Mucosal Immunity

Review Article...

KEY POINTS Trout have limited IgM and IgT repertoire diversity in NALT. Intranasal vaccination in trout triggers systemic and mucosal Ig response. IgM and IgT respond to i.p. and intranasal bacterin vaccination. Abstract Bony fish represent the most basal vertebrate branch with a dedicated mucosal immune system, which comprises immunologically heterogeneous microenvironments armed with innate and adaptive components. In rainbow trout (Oncorhynchus mykiss), a nasopharynx-associated lymphoid tissue (NALT) was recently described as a diffuse network of myeloid and lymphoid cells located in the olfactory organ of fish. Several studies have demonstrated high levels of protection conferred by nasal vaccines against viral and bacterial pathogens; however, the mechanisms underlying the observed protection are not well understood. We applied 5′RACE and a deep sequencing–based approach to investigate the clonal structure of the systemic and mucosal rainbow trout B cell repertoire. The analysis of Ig repertoire in control trout suggests different structures of IgM and IgT spleen and NALT repertoires, with restricted repertoire diversity in NALT. Nasal and injection vaccination with a bacterial vaccine revealed unique dynamics of IgM and IgT repertoires at systemic and mucosal sites and the remarkable ability of nasal vaccines to induce spleen Ig responses. Our findings provide an important immunological basis for the effectiveness of nasal vaccination in fish and other vertebrate animals and will help the design of future nasal vaccination strategies. Footnotes This work was supported by USDA AFRI Grant 2DN70-2RDN7 (to I.S.). S.M. also received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA Grant Agreement 600391. The dataset presented in this article has been submitted to the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/sra/) under accession number PRJNA551127. The online version of this article contains supplemental material. Abbreviations used in this article: D-NALT diffuse NALT ERM enteric red mouth HSD honestly significant difference HSR highly shared responding IMGT ImMunoGeneTics i.n. intranasally MID molecular identifier NALT nasopharynx-associated lymphoid tissue O-MALT MALT with well-organized SLOs O-NALT organized NALT PBT PBS pH 7.4 with 0.05% Tween 20 SLO secondary lymphoid organ UID unique molecular identifier. Received February 7, 2019. Accepted July 9, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

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Bacterial superantigens spur IgA secretion Mucosal IgA is abundant and interacts with the gut microbiome. To examine microbial induction of IgA in humans, Bunker et al. screened microbiota from infants against mouse and human IgA. Unexpectedly, they saw a subset of samples bound IgA in a way that indicated the presence of superantigens, which bind T cell receptors or B cell receptors outside of the typical antigen-binding region, leading to nonspecific activation. Putative superantigens were identified in commensal members of Lachnospiraceae, which activated human VH3-positive B cells and induced IgA production in mice. These data identify commensal superantigens and suggest that they may be dominant forces behind IgA production in humans. Abstract IgA is prominently secreted at mucosal surfaces and coats a fraction of the commensal microbiota, a process that is critical for intestinal homeostasis. However, the mechanisms of IgA induction and the molecular targets of these antibodies remain poorly understood, particularly in humans. Here, we demonstrate that microbiota from a subset of human individuals encode two protein “superantigens” expressed on the surface of commensal bacteria of the family Lachnospiraceae such as Ruminococcus gnavus that bind IgA variable regions and stimulate potent IgA responses in mice. These superantigens stimulate B cells expressing human VH3 or murine VH5/6/7 variable regions and subsequently bind their antibodies, allowing these microbial organisms to become highly coated with IgA in vivo. These findings demonstrate a previously unappreciated role for commensal superantigens in host-microbiota interactions. Furthermore, as superantigen-expressing strains show an uneven distribution across human populations, they should be systematically considered in studies evaluating human B cell responses and microbiota during homeostasis and disease. Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works http://www.sciencemag.org/about/science-licenses-journal-article-reuse This is an article distributed under the terms of the Science Journals Default License.

Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings.

Nutritional status potentially influences immune responses; however, how nutritional signals regulate cellular dynamics and functionality remains obsc…...

Chronic rhinosinusitis (CRS) is defined as inflammation of the mucosal lining of the nasal cavity and paranasal sinuses that has been present for more than 3 months, causing characteristic symptoms such as nasal blockage, discharge, reduction or loss of smell sensation and facial pressure. It is a broad clinical description that encompasses several phenotypes, most often divided into CRS with polyps and CRS without polyps. CRS may be the endpoint of several different inflammatory pathways and may be secondary to specific conditions such as cystic fibrosis or fungal aetiology, but most often cannot be attributed to a single pathophysiological trigger. CRS places an enormous burden on both physicians and its sufferers. It is common among the general population, affecting approximately 11% of UK adults,1 and causes greater detriment to quality of life (QoL) than angina or chronic lower respiratory tract disease.2 Not only is it a QoL issue, patients with CRS frequently have comorbid asthma, and poorly controlled CRS is associated with more frequent asthma exacerbations and a need for hospitalisation. The socio-economic cost of CRS is significant with 57% of patients reporting absenteeism and 28% experiencing associated anxiety and depression.3 4 One per cent of all UK adults will visit their general practitioner (GP) with CRS symptoms each year and require an average of four appointments each year; despite this, one in three patients in primary care has poorly controlled symptoms.5 CRS that cannot be adequately managed in primary care may require referral to secondary care, and data from Hospital Episode Statistics show that in a single year there were approximately 120 000 outpatient consultations for CRS and 40 000 sinus operations performed in England and Wales.6 However, there remains considerable debate regarding optimum management strategies leading to wide variation in practice.7 Treatment evidence and guidelines The touchstone for treatment of CRS is The European Position Paper on Rhinosinusitis and Nasal Polyps published in 2012 (EPOS 2012).8 EPOS 2012 syntheses the best available evidence and expert opinion into easy to follow treatment flowcharts for both primary care physicians and ear, nose and throat specialists, but acknowledges the large gaps in high-quality trial data on which to base their guidance. In the intervening 7 years since EPOS was published, the International Consensus Statement on Allergy and Rhinology (ICAR)9 was agreed by a multinational working group who undertook a comprehensive overview of the literature. The working group graded the available evidence and used it as the basis for recommendations; where no evidence was available, no recommendation was made. ICAR is therefore an exhaustive insight into the current state of the science in CRS and an invaluable tool for the otolaryngology community; for primary care, however, the EPOS 2012 remains perhaps the more accessible guide. In addition, there have also been several Cochrane reviews10–16 of treatments available for CRS, and these reviews along with the international consensus guidelines have been used to synthesise a National Institute for Health and Care Excellence (NICE) clinical knowledge summary, most recently updated in 2018.17 Intranasal treatment The foundation of CRS treatment is regular use of intranasal saline irrigation and corticosteroids and this strategy finds unanimous favour among the guidelines mentioned above. The evidence is weak but consistent: a Cochrane systematic review studied the effects of saline irrigation in people with chronic sinusitis.12 This identified only two studies that could robustly be included—one which compared the effect of high volume hypertonic saline irrigation to placebo in patients with CRS both with and without polyps, and another which studied only patients with polyps and compared the use of nasal saline irrigation. This Cochrane review concluded that there was weak evidence from these trials to support the use of nasal saline irrigation. In addition, it is a low-cost treatment which with low risk of adverse events. For this reason, it is recommended for virtually all patients with CRS although in practice is usually used in combination with other therapies. Intranasal corticosteroids are similarly favoured by all expert guidelines. There is a greater number of trials on which to base this opinion. A Cochrane systematic review11 identified (search date August 2015) 18 randomised controlled trials which studied the use of intranasal steroids versus placebo in CRS. The majority of these studies included patients with nasal polyps. Regular intranasal corticosteroid use was reported to be superior to placebo in all reported symptoms, although there was no evidence to support an overall improvement in QoL. A further Cochrane review of the different formulations of intranasal corticosteroids and methods of delivery13 did not identify any single agent with convincing evidence of superiority; however, there is an advantage offered by the second-generation agents (eg, mometasone furoate, fluticasone propionate, fluticasone furoate) which have favourable pharmacokinetic characteristics that minimise systemic bioavailability (<1%) compared with older intranasal corticosteroids (eg, beclomethasone diproprionate, betamethasone). Oral corticosteroids Oral corticosteroids are commonly prescribed in the treatment of CRS although there is a distinct lack of evidence for their efficacy. The NICE Clinical Knowledge Summary (CKS) makes no reference to their use. A Cochrane review in 201616 identified no studies of their use in CRS without polyps, a fact which is also reflected in the ICAR guideline.9 Their use in patients with polyps is better established, with several studies demonstrating short-term efficacy of oral corticosteroids in improving CRS-related QoL scores. Treatment courses are short—a typical regime might be 30 mg per day of prednisolone for 2–3 weeks—and thus the risk of side effects such as adrenal suppression and loss of bone mass is minimal. However, there is a risk of side effects such as gastrointestinal disturbance and insomnia even with these short courses. Patients should also be warned of the risk of osteonecrosis—a risk which may occur at doses of steroid previously thought to be safe (lowest reported associated total dose 105 mg, median associated dose 981 mg).18 The benefit of oral corticosteroids typically last 3–6 months, and so are a reasonable choice for patients who have not improved on the first line of saline irrigation and topical corticosteroids. However, an evidence‐based risk analysis of oral corticosteroid use in CRS with polyps performed by Leung et al 19 demonstrated that risk exceeded benefit if used more frequently than once every 2 years. Oral corticosteroid use is therefore restricted to short, infrequent courses, and with full disclosure of the potential serious associated side effects for patients. Antibiotics Where there is consensus recommending the use of nasal douches and corticosteroids, there is controversy regarding the use of antibiotics. Antibiotics are one of the most commonly prescribed medicines for CRS: of the 1% of UK adults with CRS who visit their GP each year, 91% of them will receive an antibiotic prescription.20 They will often receive not just one but repeated courses of antibiotics.21 There is pressure on GPs to use antibiotics as a first-line treatment, as recently some Clinical Commissioning Groups have insisted on a 3-month trial of macrolide antibiotics prior to secondary care referral.22 With the exception of acute infective exacerbations, routine use of antibiotics is controversial for three main reasons: first; the lack of high-quality evidence to support their efficacy; second, the emerging threat of antibiotic resistance and third, the side effects which may accompany some of the most commonly used agents. In 2016, the ICAR guideline noted a paucity of evidence for antibiotic use9; however, on balance it recommended that patients with polyps should not be prescribed short courses of non-macrolide antibiotics, unless in the particular circumstances of suffering an acute exacerbation. No conclusions could be drawn on longer courses, or for patients without polyps. This echoes the findings of a Cochrane review of the use of antibiotics in CRS, which found very little evidence that non-macrolide antibiotics are effective in patients with CRS although only two studies were fit for inclusion in analysis.15 These recommendations guided the NICE CKS17 to make the recommendation to seek specialist advice before initiating long-term antibiotics in primary care. It is, however, recognised that there does remain a role for appropriate use of macrolide antibiotics in specific circumstances. In particular, there is growing interest in immune-modulating and anti-inflammatory effects of macrolides in chronic airway inflammatory disease, with low-dose long-term macrolides being prescribed for its effects on the immune response and not primarily as an anti-bacterial agent.23 The Cochrane review of 2016 noted that there was a moderate quality of evidence of a modest improvement in disease‐specific QoL in patients with CRS without nasal polyps receiving 3 months of a macrolide.15 However, this improvement was short-lived, as 3 months following the cessation of the antibiotics there was no measurable effect of treatment. Resistance Antibiotic resistance is considered one of the most significant threats to patients’ safety in Europe.24 Evaluating effectiveness of antibiotics and promoting appropriate usage is integral to the UK 5-year antimicrobial resistance strategy.25 Given the high prevalence of CRS and the variability in prescribing, overuse of inappropriate antibiotics may represent a public health danger through selective pressure on bacteria and resistance. In particular, macrolide resistance has been noted to have implications in infections secondary to Streptococcus pneumoniae (upper and lower respiratory tract infections) and Mycoplasma genitalium (sexually transmitted infections), leading to longer duration of illness and requirement for multiple antibiotic courses.26 Side effects Antibiotics are commonly associate with wide range of side effects ranging from the mild (rash, nausea, diarrhoea) to the life threatening (anaphylaxis). Specific to the use of macrolides are concerns about potential cardiovascular side effects.27 There have been a number of publications raising concerns about cardiac toxicity with erythromycin in patients with a prolonged QT interval.28 29 A 2016 study which looked at adverse outcomes associated with clarithromycin use found a significant association was found between clarithromycin use and cardiovascular mortality, where longer durations of clarithromycin use were associated with more cardiovascular events.29 By contrast, this association was not found with use of β-lactam antibiotics leading the authors to hypothesise that it was an effect specific to clarithromycin. This hypothesis was unintentionally tested by the lead investigators of the CLARICOR trial (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) who had planned to measure the efficacy of a 2-week course of 500 mg clarithromycin two times per day to improve the clinical manifestations of stable coronary heart disease.30 The study was halted prematurely due to the finding of excess deaths in the intervention group: all-cause mortality was significantly higher in the group had taken clarithromycin, an effect which persisted for 10 years post-intervention. The use of clarithromycin in patients with known cardiovascular disease is therefore only undertaken with a significant degree of caution. Surgery Patients who are referred to secondary care who are considered to have tried and failed appropriate medical therapy – which is to say, a sufficient trial of nasal douching and topical steroids—are considered candidates for endoscopic sinus surgery (ESS).31 32 ESS is a loosely defined procedure and can range from very simple balloon expansion of the sinus openings, to extensive procedures that open every bony partition within the sinuses. The risks of surgery include epistaxis, breach of the skull base with resultant CSF leak or meningitis and injury to the intraorbital structures which may result in impaired vision. Insufficient evidence to define the role and extent of surgery contributes to a fivefold variation in UK intervention rates,33 with wide variation in surgical practice and very high rates of revision surgery.34 35 Such uncertainty resulted in inclusion of ESS in the NICE Database of Treatment Uncertainties.36 However, there can be no doubt that in appropriately selected patients, surgery offers significant and durable relief from symptoms. The largest UK study of CRS and its outcomes demonstrated that not only was there a significant improvement in patient-reported symptoms following ESS, but that patients who had surgery earlier in their disease course had a greater degree of improvement that lasted longer versus those who underwent delayed surgery.37 In addition to improving nasal symptoms, a systematic review demonstrated that ESS is associated with improved asthma control with significantly fewer attacks, hospitalisations, and a reduced requirement for medication use following sinus surgery in patients with comorbid CRS and asthma.38 Each of the international consensus guidelines referenced above recommends that patients who have tried a course of appropriate medical therapy but do not have control of their symptoms should be considered as a candidate for surgery.8 9 The path forwards In the last two decades, the majority of new treatments that have become available for CRS have in the main been refinements rather than revolutions—for example, new formulations of intranasal steroids or third-generation antihistamines. However, there are some genuinely new and exciting innovations which are on the cusp of integration to clinical practice. Monoclonal antibodies that bind to targets such as IgE, interleukin-4 (IL-4) and IL-5 were developed primarily as treatments for asthma, but clinical trials have demonstrated that several of these agents may also be effective in CRS with polyps.39 At present, they remain expensive and are limited to subsets of patients with difficult to treat asthma, but as prices fall in future and evidence for their efficacy accumulates then in future they may become available for the treatment of CRS. There have also been several promising avenues of research that may unlock further therapeutic targets, such as the role of the microbiome in sinus disease. However, as alluded to in the many international guidelines, there is a paucity of evidence for many of the treatments that are currently used in CRS before even considering new innovations. This has led to a redoubling of efforts in CRS research to produce high-quality evidence for commonly available treatments. Key to these efforts is the need to accurately define the endotypes of disease which will be studied in trials, as broad clinical phenotypes such as ‘polyps’ may encompass a wide range of underlying pathophysiology. Tightly defining the endotypes of disease for trial inclusion will permit robust examination of the response to treatment in each subgroup. Meta-analyses of CRS outcomes have been hampered by the broad clinical phenotypes, and using precise endotypes will enhance our ability to pool data from multiple trials; this will also be enabled by international consensus statements that define key criteria such appropriateness for ESS40 and standardised sets of outcome measures;41 and funding has been secured for one of the largest ever trials of interventions in CRS which will specifically examine the question of the efficacy of both macrolides and ESS (the MACRO trial42) in subgroups of patients defined by precise clinical and pathological parameters. At present, treatment of CRS exists in a time of genuine clinical equipoise where treatment is empirical and even international guidelines depend more heavily on expert opinion than robust scientific statements. Ongoing research endeavours aim to transform the treatment of CRS and usher in the era of precise, personalised medicine for these patients. Main messages Chronic rhinosinusitis (CRS) is a common disease in UK adults and causes significant detriment to life. The best evidence for effective treatment is for topical intranasal corticosteroids and saline irrigation. For patients who do not respond to this first-line treatment, there are many potential avenues for further treatment but there is controversy about which strategy is the most effective Current research questions Is it possible to identify specific endotypes of CRS to replace the broad clinical phenotypes that we currently base our treatment plans on? Are macrolide antibiotics an effective treatment in CRS? Is best medical treatment superior to surgery in the treatment of CRS? Key references Fokkens WJ, et al, European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Rhinolgy 2012 3 p preceding table of contents, 1–298. Orlandi RR, et al, International Consensus Statement on Allergy and Rhinology: Rhinosinusitis. Int Forum Allergy Rhinol 2016. 6 Suppl 1: p. S22-209. NICE. Sinusitis. 2018; Available from: https://cks.nice.org.uk/sinusitis%23!scenario:1 Head K, et al, Systemic and topical antibiotics for chronic rhinosinusitis. Cochrane Database Syst Rev 2016. 4: p. CD011994 Hopkins C, et al, Long-term outcomes from the English national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis. Laryngoscope 2009. 119 : p. 2459–65. Self-assessment questions Which of the following are typical symptoms of chronic rhinosinusitis? (a) Bleeding and crusting (b) Unilateral blood tinged discharge (c) Blockage, discharge, loss of sense of smell, facial pressure (d) Visual disturbance The first-line treatment for chronic rhinosinusitis (CRS) is oral steroids and antibiotics. True or false? A prolonged course of antibiotics (eg, up to 3 months) may occasionally be used in specific circumstances. What group of antibiotics has the best evidence to support their use for prolonged courses in CRS? (a) Penicillins (b) Macrolides (c) Aminoglycosides (d) Fluoroquinolones And what adverse effects should the patient be advised of with these long-term antibiotics? (a) Cardiac comorbidity (b) Osteonecrosis of the femoral head (c) Epistaxis (d) Infertility There is good evidence to support the superiority of surgical treatment of CRS compared with medical treatment. True or false? Answers Answer: (c) These are typical CRS symptoms. Bleeding and crusting should raise the possibility of vasculitis, septal perforations, or recreational cocaine use. Unilateral blood tinged discharge is a red flag sign that should prompt concerns of malignancy. Visual disturbance may be caused by rare complications of CRS, but is not at all typical. Answer: False. The first-line treatment for CRS should be topical steroids and saline irrigation. Answer: Macrolides. Answer: Cardiac comorbidity, particularly in patients with known heart disease. Osteonecrosis of the femoral head is a complication of oral steroids while topical steroids may cause epistaxis. Macrolides are not recognised to cause infertility but their use should be restricted during pregnancy. The Food and Drug Administration of USA recommend that if a macrolide must be used in pregnancy then azithromycin is category B (ie, safe in animal studies) while clarithromycin is category C (ie, shown to cause harm in animal studies). Answer: False. There are very few high-quality trials that compare medical treatment to surgery, and meta-analysis is made difficult by wide variability in study protocols. References ↵ Hastan D , Fokkens WJ , Bachert C , et al . Chronic rhinosinusitis in Europe--an underestimated disease. A GA²LEN study. Allergy 2011;66:1216–23.doi:10.1111/j.1398-9995.2011.02646.x ↵ Gliklich RE , Metson R . The health impact of chronic sinusitis in patients seeking otolaryngologic care. Otolaryngol Head Neck Surg 1995;113:104–9.doi:10.1016/S0194-5998(95)70152-4 ↵ Sahlstrand-Johnson P , Ohlsson B , Von Buchwald C , et al . A multi-centre study on quality of life and absenteeism in patients with CRS referred for endoscopic surgery. Rhinology 2011;49:420–8.doi:10.4193/Rhino11.101 OpenUrlPubMed ↵ Erskine SE , Hopkins C , Clark A , et al . Chronic rhinosinusitis and mood disturbance. Rhin 2017;55:113–9.doi:10.4193/Rhin16.111 OpenUrl ↵ Lange B , Holst R , Thilsing T , et al . Quality of life and associated factors in persons with chronic rhinosinusitis in the general population: a prospective questionnaire and clinical cross-sectional study. Clin Otolaryngol 2013;38:474–80.doi:10.1111/coa.12189 OpenUrlCrossRefPubMed ↵Hospital Episode Statistics Department of Health; 2013. ↵ Vennik J , Eyles C , Thomas M , et al . Management strategies for chronic rhinosinusitis: a qualitative study of GP and ENT specialist views of current practice in the UK. BMJ Open 2018;8:e022643.doi:10.1136/bmjopen-2018-022643 ↵ Fokkens WJ , Lund VJ , Mullol J , et al . EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists. Rhinology 2012;50:1–12.doi:10.4193/Rhino50E2 OpenUrlCrossRefPubMed ↵ Orlandi RR , Kingdom TT , Hwang PH , et al . International Consensus Statement on Allergy and Rhinology: Rhinosinusitis. Int Forum Allergy Rhinol 2016;6 Suppl 1:S22–S209.doi:10.1002/alr.21695 OpenUrl ↵ Head K , Sharp S , Chong L-Y , et al . Topical and systemic antifungal therapy for chronic rhinosinusitis. Cochrane Database Syst Rev 2018;16.doi:10.1002/14651858.CD012453.pub2 ↵ Chong LY , Head K , Hopkins C , et al . Intranasal steroids versus placebo or no intervention for chronic rhinosinusitis. Cochrane Database Syst Rev 2016;115.doi:10.1002/14651858.CD011996.pub2 ↵ Chong LY , Head K , Hopkins C , et al . Saline irrigation for chronic rhinosinusitis. Cochrane Database Syst Rev 2016;67.doi:10.1002/14651858.CD011995.pub2 ↵ Chong LY , Head K , Hopkins C , et al . Different types of intranasal steroids for chronic rhinosinusitis. Cochrane Database Syst Rev 2016;25(Suppl 2).doi:10.1002/14651858.CD011993.pub2 ↵ Head K , Chong LY , Hopkins C , et al . Short-course oral steroids as an adjunct therapy for chronic rhinosinusitis. Cochrane Database Syst Rev 2016;27.doi:10.1002/14651858.CD011992.pub2 ↵ Head K , Chong LY , Piromchai P , et al . Systemic and topical antibiotics for chronic rhinosinusitis. Cochrane Database Syst Rev 2016;19.doi:10.1002/14651858.CD011994.pub2 ↵ Head K , Chong LY , Hopkins C , et al . Short-course oral steroids alone for chronic rhinosinusitis. Cochrane Database Syst Rev 2016;2.doi:10.1002/14651858.CD011991.pub2 ↵NICE. Sinusitis, 2018. Available: https://cks.nice.org.uk/sinusitis#!scenario:1 ↵ Kennedy P , Bassiouni A , Psaltis A , et al . Avascular necrosis after oral corticosteroids in otolaryngology: Case report and review of the literature. Allergy Rhinol 2016;7:50–4.doi:10.2500/ar.2016.7.0142 OpenUrl ↵ Leung RM , Dinnie K , Smith TL . When do the risks of repeated courses of corticosteroids exceed the risks of surgery? Int Forum Allergy Rhinol 2014;4:871–6.doi:10.1002/alr.21377 OpenUrl ↵ Gulliford MC , Dregan A , Moore MV , et al . Continued high rates of antibiotic prescribing to adults with respiratory tract infection: survey of 568 UK general practices. BMJ Open 2014;4:e006245.doi:10.1136/bmjopen-2014-006245 ↵ Akkerman AE , Kuyvenhoven MM , van der Wouden JC , et al . Prescribing antibiotics for respiratory tract infections by GPs: management and prescriber characteristics. Br J Gen Pract 2005;55:114–8. ↵ Soni-Jaiswal A , Philpott C , Hopkins C . The impact of commissioning for rhinosinusitis in England. Clin Otolaryngol 2015;40:639–45.doi:10.1111/coa.12430 OpenUrl ↵ Cervin A , Wallwork B . Macrolide therapy of chronic rhinosinusitis. Rhinology 2007;45:259–67. ↵ Lodato EM , Kaplan W . Priority Medicines for Europe and the World "A Public Health Approach to Innovation": Background Paper 6.1 Antimicrobial resistance World Health Organisation; 2013. ↵ Davies SC , Gibbens N . UK Five Year Antimicrobial Resistance Strategy 2013 to 2018 Department of Health and Department for Environment, Food & Rural Affairs; 2013. ↵ Gaynor M , Mankin AS . Macrolide antibiotics: binding site, mechanism of action, resistance. Curr Top Med Chem 2003;3:949–60.doi:10.2174/1568026033452159 ↵ Gibbins NE , Theokli C , Hopkins C . Time to reconsider guidelines on clarithromycin in chronic rhinosinusitis? BMJ 2013;346:f2678.doi:10.1136/bmj.f2678 ↵ Wong AYS , Chan EW , Anand S , et al . Managing Cardiovascular Risk of Macrolides: Systematic Review and Meta-Analysis. Drug Saf 2017;40:663–77.doi:10.1007/s40264-017-0533-2 OpenUrlCrossRef ↵ Cheng Y-J , Nie X-Y , Chen X-M , et al . The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk. J Am Coll Cardiol 2015;66:2173–84.doi:10.1016/j.jacc.2015.09.029 OpenUrlFREE Full Text ↵ Winkel P , Hilden J , Hansen JF , et al . Clarithromycin for stable coronary heart disease increases all-cause and cardiovascular mortality and cerebrovascular morbidity over 10years in the CLARICOR randomised, blinded clinical trial. Int J Cardiol 2015;182:459–65.doi:10.1016/j.ijcard.2015.01.020 OpenUrl ↵ Baguley C , Brownlow A , Yeung K , et al . The fate of chronic rhinosinusitis sufferers after maximal medical therapy. Int Forum Allergy Rhinol 2014;4:525–32.doi:10.1002/alr.21315 OpenUrl ↵ Young LC , Stow NW , Zhou L , et al . Efficacy of medical therapy in treatment of chronic rhinosinusitis. Allergy Rhinol 2012;3:8–12.doi:10.2500/ar.2012.3.0027 OpenUrl ↵ Hopkins C . Commissioing Guide: Chronic Rhinosinusitis. Royal College of Surgeons of England London; 2016. ↵ Philpott C , Hopkins C , Erskine S , et al . The burden of revision sinonasal surgery in the UK-data from the Chronic Rhinosinusitis Epidemiology Study (CRES): a cross-sectional study. BMJ Open 2015;5:e006680.doi:10.1136/bmjopen-2014-006680 ↵ Hopkins C , Slack R , Lund V , et al . Long-term outcomes from the English national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis. Laryngoscope 2009;119:2459–65.doi:10.1002/lary.20653 ↵NICE. Database of Uncertainties of Treatments. ↵ Hopkins C , Rimmer J , Lund VJ . Does time to endoscopic sinus surgery impact outcomes in Chronic Rhinosinusitis? Prospective findings from the National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis. Rhinology 2015;53:10–17.doi:10.4193/Rhin13.217 OpenUrl ↵ Vashishta R , Soler ZM , Nguyen SA , et al . A systematic review and meta-analysis of asthma outcomes following endoscopic sinus surgery for chronic rhinosinusitis. Int Forum Allergy Rhinol 2013;3:788–94.doi:10.1002/alr.21182 OpenUrlCrossRefPubMed ↵ Pauwels B , Jonstam K , Bachert C . Emerging biologics for the treatment of chronic rhinosinusitis. Expert Rev Clin Immunol 2015;11:349–61.doi:10.1586/1744666X.2015.1010517 OpenUrlCrossRefPubMed ↵ Rudmik L , Soler ZM , Hopkins C , et al . Defining appropriateness criteria for endoscopic sinus surgery during management of uncomplicated adult chronic rhinosinusitis: a RAND/UCLA appropriateness study. Int Forum Allergy Rhinol 2016;6:557–67.doi:10.1002/alr.21769 OpenUrl ↵ Hopkins C , Hettige R , Soni-Jaiswal A , et al . CHronic Rhinosinusitis Outcome MEasures (CHROME), developing a core outcome set for trials of interventions in chronic rhinosinusitis. Rhinology 2018;56:22–32.doi:10.4193/Rhin17.247 OpenUrl ↵ Philpott C , le Conte S , Beard D , et al . Clarithromycin and endoscopic sinus surgery for adults with chronic rhinosinusitis with and without nasal polyps: study protocol for the MACRO randomised controlled trial. Trials 2019;20:246.doi:10.1186/s13063-019-3314-7

The first ever early clinical trial for a vaccine for genital chlamydia has shown it to be safe and effective at provoking an immune response.The latest...

KEY POINTS A fix/permeabilization approach allows isolation of Ag- and isotype-specific ASC. IgM, IgG, and IgA ASC have shared and distinct transcriptome components. Each ASC isotype displays distinct, expanded CDR3 regions. Abstract Ab-secreting cells (ASC) or plasma cells are essential components of the humoral immune system. Although Abs of different isotypes have distinct functions, it is not known if the ASC that secrete each isotype are also distinct. ASC downregulate their surface BCR upon differentiation, hindering analyses that couple BCR information to other molecular characteristics. In this study, we developed a methodology using fixation, permeabilization, and intracellular staining coupled with cell sorting and reversal of the cross-links to allow RNA sequencing of isolated cell subsets. Using hemagglutinin and nucleoprotein Ag-specific B cell tetramers and intracellular staining for IgM, IgG, and IgA isotypes, we were able to derive and compare the gene expression programs of ASC subsets that were responding to the same Ags following influenza infection in mice. Intriguingly, whereas a shared ASC signature was identified, each ASC isotype-specific population expressed distinct transcriptional programs controlling cellular homing, metabolism, and potential effector functions. Additionally, we extracted and compared BCR clonotypes and found that each ASC isotype contained a unique, clonally related CDR3 repertoire. In summary, these data reveal specific complexities in the transcriptional programming of Ag-specific ASC populations. Footnotes This work was supported by National Institutes of Health (NIH) Grants 5R01 CA095318 (to C.D.S.), 1R01 AI123733 and P01 AI125180 (to J.M.B.), and NIH F31 AI138391 (to M.J.P.). The RNA sequence data presented in this article have been submitted to the National Center for Biotechnology Information's Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE124578. The online version of this article contains supplemental material. Received March 8, 2019. Accepted August 13, 2019. Copyright © 2019 by The American Association of Immunologists, Inc.

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Abstract Background Chronic Helicobacter pylori infection is the cause of peptic ulcers in a subpopulation of individuals and a risk factor for the development of gastric cancer. A vaccine against ...

Abstract Lectins are found in most living organisms, providing immune surveillance by binding to carbohydrate ligands. In fishes, C-type lectins were isolated from mucus of respiratory organs (skin and gills), where they aid the mucosal immune response in regulating microbiota and suppressing pathogens. In shrimp, however, no mucosal immunity or any form of gill-specific immune defense has been reported, and most identified C-type lectins are associated with hemocyte cellular and humoral responses. Interestingly, our microarray analysis revealed the localization of highly expressed novel biodefense genes in gills, among which is Marsupenaeus japonicus gill C-type lectin (MjGCTL), which we previously reported. Gill mucus collected from M. japonicus displayed similar bacterial agglutination ability as observed with recombinant MjGCTL. This agglutinating ability can be attributed to endogenous MjGCTL (nMjGCTL) detected in gill mucus, which was confirmed with an agglutination assay using purified nMjGCTL from gills. In addition, nMjGCTL also promoted in vivo bacterial phagocytosis by hemocytes. In vivo knockdown of MjGCTL resulted in a compromised immune system, which was manifested by impaired agglutination capacity of gill mucus and downregulation of the gill antimicrobial peptides, crustin and penaeidin. Shrimp immunocompromised by MjCGTL knockdown, apparently lost the ability to respond to attaching and penetrating bacteria. This was evident as increased total bacteria and Vibrio counts in both gills and hemolymph, which were correlated with low survival during a bacterial challenge. These results reveal immune defense by shrimp gills resembling a primitive form of mucosal immunity.

Kawasaki disease (KD) is the leading cause of acquired heart disease among children,
and the etiology is unknown. Noval Rivas et al. demonstrate that a murine model of KD vasculitis is dependent on intestinal barrier dysfunction leading to secretory IgA leakage and IgA-C3 immune complex deposition...

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Clinical benefits of cytokine blockade in ileal Crohn’s disease (iCD) are limited to a subset of patients.Here, we applied single-cell technologies t…...

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