Reduced Satb1 expression predisposes CD4+ T conventional cells to Treg suppression and promotes transplant survival.

Limiting CD4+ T cell responses is important to prevent solid organ transplant rejection. In a mouse model of costimulation blockade-dependent cardiac allograft tolerance, we previously reported that alloreactive CD4+ conventional T cells (Tconvs) develop dysfunction, losing proliferative capacity. In parallel, induction of transplantation tolerance is dependent on the presence of regulatory T cells (Tregs). Whether susceptibility of CD4+ Tconvs to Treg suppression is modulated during tolerance induction is unknown. We found that alloreactive Tconvs from transplant tolerant mice had augmented sensitivity to Treg suppression when compared with memory T cells from rejector mice and expressed a transcriptional profile distinct from these memory T cells, including down-regulated expression of the transcription factor Special AT-rich sequence-binding protein 1 (Satb1). Mechanistically, Satb1 deficiency in CD4+ T cells limited their expression of CD25 and IL-2, and addition of Tregs, which express higher levels of CD25 than Satb1-deficient Tconvs and successfully competed for IL-2, resulted in greater suppression of Satb1-deficient than wild-type Tconvs in vitro. In vivo, Satb1-deficient Tconvs were more susceptible to Treg suppression, resulting in significantly prolonged skin allograft survival. Overall, our study reveals that transplantation tolerance is associated with Tconvs' susceptibility to Treg suppression, via modulated expression of Tconv-intrinsic Satb1. Targeting Satb1 in the context of Treg-sparing immunosuppressive therapies might be exploited to improve transplant outcomes.

FAPI PET uptake patterns after invasive medical interventions: a single center retrospective analysis.

PURPOSE: Fibroblast activation protein (FAP)-inhibitor (FAPI)-PET tracers allow imaging of the FAP-expressing cancer associated fibroblasts (CAF) and also the normal activated fibroblasts (NAF) involved in inflammation/fibrosis that may be present after invasive medical interventions. We evaluated [68Ga]Ga-FAPI-46 uptake patterns post-medical/invasive non-systemic interventions. METHODS: This single-center retrospective analysis was conducted in 79 consecutive patients who underwent [68Ga]Ga-FAPI-46 PET/CT. Investigators reviewed prior patient medical/invasive interventions (surgery, endoscopy, biopsy, radiotherapy, foreign body placement (FBP) defined as implanted medical/surgical material present at time of scan) and characterized the anatomically corresponding FAPI uptake intensity both visually (positive if above surrounding background) and quantitatively (SUVmax). Interventions with missing data/images or confounders of [68Ga]Ga-FAPI-46 uptake (partial volume effect, other cause of increased uptake) were excluded. Available correlative FDG, DOTATATE and PSMA PET/CTs were analyzed when available. RESULTS: 163 medical/invasive interventions (mostly surgeries (49%), endoscopies (18%) and non-surgical biopsies (10%)) in 60 subjects were included for analysis. 43/163 (26%) involved FBP. FAPI uptake occurred in 24/163 (15%) of interventions (average SUVmax 3.2 (mild), range 1.5-5.1). The median time-interval post-intervention to FAPI-PET was 47.5 months and was shorter when FAPI uptake was present (median 9.5 months) than when absent (median 60.1 months; p = 0.001). Cut-off time beyond which no FAPI uptake would be present post-intervention without FBP was 8.2 months, with a sensitivity, specificity, positive predictive value and negative predictive value of 82, 90, 99 and 31% respectively. No optimal cutoff point could be determined when considering interventions with FBP. No significant difference was detected between frequency of [68Ga]Ga-FAPI-46 and [18F]FDG uptake in intervention sites. Compared to [68Ga]Ga-PSMA-11, [68Ga]Ga-FAPI-46 revealed more frequent and intense post-interventional tracer uptake. CONCLUSION: [68Ga]Ga-FAPI-46 uptake from medical/invasive interventions without FBP appears to be time dependent, nearly always absent beyond 8 months post-intervention, but frequently present for years with FBP.

Metabolomics-based pharmaceutical evaluation of different parts of Swertia chirayita (Roxb.) Buch.-Ham. ex C.B. Clarke from the western Himalayas.

Swertia species are common ingredients in numerous herbal remedies. It is also used to treat a wide range of illnesses and possess diverse therapeutic activities. The aim of the study is to elucidate the comprehensive metabolomics profile of Swertia chirayita and the role of various extraction methods in the phytochemical compositions of the extracts of S. chirayita, and their antioxidant and enzyme inhibitory activities. Extraction of the stems, leaves, and flowering tops of S. chirayita was performed by maceration, infusion, and soxhlation using methanol and water as solvent. Extracts were subjected to phytochemical profiling by a liquid-chromatographic system. Antioxidant and enzyme inhibitory activity was carried out. The metabolomics profiling showed that a diverse range of specialized metabolites were present in the stems and leaves & flowering tops of the plant. All the extracts showed substantial antioxidant and enzyme inhibitory activities further confirmed by molecular docking studies. This study appraised the use of S. chirayita aerial parts as a potential antioxidant and its therapeutic application in various chronic illnesses including Alzheimer's disease, diabetes, and other skin-related disorders.

Comparison of guidelines for biological ancillary materials used for the manufacture of gene and cellular therapy products in Asia.

BACKGROUND AIMS: Although biologiocal ancillay materials (AMs) have specific risk associated with their derivations, it plays key role to manufature cell and gene therapy (CGT) products. It is important to understand the regulation relevant to AMs for developers. METHODS: The authors investigated the guidelines and pharmacopeia (hereinafter referred to as "guidelines") for biological AMs used for the manufacture of CGT products in Asia (China, India, Japan, Korea and Taiwan). In addition, the authors benchmarked the relevant guidelines in the United States (US) and European Union (EU). RESULTS AND DISCUSSIONS: The guidelines could be classified into two types based on whether specific AMs are scoped: (i) general guidelines for risk assessment of AMs and (ii) guidelines for specific AMs. The authors compared the risk categories for each type of AM provided in the general guidelines between the US and China and the specific requirements for bovine serum and trypsin in the guidelines of China, Japan, Taiwan, US and EU. The authors further compiled in-depth descriptions of the respective regulations in China, India, Japan, Korea and Taiwan. There is limited availability of some guidelines for specific AMs. Moreover, there are no common requirements established across the surveyed countries and regions. Therefore, the authors suggest a risk assessment approach for AMs with consideration of their biological origin and traceability, production steps applied and ability to control or remove AMs from the final medicinal product over the CGT manufacturing process.

Nuclear receptor Nr1d1 alleviates asthma by abating GATA3 gene expression and Th2 cell differentiation.

Nuclear receptors are a unique family of transcription factors that play cardinal roles in physiology and plethora of human diseases. The adopted orphan nuclear receptor Nr1d1 is a constitutive transcriptional repressor known to modulate several biological processes. In this study, we found that Nr1d1 plays a decisive role in T helper (Th)-cell polarization and transcriptionally impedes the formation of Th2 cells by directly binding to the promoter region of GATA binding protein 3 (GATA3) gene. Nr1d1 interacts with its cellular companion, the nuclear receptor corepressor and histone deacetylase 3 to form a stable repression complex on the GATA3 promoter. The presence of Nr1d1 also imparts protection against associated inflammatory responses in murine model of asthma and its ligand SR9011 eased disease severity by suppressing Th2 responses. Moreover, Chip-seq profiling uncovered Nr1d1 interactions with other gene subsets that impedes Th2-linked pathways and regulates metabolism, immunity and brain functions, therefore, providing empirical evidence regarding the genetic link between asthma and other comorbid conditions. Thus, Nr1d1 emerges as a molecular switch that could be targeted to subdue asthma.

Rational Computational Approaches in Drug Discovery: Potential Inhibitors for Allosteric Regulation of Mutant Isocitrate Dehydrogenase-1 Enzyme in Cancers.

Mutations in homodimeric isocitrate dehydrogenase (IDH) enzymes at specific arginine residues result in the abnormal activity to overproduce D-2 hydroxyglutarate (D-2HG), which is often projected as solid oncometabolite in cancers and other disorders. As a result, depicting the potential inhibitor for D-2HG formation in mutant IDH enzymes is a challenging task in cancer research. The mutation in the cytosolic IDH1 enzyme at R132H, especially, may be associated with higher frequency of all types of cancers. So, the present work specifically focuses on the design and screening of allosteric site binders to the cytosolic mutant IDH1 enzyme. The 62 reported drug molecules were screened along with biological activity to identify the small molecular inhibitors using computer-aided drug design strategies. The designed molecules proposed in this work show better binding affinity, biological activity, bioavailability, and potency toward the inhibition of D-2HG formation compare to the reported drugs in the in silico approach.

Target-based in-silico screening of basil polysaccharides against different epigenetic targets responsible for breast cancer.

PURPOSE: Breast cancer (BC) is one of the leading types of cancer found in women. One of the causes reported for BC is improper regulation of epigenetic modifications. Various epigenetic targets such as histone deacetylases (HDAC) and histone acetyltransferases (HAT) regulate many types of cancer, including BC. Basil is known to possess anti-cancer properties; however, the role of its polysaccharides against different epigenetic targets is still not very clear. Therefore, the molecular docking method is used to find out the binding potential of the BPSs against different epigenetic targets responsible for BC. METHODS: All the basil polysaccharides (BPSs) were screened against the diverse epigenetic targets reported for BC (HDAC1-2, 4-8, and HAT) using molecular docking studies alongwith swissADME studies to check the drug likeliness of the BPSs. RESULTS: It was found that glucosamine ring, glucosamine linear, glucuronic acid linear, rhamnose linear, glucuronic acid ring, galactose ring, mannose, glucose, and xylose were exhibited consistent binding potential against the epigenetic targets (HDAC1, HDAC2, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HAT,) responsible for BC. CONCLUSION: This is the first report where BPSs were reported against these epigenetic targets. These studies can help to understand the underlying mechanism of BPSs used against epigenetic targets for BC. These results can be further validated experimentally to confirm their potential as a promising inhibitor against the epigenetic targets (HDAC1-2, 4-8, and HAT) having a role in BC.

Nonclinical and quality assessment of cell therapy products: Report on the 4th Asia Partnership Conference of Regenerative Medicine, April 15, 2021.

The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future.

Aquaporin-mediated transport: Insights into metalloid trafficking.

Metalloids in plants have diverse physiological effects. From being essential to beneficial to toxic, they have significant effects on many physiological processes, influencing crop yield and quality. Aquaporins are a group of membrane channels that have several physiological substrates along with water. Metalloids have emerged as one of their important substrates and they are found to have a substantial role in regulating plant metalloid homeostasis. The present review comprehensively details the multiple isoforms of aquaporins having specificity for metalloids and being responsible for their influx, distribution or efflux. In addition, it also highlights the usage of aquaporin-mediated transport as a selection marker in toxic screens and as tracer elements for closely related metalloids. Therefore, aquaporins, with their imperative contribution to the regulation of plant growth, development and physiological processes, need more research to unravel the metalloid trafficking mechanisms and their future applications.

Non-clinical assessment of cell therapy products: the perspective from five Asian countries/regions based on regulatory guidelines and the underpinning rationales.

BACKGROUND AIMS: Cell-based regenerative medicine is an innovative field that can potentially alter the overall survival and quality of life of patients with devastating diseases. Several cell therapy products (CTPs) have been approved within the last two decades, and more are under development. The establishment of an effective developmental strategy in accordance with the regulatory bodies of each country/region is crucial for fast delivery of each respective CTP. In particular, facilitating investigational new drug (IND) approval is important for accelerating the transition from non-clinical to clinical research/trial phases. METHODS: Here the authors compared the non-clinical prerequisites for initiating clinical studies in five Asian countries/regions (India, China, Korea, Taiwan and Japan) from an industry viewpoint. The authors first identified the differences and tried to clarify the perspectives/considerations underpinning the different requirements. RESULTS: The authors' findings revealed that differences in regulations and development experiences, especially with CTPs, have led to clear differences in the non-clinical study package and its corresponding study design. CONCLUSIONS: By sharing experiences of the research and development of CTPs among Asian countries/regions and including not only industry but also regulatory authorities, we will be able to expedite cross-border IND approval and eventually contribute to the early delivery of innovative CTPs to many Asian patients.

Investigating the genetic susceptibility to exertional heat illness.

BACKGROUND: We aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap. METHODS: The coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature. RESULTS: We found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI. CONCLUSION: We confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.

In silico, in-vitro and in vivo screening of biological activities of citral.

Citral, one of the main components of lemongrass oil (65-85%), is known to possess various medicinal properties like enhancing skin health and vision-improvement. It also acts as flavoring agent, used in perfumes and skin care products. The objective of this work was to elucidate the biological properties of citral at molecular level using an integrated in silico, in vitro and in vivo approaches. To elucidate this in silico molecular docking studies were performed with in vitro validation by DPPH scavenging activity, MTT assays, enzymatic assays and Chorio Allantoic Membrane (CAM) assay. The in silico analysis demonstrated the potential binding of citral with PPARγ ligand binding domain and vascular endothelial growth factor receptors (VEGFR-1 and VEGFR-2). Citral is already a proven anti-oxidant which is further confirmed by increased DPPH inhibition with increased citral concentration (IC50: 6.9 ± 1.68 µg/ml, p < 0.05). The results demonstrated that citral protect yeast cells from cytotoxic effects of hydrogen peroxide and also increase the activities of antioxidant enzymes like GST, SOD and LPO. It was also demonstrated to be cytotoxic to cancerous HeLa cells (IC50: 3.9 ± 0.38 µM, p < 0.01) and was found anti-angiogenic by CAM assay. This study highlights many important pharmaceutical properties of citral which can be explored further to increase its industrial applications.

A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin.

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug-efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug-efflux transporters in macrophages. This was evident from expression analysis of drug-efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible M. tuberculosis, we observed increased intracellular survival of M. tuberculosis upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, M. tuberculosis infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters in vitro We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug-efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of M. tuberculosis that arises from drug-efflux systems of the host.

Human Xenobiotic Nuclear Receptor PXR Augments Mycobacterium tuberculosis Survival.

Mycobacterium tuberculosis can evade host defense processes, thereby ensuring its survival and pathogenesis. In this study, we investigated the role of nuclear receptor, pregnane X receptor (PXR), in M. tuberculosis infection in human monocyte-derived macrophages. In this study, we demonstrate that PXR augments M. tuberculosis survival inside the host macrophages by promoting the foamy macrophage formation and abrogating phagolysosomal fusion, inflammation, and apoptosis. Additionally, M. tuberculosis cell wall lipids, particularly mycolic acids, crosstalk with human PXR (hPXR) by interacting with its promiscuous ligand binding domain. To confirm our in vitro findings and to avoid the reported species barrier in PXR function, we adopted an in vivo mouse model expressing hPXR, wherein expression of hPXR in mice promotes M. tuberculosis survival. Therefore, pharmacological intervention and designing antagonists to hPXR may prove to be a promising adjunct therapy for tuberculosis.

The development of a pragmatic, clinically driven ultrasound curriculum in a UK medical school.

Whether ultrasound (US) should be incorporated into a medical undergraduate curriculum remains a matter of debate within the medical education arena. There are clear potential benefits to its early introduction particularly with respect to the study of living anatomy and physiology in addition to the learning of clinical skills and procedures required for the graduate clinical practice. However, this needs to be balanced against what is perceived as an added value in addition to financial and time constraints which may potentially lead to the sacrifice of other aspects of the curriculum. Several medical schools have already reported their experiences of teaching US either as a standalone course or as a fully integrated vertical curriculum. This article describes and discusses the initial experience of a UK medical school that has taken the steps to develop its own pragmatic vertical US curriculum based on clinical endpoints with the intent of using US to enhance the learning experience of students and equipping them with the skills required for the safe practice as a junior doctor.

IL-17A Blockade Attenuates Obliterative Bronchiolitis and IFN-γ Cellular Immune Response in Lung Allografts.

Obliterative bronchiolitis (OB), characterized by fibrous obliteration of the small airways, is a major impediment to long-term survival in lung allograft recipients. We found previously that IL-17A is produced primarily by CD4+ T cells and γδ T cells after lung transplant in a mouse model of orthotopic lung transplant. The absence of either subset of T cells was compensated for by expansion of the other subset, which suggested that systemic blockade of IL-17A was necessary. To determine the specific role of IL-17A in the development of OB, we treated lung allograft recipients with an IL-17A antagonistic antibody. After IL-17A blockade, the incidence of OB was significantly reduced in lung allografts. IL-17A blockade also significantly attenuated the severity of acute rejection and overall lung fibrosis. The decreased OB incidence was associated with reduced lymphocyte recruitment, particularly CD8+ T cells and other IFN-γ-producing lymphocytes, to the lung allograft. Interestingly, IL-17A blockade led to an increase in the frequency of IL-17A-producing T-helper cell type 17 cells and γδ T cells in lung allografts, suggesting that IL-17A is a negative regulator of these T cells. Our data suggest that blocking IL-17A after lung transplant reduces the overall IFN-γ-mediated lymphocyte response and decreases the development of OB.

Lipoprotein LprI of Mycobacterium tuberculosis Acts as a Lysozyme Inhibitor.

Mycobacterium tuberculosis executes numerous defense strategies for the successful establishment of infection under a diverse array of challenges inside the host. One such strategy that has been delineated in this study is the abrogation of lytic activity of lysozyme by a novel glycosylated and surface-localized lipoprotein, LprI, which is exclusively present in M. tuberculosis complex. The lprI gene co-transcribes with the glbN gene (encoding hemoglobin (HbN)) and both are synchronously up-regulated in M. tuberculosis during macrophage infection. Recombinant LprI, expressed in Escherichia coli, exhibited strong binding (Kd ≤ 2 nm) with lysozyme and abrogated its lytic activity completely, thereby conferring protection to fluorescein-labeled Micrococcus lysodeikticus from lysozyme-mediated hydrolysis. Expression of the lprI gene in Mycobacterium smegmatis (8-10-fold) protected its growth from lysozyme inhibition in vitro and enhanced its phagocytosis and survival during intracellular infection of peritoneal and monocyte-derived macrophages, known to secrete lysozyme, and in the presence of exogenously added lysozyme in secondary cell lines where lysozyme levels are low. In contrast, the presence of HbN enhanced phagocytosis and intracellular survival of M. smegmatis only in the absence of lysozyme but not under lysozyme stress. Interestingly, co-expression of the glbN-lprI gene pair elevated the invasion and survival of M. smegmatis 2-3-fold in secondary cell lines in the presence of lysozyme in comparison with isogenic cells expressing these genes individually. Thus, specific advantage against macrophage-generated lysozyme, conferred by the combination of LprI-HbN during invasion of M. tuberculosis, may have vital implications on the pathogenesis of tuberculosis.

Nuclear receptor expression atlas in BMDCs: Nr4a2 restricts immunogenicity of BMDCs and impedes EAE.

The nuclear receptor (NR) superfamily of transcription factors regulates various key aspects of physiological processes; however, their role(s) in immune cells' function are just beginning to unravel. Although few NRs have been shown to be critical for dendritic cell (DC) function, a lack of knowledge about their complete representation in DCs has limited the ability to harness their full potential. Here, we performed a comprehensive NR expression profiling and identified the key members of NR superfamily being expressed in immature, immunogenic, and tolerogenic DCs. Comparative analysis revealed discrete changes in the expression of various NRs among the studied DC subtypes, indicating a likely role in the modulation of DC functionality. Next, we characterized Nr4a2, a member of orphan NR family, and found that it suppresses the activation of bone marrow derived dendritic cells triggered by LPS. Overexpression and knockdown of Nr4a2 demonstrated that Nr4a2 orchestrates the expression of immunoregulatory genes, hence inducing a tolerogenic phenotype in bone marrow derived dendritic cells. Furthermore, we also found that Nr4a2 provides protection from EAE by promoting an increase in Treg cells, while limiting effector T cells. Our findings suggest a previously unidentified role for Nr4a2 as a regulator of DC tolerogenicity and demonstrate its potential as therapeutic target in DC-associated pathophysiologies.

Th17 cells are not required for maintenance of IL-17A-producing γδ T cells in vivo.

γδ T cells producing interleukin-17A (γδT17) are thought to develop spontaneously in the thymus and to be maintained in the periphery. Previous studies suggested a role for T-helper 17 (Th17) cells in the maintenance of γδT17 via the expression of transforming growth factor-ß1 (TGFß1). However, we have previously found that Th17 cells were not required for expansion of γδT17 cells after lung transplant in a mouse model. Using mice deficient in signal transducer and activator of transcription 3 (STAT3) in CD4+ T cells, which are unable to develop Th17 cells, we investigated the requirement for Th17 cells and TGFß1 to maintain γδT17 cells in the lung and lymphoid tissues. At steady state, we found no defect in γδT17 cells in the thymus or periphery of these mice. Further, STAT3-deficient CD4+ T cells produced significantly higher levels of TGFß1 than wild-type CD4+ T cells under Th17 differentiation conditions in vitro. To determine whether STAT3-deficient CD4+ T cells could expand γδT17 cells in vivo, we used TCRß-/- mice, which are known to have a defect in γδT17 cells that can be rescued by Th17 cells. However, adoptive transfer of wild-type Th17 cells or bulk CD4+ T cells did not expand γδT17 cells in TCRß-/- mice. In contrast, interferon-γ+ γδ T cells preferentially expanded, particularly in the lungs. Interestingly, we found in vivo and in vitro that TGFß1 may negatively regulate the pool of γδT17 cells. Our data suggest that Th17 cells and TGFß1 are not required for the maintenance of γδT17 cells.

Transient aortitis documented by positron emission tomography in a case series of men and transgender women infected with syphilis.

OBJECTIVES: Syphilis infection persists globally contributing to preventable and treatable morbidity and mortality. How extensive early syphilis disseminates is unknown. To better understand the relationship between early syphilis infection and inflammation over time, our study enrolled six individuals recently infected with syphilis for sequential positron emission tomography (PET) scans. METHODS: We evaluated a case series of six individuals with high syphilis titres (two secondary, two early latent and two latent, unknown duration, but with high titre) who received sequential PET scans to assess inflammation over time and its response to treatment. RESULTS: At time of PET scan, four of the six individuals were co-infected with HIV. One of the four was not on antiretroviral therapy and three of the four were not virally suppressed (viral load of >400 copies/mL). Baseline rapid plasma reagin (RPR) titres ranged from 1:64 to 1:256 (four of the six participants had prior non-reactive RPR results). Five of the six participants had mild to intense hypermetabolic PET scan activity consistent with cervical (n=5), axillary (n=4), inguinal (n=5) and retroperitoneal (n=1) adenopathy. Mild hypermetabolic activity in the thoracic aortic wall, suggesting aortitis, was present among the same five participants and resolved within 30 days for four of the five participants and 60 days for the other participant. However, widespread lymphadenopathy remained present in PET scans up to 3 months following treatment in two participants. We did not find any abnormal PET scan activity of the central nervous system. CONCLUSION: We found abnormal aortic wall PET scan activity suggesting aortitis to be common in a case series of patients with early syphilis. In research settings, PET scans may be a sensitive tool to monitor inflammation associated with syphilis.