Recirculating Intestinal IgA-Producing Cells Regulate Neuroinflammation via IL-10.

Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

Eo, what are we doing here?

A plethora of studies have established the importance of eosinophils in protective immunity against infections and in allergy. In this issue of Immunity, Ignacio et al. (2022) define a vital for eosinophils in coordinating a microbiota-epithelial-immune axis that maintains intestinal homeostasis.

Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation.

Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.

The influence of aging and the microbiome in multiple sclerosis and other neurologic diseases.

The human gut microbiome is well-recognized as a key player in maintaining health. However, it is a dynamic entity that changes across the lifespan. How the microbial changes that occur in later decades of life shape host health or impact age-associated inflammatory neurological diseases such as multiple sclerosis (MS) is still unclear. Current understanding of the aging gut microbiome is largely limited to cross-sectional observational studies. Moreover, studies in humans are limited by confounding host-intrinsic and extrinsic factors that are not easily disentangled from aging. This review provides a comprehensive summary of existing literature on the aging gut microbiome and its known relationships with neurological diseases, with a specific focus on MS. We will also discuss preclinical animal models and human studies that shed light on the complex microbiota-host interactions that have the potential to influence disease pathology and progression in aging individuals. Lastly, we propose potential avenues of investigation to deconvolute features of an aging microbiota that contribute to disease, or alternatively promote health in advanced age.

Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44.

B cells thwart antigenic aggressions by releasing immunoglobulin M (IgM), IgG, IgA, and IgE, which deploy well-understood effector functions. In contrast, the role of secreted IgD remains mysterious. We found that some B cells generated IgD-secreting plasma cells following early exposure to external soluble antigens such as food proteins. Secreted IgD targeted basophils by interacting with the CD44-binding protein galectin-9. When engaged by antigen, basophil-bound IgD increased basophil secretion of interleukin-4 (IL-4), IL-5, and IL-13, which facilitated the generation of T follicular helper type 2 cells expressing IL-4. These germinal center T cells enhanced IgG1 and IgE but not IgG2a and IgG2b responses to the antigen initially recognized by basophil-bound IgD. In addition, IgD ligation by antigen attenuated allergic basophil degranulation induced by IgE co-ligation. Thus, IgD may link B cells with basophils to optimize humoral T helper type 2-mediated immunity against common environmental soluble antigens.

Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice.

The paradigm that macrophages that reside in steady-state tissues are derived from embryonic precursors has never been investigated in the intestine, which contains the largest pool of macrophages. Using fate-mapping models and monocytopenic mice, together with bone marrow chimera and parabiotic models, we found that embryonic precursor cells seeded the intestinal mucosa and demonstrated extensive in situ proliferation during the neonatal period. However, these cells did not persist in the intestine of adult mice. Instead, they were replaced around the time of weaning by the chemokine receptor CCR2-dependent influx of Ly6C(hi) monocytes that differentiated locally into mature, anti-inflammatory macrophages. This process was driven largely by the microbiota and had to be continued throughout adult life to maintain a normal intestinal macrophage pool.

Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair.

Type 2 inflammatory responses can be elicited by diverse stimuli, including toxins, venoms, allergens, and infectious agents, and play critical roles in resistance and tolerance associated with infection, wound healing, tissue repair, and tumor development. Emerging data suggest that in addition to characteristic type 2-associated cytokines, the epidermal growth factor (EGF)-like molecule Amphiregulin (AREG) might be a critical component of type 2-mediated resistance and tolerance. Notably, numerous studies demonstrate that in addition to the established role of epithelial- and mesenchymal-derived AREG, multiple leukocyte populations including mast cells, basophils, group 2 innate lymphoid cells (ILC2s), and a subset of tissue-resident regulatory CD4(+) T cells can express AREG. In this review, we discuss recent advances in our understanding of the AREG-EGF receptor pathway and its involvement in infection and inflammation and propose a model for the function of this pathway in the context of resistance and tissue tolerance.

Patient Perceptions of Surveillance of Small Abdominal Aortic Aneurysms in the Over 85s.

BACKGROUND: Recently instigated local practice for patients with small abdominal aortic aneurysms (AAAs) involves contacting all patients, aged ≥85 years, to discuss with them the advantages and disadvantages of removal from surveillance. However, reasons why patients opt to remain on, or come off, surveillance, are currently unknown. The present study's objective is to explore patient perception of surveillance decision-making. METHODS: A mixed-methods exploratory evaluation was undertaken using patient feedback obtained from a telephone survey. All patients aged ≥85 years, who had a consultation regarding ongoing surveillance of small AAAs (30-49 mm), and consented, were contacted by researchers, who conducted semi-structured interviews concerning factors influencing decision-making. RESULTS: A total of 24 patients (20 male; mean age = 86.9 years) were interviewed; 16 of 24 (66%) had opted to remain on surveillance, with no age difference between those opting in or out. Most felt surveillance was important (91%), and that it made them feel safer (73%). The majority (73%) thought they knew what happened when their AAA reached threshold (5.5 cm), what happened when a threshold AAA is not fixed (64%), and how major AAA surgery is (59%). However, actual knowledge was poor: most (91%) correctly understood surgery was major, but 56% thought that threshold AAA meant certain death or rupture; and 38% thought immediate surgery was required. Thematic analysis expounded patients' beliefs regarding surveillance, which were summarized in 3 distinct subgroups: reliance on professionals' opinions, needing peace of mind, and poor understanding. CONCLUSIONS: While most patients find surveillance reassuring, patient knowledge of AAA management at threshold is poor, potentially impacting surveillance decision-making. Elderly patients, with small AAAs contemplating ongoing surveillance, need to be better informed about AAA management at threshold to support shared decision-making.

Vasoactive intestinal peptide promotes host defense against enteric pathogens by modulating the recruitment of group 3 innate lymphoid cells.

Group 3 innate lymphoid cells (ILC3s) control the formation of intestinal lymphoid tissues and play key roles in intestinal defense. They express neuropeptide vasoactive intestinal peptide (VIP) receptor 2 (VPAC2), through which VIP modulates their function, but whether VIP exerts other effects on ILC3 remains unclear. We show that VIP promotes ILC3 recruitment to the intestine through VPAC1 independent of the microbiota or adaptive immunity. VIP is also required for postnatal formation of lymphoid tissues as well as the maintenance of local populations of retinoic acid (RA)-producing dendritic cells, with RA up-regulating gut-homing receptor CCR9 expression by ILC3s. Correspondingly, mice deficient in VIP or VPAC1 suffer a paucity of intestinal ILC3s along with impaired production of the cytokine IL-22, rendering them highly susceptible to the enteric pathogen Citrobacter rodentium This heightened susceptibility to C. rodentium infection was ameliorated by RA supplementation, adoptive transfer of ILC3s, or by recombinant IL-22. Thus, VIP regulates the recruitment of intestinal ILC3s and formation of postnatal intestinal lymphoid tissues, offering protection against enteric pathogens.

Restriction of Viral Replication, Rather than T Cell Immunopathology, Drives Lethality in Murine Norovirus CR6-Infected STAT1-Deficient Mice.

Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. In this study, we used colonization with the model commensal murine norovirus (MNV; strain CR6) to interrogate host-directed mechanisms of viral regulation, and we show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In addition to restricting CR6 replication to the intestinal tract, we show that STAT1 regulates antiviral CD4+ and CD8+ T cell responses and prevents systemic viral-induced tissue damage and disease. Despite altered T cell responses that resemble those that mediate lethal immunopathology in systemic viral infections in STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. However, therapeutic administration of an antiviral compound limited viral replication, preventing virus-induced tissue damage and death without impacting the generation of inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa and that uncontrolled viral replication mediates disease rather than the concomitant development of dysregulated antiviral T cell responses in STAT1-deficient mice. IMPORTANCE The intestinal microbiota is a collection of bacteria, archaea, fungi, and viruses that colonize the mammalian gut. Coevolution of the host and microbiota has required development of immunological tolerance to prevent ongoing inflammatory responses against intestinal microbes. Breakdown of tolerance to bacterial components of the microbiota can contribute to immune activation and inflammatory disease. However, the mechanisms that are necessary to maintain tolerance to viral components of the microbiome, and the consequences of loss of tolerance, are less well understood. Here, we show that STAT1 is integral for preventing escape of a commensal-like virus, murine norovirus CR6 (MNV CR6), from the gut and that in the absence of STAT1, mice succumb to infection-induced disease. In contrast to the case with other systemic viral infections, mortality of STAT1-deficient mice is not driven by immune-mediated pathology. Our data demonstrate the importance of host-mediated geographical restriction of commensal-like viruses.

Thymic stromal lymphopoietin-mediated extramedullary hematopoiesis promotes allergic inflammation.

Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern-recognition receptor (PRR)-expressing HSCs, EMH, and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for thymic stromal lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages, dendritic cells, and granulocytes and that these cells contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway might operate in human disease. These data identify that TSLP-induced EMH contributes to the development of allergic inflammation and indicate that EMH is a conserved mechanism of innate immunity.

Patient Satisfaction with Tele- and Video-Consultation in the COVID-19 Era - A Survey of Vascular Surgical Patients.

BACKGROUND: The COVID 19 pandemic has resulted in the increasing use of telemedicine due to the advantages of avoiding viral transmission. Evidence suggests that telemedicine, for certain conditions, may be as effective as face-to-face consultations; however, there is no research to date regarding vascular patients' acceptance or satisfaction with telemedicine during and after the COVID-19 pandemic. METHODS: A patient satisfaction interview was designed to survey three aspects of the service: patient acceptability of teleconsultations as a replacement to physical clinics; their views of teleconsultation during the pandemic; and the future role of teleconsultations postpandemic. Patients undergoing remote teleconsultation (either by telephone or video software), between April and June 2020 were suitable for inclusion. Patients were contacted by telephone in August 2020 to undertake the survey. Local "Research and Development" approval was obtained. RESULTS: A total of 333 patients had a consultation with a vascular consultant between April and June 2020, of which 178 were teleconsultations. Successful contact was made with 72 patients, of whom 68 agreed to participate; 10 patients had undergone video consultations, while the remainder had telephone consultations. Teleconsultations were widely viewed as acceptable, and over 90% of patients felt they were beneficial. 91% felt that not needing to travel for appointments was advantageous to them. The option of teleconsultation during the COVID pandemic was valued by 94% of the cohort. While all interviewees felt teleclinics should continue during the pandemic, the majority (74%) also wanted to use teleconsultations for clinic appointments after the pandemic. CONCLUSIONS: Telemedicine is viewed by vascular patients as generally acceptable and beneficial for use during the pandemic. The majority of patients wanted future telemedicine appointments postpandemic. Telemedicine services started as a result of the COVID-19 pandemic, which may have been viewed as a temporary measure, should be planned to continue long term.

Cluster randomised control trial of the effect on attendance and outcomes of multi-disciplinary teams involving psychologists during pelvic floor muscle training for pelvic floor dysfunction.

Pelvic floor muscle training (PFMT) is effective, acceptable to patients, and cost efficient as a treatment for Pelvic Floor Dysfunction (PFD). However, PFMT outcomes are mediated by patient variables, such as depression, anxiety, motivation, and health values. The current study examined whether multi-disciplinary provision of PFMT involving a psychologist would improve attendance and outcomes (Clinical Trial Registration: NCT02549157). 88 consecutively referred patients (age 28 - 85 years), with a variety of PFD, were randomised into two groups: PFMT treatment as usual (n = 47), and PFMT with a psychologist involved (n = 41). Patients received 6-month out-patient physiotherapy. More patients with the psychologist completed the course, and there were significantly greater improvements in subjective symptoms (Queensland scale), quality of life (EQ-5D), and anxiety (HADS), although not in objective measures (Oxford Grading) or depression (HADS). These results suggest that an MDT including a psychologist during PFMT intervention treatment may help some patients.IMPACT STATEMENTWhat is already known on this subject? Pelvic floor muscle training (PFMT) is effective, acceptable to patients, and cost efficient as a treatment for Pelvic Floor Dysfunction (PFD). However, PFMT outcomes are mediated by patient variables, such as depression, anxiety, motivation, and health values. The effectiveness of a multi-disciplinary team delivering both PFMT and psychological support simultaneously to women undergoing PFMT for PFD is unknown.What do the results of this study add? Psychological support delivered alongside PFMT increased patient attendance, improved subjective ratings of pelvic floor functioning, health-related quality of life, and reduced anxiety. This is one of the first demonstrations that this can be achieved through a multi-disciplinary team delivering their support simultaneously to the patients.What are the implications of these findings for clinical practice and/or further research? Improving subjective functioning and reducing attrition rates in PFD patients has cost implications in terms of reduced need for surgery, and making future surgery more effective. The inclusion of brief, easily delivered psychological support, integrated into the PFMT sessions in a multidisciplinary way may represent an extremely cost effective method of improving the service for these patients.

Acceptability and effectiveness of a multidisciplinary team approach involving counselling for mesh-removal patients.

Patients with complications following mesh removal risk a variety of symptoms, and can view medical intervention negatively. This study explored the patient-acceptability of a Multidisciplinary Team (MDT), and whether the presence of a Counsellor would be accepted and effective. Twenty consecutively referred women, who had undergone mesh-removal but experienced complications were interviewed about their experiences, and completed the Queensland scale for pelvic floor symptoms, McGill Pain Questionnaire, and Hospital Anxiety and Depression Scales, before and after treatment. Patients had high levels of pelvic-floor symptoms, sensory and affective pain, anxiety, and depression. 70% reported a positive MDT experience; predicted by higher anxiety, and lower depression. 60% elected to receive Counselling, which commenced within one week of referral, typically lasted 1-4 sessions, and reduced pelvic-floor symptoms, affective pain, anxiety, and depression. Results suggest that the MDT approach is generally acceptable for this patient group, and that mesh-removal patients accept and benefit from input by a Counsellor.Impact statementWhat is already known on this subject? Concerns have been raised regarding the safety of mesh insertion. Multidisciplinary Teams (MDTs) are suggested to offer a strong approach to managing many women's health conditions, but no studies have examined mesh-removal patients, making generalisation difficult to the current patient group. Furthermore, it is unknown whether an MDT approach, including a Counsellor, would be acceptable to mesh-removal patients.What do the results of this study add? Patients had high levels of pelvic-floor symptoms, pain, anxiety, and depression. 70% reported the MDT experience as positive, predicted by higher anxiety, and lower depression. 60% elected to receive Counselling, which reduced pelvic-floor symptoms, affective pain, anxiety, and depression.What are the implications of these findings for clinical practice and/or further research? The Counselling provided as part of the MDT approach was able to commence quickly, did not require many sessions, and reduced reported pelvic-floor symptoms, affective pain, anxiety, and depression. These findings suggest that an MDT approach involving Counselling is generally acceptable, and that mesh-removal patients accept and benefit from the input of a Counsellor, as part of their treatment.

Commensal bacteria calibrate the activation threshold of innate antiviral immunity.

Signals from commensal bacteria can influence immune cell development and susceptibility to infectious or inflammatory diseases. However, the mechanisms by which commensal bacteria regulate protective immunity after exposure to systemic pathogens remain poorly understood. Here, we demonstrate that antibiotic-treated (ABX) mice exhibit impaired innate and adaptive antiviral immune responses and substantially delayed viral clearance after exposure to systemic LCMV or mucosal influenza virus. Furthermore, ABX mice exhibited severe bronchiole epithelial degeneration and increased host mortality after influenza virus infection. Genome-wide transcriptional profiling of macrophages isolated from ABX mice revealed decreased expression of genes associated with antiviral immunity. Moreover, macrophages from ABX mice exhibited defective responses to type I and type II IFNs and impaired capacity to limit viral replication. Collectively, these data indicate that commensal-derived signals provide tonic immune stimulation that establishes the activation threshold of the innate immune system required for optimal antiviral immunity.

A critical analysis of helminth immunotherapy in multiple sclerosis.

Helminthic worms are ancestral members of the intestinal ecosystem that have been largely eradicated from the general population in industrialized countries. Immunomodulatory mechanisms induced by some helminths mediate a "truce" between the mammalian host and the colonizing worm, thus allowing for long-term persistence in the absence of immune-mediated collateral tissue damage. This concept and the geographic discrepancy between global burdens of chronic inflammatory diseases and helminth infection have sparked interest in the potential of using helminthic worms as a therapeutic intervention to limit the progression of autoimmune diseases such as multiple sclerosis (MS). Here, we present and evaluate the evidence for this hypothesis in the pre-clinical animal model of MS, experimental autoimmune encephalitis, in helminth-infected MS patients and in clinical trials of administered helminth immunotherapy (HIT).

Correction: Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

[This corrects the article DOI: 10.1371/journal.ppat.1005684.].

Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis.

The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3(ΔIEC) mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3(ΔIEC) mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3(ΔIEC) mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3(ΔIEC) mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.

Type I Interferon Receptor Deficiency in Dendritic Cells Facilitates Systemic Murine Norovirus Persistence Despite Enhanced Adaptive Immunity.

In order for a virus to persist, there must be a balance between viral replication and immune clearance. It is commonly believed that adaptive immunity drives clearance of viral infections and, thus, dysfunction or viral evasion of adaptive immunity is required for a virus to persist. Type I interferons (IFNs) play pleiotropic roles in the antiviral response, including through innate control of viral replication. Murine norovirus (MNoV) replicates in dendritic cells (DCs) and type I IFN signaling in DCs is important for early control of MNoV replication. We show here that the non-persistent MNoV strain CW3 persists systemically when CD11c positive DCs are unable to respond to type I IFN. Persistence in this setting is associated with increased early viral titers, maintenance of DC numbers, increased expression of DC activation markers and an increase in CD8 T cell and antibody responses. Furthermore, CD8 T cell function is maintained during the persistent phase of infection and adaptive immune cells from persistently infected mice are functional when transferred to Rag1-/- recipients. Finally, increased early replication and persistence are also observed in mixed bone marrow chimeras where only half of the CD11c positive DCs are unable to respond to type I IFN. These findings demonstrate that increased early viral replication due to a cell-intrinsic innate immune deficiency is sufficient for persistence and a functional adaptive immune response is not sufficient for viral clearance.