remains limited. In this context, social media platforms, particularly X (formerly Twitter), provide a unique opportunity to gather large-scale public health-related data. Objectives: In this study, we aimed to survey participants’ uses and opinions on nutritional supplements in prevention or treatment of respiratory tract infections, by using X. Methods: A survey was conducted between 1st and 15th December 2022. A single open-ended question “Which are the best dietary supplements to counteract respiratory infections?“ was asked. One week after the start of the survey, a poll was posted to get more relevant information and boost the survey's reach. Total endorsements were calculated for each tweet posted as the total sum of replies, retweets, and likes. Results: The open-ended question received a total of 118 retweets, 39 quotes, and 371 likes, while the poll received 56 retweets, 13 quotes, and 67 likes. A total of 495 replies, 2,251 retweets, 5,118 likes, and 148 quotes were received for the question and its related tweets. Vitamin D (1,607 endorsements), zinc (1,347 endorsements), vitamin C (803 endorsements), magnesium (694 endorsements), and honey (661 endorsements) were the nutritional supplements that received most endorsements. Conclusion: Various foods, drinks, and natural ingredients have been suggested as potentially helpful for counteracting respiratory infections. Approximately half of respondents indicated using such supplements for themselves. The result of this study supports the idea that the X platform can be used as an effective survey tool to study global health-related behaviours and trends.
Harnessing the neuroprotective effect of oral administration of benfotiamine in MPTP induced Parkinson's disease in rats.
The study was performed to evaluate the neuroprotective effects of Benfotiamine (BFT) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in rats. The rats were given daily doses of BFT (100 mg/kg, 200 mg/kg) through oral administration for 42 days. The rats were given a single bilateral dosage of MPTP (0.1 mg/nostril) intranasally once before the drug treatment to induce PD. On day 42, the animals were subjected to various behavioral paradigms. Post-treatment with BFT for 42 days significantly improved the motor and nonmotor fluctuations of MPTP. The results demonstrated that treatment with BFT ameliorated MPTP-induced disorders in behavior, body balance, and dopamine levels in the mid-brain. Among the post-treated groups, a high dose of BFT was the most effective treatment. Mean values are indicated in ±SEM, n = 5***(p
Mucoepidermoid carcinoma of the bronchus: is conservative surgery always justified?
A case of mucoepidermoid carcinoma of the bronchus in a 7-year-old boy is reported. The patient underwent right pneumonectomy. Histologically, the tumor was a low-grade muco-epidermoid carcinoma arising from the bronchus with lymph node metastasis in the drainage area. Presence of lymph node metastasis in this low-grade tumor suggests the possibility of early progression of disease in what has until now been considered a very slow growing tumor. Aggressive surgery may be necessary in these situations.
A linear ontogeny accounts for the development of naive, memory, and tumor-infiltrating regulatory T cells in mice.
Regulatory T cells (Treg cells) are critical regulators of adaptive immunity and the pathophysiology of antitumoral immunity. Treg cells are both generated during thymic development and induced from peripheral conventional T cells. How these distinct pathways contribute to the homeostasis of circulating Treg cells in health and disease remains unclear. We addressed this question using multiple fate-mapping mouse systems and modeling. Naive and effector/memory (EM) Treg cells exhibit distinct dynamics but are both continuously replenished by de novo generation throughout life. The predominant precursors of circulating EM Treg cells are naive thymic Treg cells and not conventional T cells, a process driven by self rather than foreign antigen recognition. Using the same fate reporters and three tumor models, we demonstrate that infiltrating Treg cells specifically derive from preexisting EM Treg cells. In summary, we define a linear ontogeny of Treg cells from the thymus to EM, driven by self-antigen recognition, that then gives rise to tumor-infiltrating Treg cells.
Multidisciplinary evidence-based consensus statements on salvage surgery for recurrent head and neck cancer (International Centre for Recurrent head and neck Cancer).
BACKGROUND: Recurrent head and neck squamous cell carcinomas (rHNSCC) are an understudied subgroup, lacking high quality evidence and thus gold standard management recommendations, resulting in significant variations in practice. The aim of this project was to deliver a national multi-disciplinary expert consensus on patients with rHNSCC managed by curative salvage surgery. METHODS: The AGREEII protocol guided the Delphi process. Best practice statements were developed after literature review on the perioperative management and surgical salvage of major rHNSCC subsites. Members of the International centre for Recurrent head and neck cancer (IREC) network, and other UK based professional stakeholder organisations were invited into an online Delphi study. Participants voted upon statements over three rounds, with items modified in response to vote thresholds and comments. RESULTS: Twenty-eight experts participated including 11 otolaryngologists, 7 oncologists, 9 oral and maxillofacial surgeons, and 1 speech and language therapist. Consensus was achieved on 73 statements, with 29 (39.7%) achieving unanimous (threshold: 100%) and 25 (34.2%) (threshold >90%) agreement. CONCLUSIONS: Salvage surgery for rHNSCC are challenging cases that require intensive multidisciplinary input to achieve cure while balancing impact on function and quality-of-life. In this article, we provide a large series of statements based on UK-wide expert consensus, that will guide clinicians through the complex intra- and perioperative management of patients undergoing surgical salvage.
Asparagine availability controls germinal center B cell homeostasis.
The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
An HLA-E-targeted TCR bispecific molecule redirects T cell immunity against Mycobacterium tuberculosis.
Peptides presented by HLA-E, a molecule with very limited polymorphism, represent attractive targets for T cell receptor (TCR)-based immunotherapies to circumvent the limitations imposed by the high polymorphism of classical HLA genes in the human population. Here, we describe a TCR-based bispecific molecule that potently and selectively binds HLA-E in complex with a peptide encoded by the inhA gene of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis in humans. We reveal the biophysical and structural bases underpinning the potency and specificity of this molecule and demonstrate its ability to redirect polyclonal T cells to target HLA-E-expressing cells transduced with mycobacterial inhA as well as primary cells infected with virulent Mtb. Additionally, we demonstrate elimination of Mtb-infected cells and reduction of intracellular Mtb growth. Our study suggests an approach to enhance host T cell immunity against Mtb and provides proof of principle for an innovative TCR-based therapeutic strategy overcoming HLA polymorphism and therefore applicable to a broader patient population.
Emulsion and liposome-based adjuvanted R21 vaccine formulations mediate protection against malaria through distinct immune mechanisms.
Adjuvanted protein vaccines offer high efficacy, yet most potent adjuvants remain proprietary. Several adjuvant compounds are being developed by the Vaccine Formulation Institute in Switzerland for global open access clinical use. In the context of the R21 malaria vaccine, in a mouse challenge model, we characterize the efficacy and mechanism of action of four Vaccine Formulation Institute adjuvants: two liposomal (LQ and LMQ) and two squalene emulsion-based adjuvants (SQ and SMQ), containing QS-21 saponin (Q) and optionally a synthetic TLR4 agonist (M). Two R21 vaccine formulations, R21/LMQ and R21/SQ, offer the highest protection (81%-100%), yet they trigger different innate sensing mechanisms in macrophages with LMQ, but not SQ, activating the NLRP3 inflammasome. The resulting in vivo adaptive responses have a different TH1/TH2 balance and engage divergent innate pathways while retaining high protective efficacy. We describe how modular changes in vaccine formulation allow for the dissection of the underlying immune pathways, enabling future mechanistically informed vaccine design.
Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis.
OBJECTIVE: To investigate whether antidrug antibodies and/or drug non-trough levels predict the long-term treatment response in a large cohort of patients with rheumatoid arthritis (RA) treated with adalimumab or etanercept and to identify factors influencing antidrug antibody and drug levels to optimize future treatment decisions. METHODS: A total of 331 patients from an observational prospective cohort were selected (160 patients treated with adalimumab and 171 treated with etanercept). Antidrug antibody levels were measured by radioimmunoassay, and drug levels were measured by enzyme-linked immunosorbent assay in 835 serial serum samples obtained 3, 6, and 12 months after initiation of therapy. The association between antidrug antibodies and drug non-trough levels and the treatment response (change in the Disease Activity Score in 28 joints) was evaluated. RESULTS: Among patients who completed 12 months of followup, antidrug antibodies were detected in 24.8% of those receiving adalimumab (31 of 125) and in none of those receiving etanercept. At 3 months, antidrug antibody formation and low adalimumab levels were significant predictors of no response according to the European League Against Rheumatism (EULAR) criteria at 12 months (area under the receiver operating characteristic curve 0.71 [95% confidence interval (95% CI) 0.57, 0.85]). Antidrug antibody-positive patients received lower median dosages of methotrexate compared with antidrug antibody-negative patients (15 mg/week versus 20 mg/week; P = 0.01) and had a longer disease duration (14.0 versus 7.7 years; P = 0.03). The adalimumab level was the best predictor of change in the DAS28 at 12 months, after adjustment for confounders (regression coefficient 0.060 [95% CI 0.015, 0.10], P = 0.009). Etanercept levels were associated with the EULAR response at 12 months (regression coefficient 0.088 [95% CI 0.019, 0.16], P = 0.012); however, this difference was not significant after adjustment. A body mass index of ≥30 kg/m(2) and poor adherence were associated with lower drug levels. CONCLUSION: Pharmacologic testing in anti-tumor necrosis factor-treated patients is clinically useful even in the absence of trough levels. At 3 months, antidrug antibodies and low adalimumab levels are significant predictors of no response according to the EULAR criteria at 12 months.